Indole AHR inhibitors and uses thereof

文档序号：1471268 发布日期：2020-02-21 浏览：23次中文

阅读说明：本技术 吲哚ahr抑制剂和其用途 (Indole AHR inhibitors and uses thereof ) 是由 A·C·卡斯特罗 C·A·埃万斯于 2018-04-20 设计创作，主要内容包括：本发明提供了可用作AHR抑制剂的化合物、其组合物以及其使用方法。(The present invention provides compounds useful as AHR inhibitors, compositions thereof, and methods of using the same.)

1. A compound of the formula I' is provided,

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from:

each p is independently 0, 1 or 2 as valency permits;

each R¹Independently selected from R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂；

Each R is independently hydrogen, deuterium, or an optionally substituted group selected from: c_1-6Aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated, or aromatic ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, other than nitrogen;

each of or R^x、R^yAnd R^zIndependently selected from R, halogen, cyano, nitro, -OR, -SR, -N (R)₂、-N(R)C(O)R、-C(O)N(R)₂、-C(O)N(R)OR、-N(R)C(O)N(R)₂、-N(R)C(O)OR、-OC(O)N(R)₂、-N(R)SO₂R、-SO₂RN(R)₂-C (O) R, -C (O) OR, -OC (O) R, -C (O) OR, -S (O) R OR-SO₂R, or:

two R on the same carbon^xTogether form ═ OOr ═ S; or:

two R on the same carbon^yTogether form ═ O or ═ S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, a 7-10 membered bicyclic moiety unsaturated or aromatic carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 12-15 membered moiety unsaturated or aromatic tricyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring C is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹is a covalent bond or optionally substituted C_1-6A linear or branched divalent hydrocarbon chain, wherein L¹Optionally containing methylene units of-Cy-, -O-, -S-, -NR-, -C (O) O-, -OC (O) -, -C (O) N (R) -, -N (R) C (O) -, -SO₂-、-N(R)SO₂-or-SO₂N (R) -S substitution; and is

-Cy-is a 3-8 membered divalent saturated, partially unsaturated or aromatic monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8-10 membered divalent saturated, partially unsaturated or aromatic bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

with the proviso that when ring A is

2. The compound of claim 1, wherein the compound is selected from any one of formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, I-l, I-m, I-n, I-o, and I-p:

3. The compound of claim 1, wherein the compound is selected from any one of formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-j, II-k, II-l, II-m, II-n, II-o, and II-p:

4. The compound of claim 1, wherein the compound is selected from any one of formulas III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, III-j, III-k, III-l, III-m, III-n, III-o, III-p, III-q, III-r, III-s, III-t, III-u, III-v, III-w, III-x, III-y, III-z, III-aa, III-bb, III-cc, III-dd, III-ee, III-ff, III-gg, III-hh, III-ii, III-jj, and III-kk:

5. The compound of claim 1, wherein the compound is selected from any one of formulas IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, IV-l, IV-m, IV-n, IV-o, IV-p, and IV-q:

6. The compound of claim 1, wherein the compound is selected from any one of formulas V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, and V-l:

7. The compound of claim 1, wherein the compound is selected from any one of formulas VI-a, VI-b, VI-c, VI-d, VI-e, and VI-f:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

8. The compound of claim 1, wherein the compound is selected from any one of formulas VII-a, VII-b, VII-o, VII-d, VII-e, VII-f, and VII-g:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

9. The compound of claim 1, wherein the compound is selected from any one of formulas VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, and VIII-f:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

10. The compound of claim 1, wherein the compound is selected from any one of formulas IX-a, IX-b, and IX-c:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

11. The compound of claim 1, wherein the compound is selected from any one of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h, and X-i:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

12. The compound of claim 1, wherein the compound is selected from any one of formulas XI-a, XI-b, XI-c, XI-d, XI-e, XI-f, XI-g, XI-h, and XI-i:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

13. The compound of claim 1, wherein the compound is selected from any one of formulas XII-a, XII-b, and XI-c:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH.

14. The compound of claim 1, wherein the compound is selected from those depicted in table 1, or a pharmaceutically acceptable salt thereof.

15. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. A method of inhibiting AHR in a patient in need thereof comprising administering to the patient the compound of claim 1, or a pharmaceutically acceptable salt thereof.

17. A method of inhibiting AHR in a biological sample comprising contacting the biological sample with the compound of claim 1, or a pharmaceutically acceptable salt thereof.

18. A method for treating an AHR-mediated disorder in a patient in need thereof, comprising administering to the patient the compound of claim 1, or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the AHR-mediated disorder is cancer.

20. The method of claim 18, wherein the AHR-mediated disorder is an inflammatory disorder.

21. The method of claim 18, wherein the compound or pharmaceutically acceptable salt thereof is administered as part of a pharmaceutically acceptable composition.

22. The method of claim 18, wherein the compound or pharmaceutically acceptable salt thereof is administered orally.

23. The method of claim 19, wherein said compound or pharmaceutically acceptable salt thereof is administered in the range of 0.01-100mg per kilogram body weight of said patient.

Background

Arene receptors (AHRs) are transcription factors that exist in the cytoplasm in an inactive state without ligands in association with HSP 90. Upon binding of the ligand, the AHR translocates to the nucleus where it dimerizes with ARNT, forming a functional transcription factor. AHR/ARNT binds to Dioxin Response Elements (DREs) in the promoters of many genes whose regulation of gene transcription is regulated. The most well-demonstrated genes regulated by AHR are the cytochrome P450 genes Cyp1b1 and Cyp1a1, where activation of AHR greatly increases the expression of these genes. Thus, Cyp1b1 and Cyp1a1 mRNA levels are selective readings for AHR activation (reviewed in Murray et al 2014).

There are many exogenous and endogenous agonists of AHR that activate the receptor. The best characterized class of exogenous ligands is dioxins. One of the first endogenous ligands to be characterized is kynurenine, produced by TDO (alzheimer (Opitz)2011) or IDO (motzrique (Mezrich) 2010). Kynurenine is a stable metabolite in the IDO/TDO pathway and is a tryptophan degradation product. Kynurenine has been shown to activate AHR, as well as other DRE driven genes, as measured by increased Cyp1a1 and/or Cyp1b1 mRNA levels in multiple cell types.

AHR activation has a tumor-promoting effect by acting directly on tumor cells and indirectly by causing immunosuppression, thus not allowing the body's own immune system to attack the tumor. For example, AHR activation by multiple ligands increases expression of FoxP3 and causes CD4+ T cells to polarize to a suppressor subpopulation, called FoxP3+ T-regulatory cells (tregs). These T-reg cells inhibit proliferation of activated T cells (phyllostachys pubescens (Funatake)2005, other references). Interestingly, kynurenine has been shown to induce immunosuppressive tregs by AHR. Kynurenine does not affect T-reg production in T cells without AHR or when an AHR antagonist is added (motzrine). In addition to T-reg, AHR activation also expanded inhibitory Tr 1T cells (Gandhi 2010). It has also been shown that IDO expression in tumor cells and T cells is regulated by AHR activation, causing increased immunosuppression (Vogel). It is likely that AHR also plays a role in immunosuppressive bone marrow cells (raney (Nguyen) 2013). Immunosuppression is often associated with high levels of anti-inflammatory cytokines and there is evidence that AHR is involved in the activation of many of these cytokines such as IL-10 (2010, waggon 2014).

There remains an unmet need to develop AHR inhibitors for the treatment of AHR-related diseases, disorders and conditions.

Disclosure of Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of AHR. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment of a variety of diseases, disorders, or conditions associated with AHR. Such diseases, disorders or conditions include those described herein.

The compounds provided by the present invention are also suitable for the study of AHR in biological and pathological phenomena; study of intracellular signal transduction pathways; and comparative evaluation of novel AHR inhibitors in vitro or in vivo.

Drawings

FIG. 1 depicts a graph showing inhibition of IL22 and cyp1a1 RNA expression levels by compounds described herein.

FIG. 2 depicts a graph showing the reduction of IL-22 protein (top) and the increase of IL-2 (bottom) by activating T cells by treatment with a compound described herein.

Figure 3 depicts a graph showing CT26 efficacy studies with vehicle, compounds described herein, anti-PD-1, and combinations thereof.

Figure 4 depicts a graph showing B16-IDO efficacy studies with vehicle, compounds described herein, anti-PD-1, and combinations thereof.

Detailed Description

1. Summary of compounds of the invention:

in certain embodiments, the present invention provides AHR inhibitors. In some embodiments, such compounds include those of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from:

each R¹Independently selected from R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂；

each of or R^x、R^yAnd R^zIndependently selected from R, halogen, cyano, nitro, -OR, -SR, -N (R)₂、-N(R)C(O)R、-C(O)N(R)₂、-N(R)C(O)N(R)₂、-N(R)C(O)OR、-OC(O)N(R)₂、-N(R)SO₂R、-SO₂RN(R)₂-C (O) R, -C (O) OR, -OC (O) R, -C (O) OR, -S (O) R OR-SO₂R, or:

two R on the same carbon^xTogether form ═ O or ═ S; or:

two R on the same carbon^yTogether form ═ O or ═ S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring C is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, the present invention provides AHR inhibitors, including compounds of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from:

each p is independently 0, 1 or 2, where valency permits;

each R¹Independently selected from R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂；

Each R is independently hydrogen, deuterium, or an optionally substituted group selected from: c_1-6Aliphatic radical, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 memberedA bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R together with their intervening atoms on the same nitrogen form a 4-7 membered saturated, partially unsaturated, or aromatic ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, other than nitrogen;

two R on the same carbon^xTogether form ═ O or ═ S; or:

two R on the same carbon^yTogether form ═ O or ═ S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring C is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, the invention provides compounds of formula I or formula I', with the proviso that when ring a is

When ring B is not

And/or ring C is not

And/or R¹Is not that

As generally defined above, ring a is selected from:

those of ordinary skill in the art will readily understand and appreciate that there are a variety of orientations for ring a. For example, and for purposes of clarity, when ring A is selected as

The following examples are contemplated, where ring a is oriented in formula I or formula I':

accordingly, such orientations are encompassed by the present invention.

In some embodiments, the present invention provides a compound of formula I or formula I', with the proviso that L¹Is not-NHCH₂CH₂-. In some embodiments, the invention provides compounds of formula I or formula I', with the proviso that when ring a is

When L is¹Is not-NHCH₂CH₂-。

2. Compounds and definitions:

the compounds of the present invention include the compounds outlined above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical Elements are identified according to the Periodic Table of the Elements (Periodic Table of the Elements), CAS version, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, "University Science Books," Sossalto (Sausaltio): 1999 and March's Advanced Organic Chemistry, 5 th edition, eds: smith (Smith, M.B.) and marque (March, J.), John willey father, inc (John Wiley & Sons), New York (New York): 2001, the entire contents of which are incorporated herein by reference.

As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle", "cycloaliphatic", or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic ring C that is fully saturated or contains one or more units of unsaturation, but which is not aromatic₃-C₆A hydrocarbon having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

The term "lower alkyl" refers to C_1-4Straight-chain or branched-chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to C substituted with one or more halogen atoms_1-4Straight-chain or branched-chain alkyl.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; or heterocyclic substitutable nitrogen, e.g. N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

As used herein, the term "divalent C_1-8(or C)_1-6) Saturated or unsaturated, linear or branched hydrocarbon chains "refers to divalent alkylene, alkenylene, and alkynylene chains that are linear or branched, as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e. - (CH)₂)_n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3.A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

As used herein, the term "cyclopropylene" refers to a divalent cyclopropyl group of the structure:

as used herein, the term "cyclobutylidene" refers to a divalent cyclobutyl group of the structure:

as used herein, the term "oxetanyl" refers to a divalent oxetanyl group of the structure:

the term "halogen" means F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety, as used in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aromatic ring".

The term "aryl", used alone or as part of a larger moiety, as used in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthalimide, phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms "heteroaryl" and "heteroar", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 pi electrons in the cyclic array, and 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the linking group or point is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2, 3-b ] -1, 4-oxazin-3 (4H) -one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic group", any of which terms includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably and refer to a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in reference to a ring atom of a heterocyclic ring includes substituted nitrogens. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or⁺NR (as in N-substituted pyrrolidinyl).

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom may be optionally substituted. Examples of said saturated or partially unsaturated heterocyclic group include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazanyl, thiazanyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl group", "heterocyclic moiety" and "heterocyclyl" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the linking group or point is on the heterocyclyl ring. The heterocyclic group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted" whether preceded by the term "optionally" or not means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. Combinations of substituents envisioned by the present invention are preferably those that form stable or chemically feasible compounds. As used herein, the term "stable" means that the compound is not substantially altered when subjected to conditions that allow its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently halogen; - (CH)₂)_0-4R^○；-(CH₂)_0-4OR^○；-O(CH₂)_0-4R^○、-O-(CH₂)_0-4C(O)OR^○；-(CH₂)_0-4CH(OR^○)₂；-(CH₂)_0-4SR^○；-(CH₂)_0-4Ph, which may be via R^○Substitution; - (CH)₂)_0-4O(CH₂)_0-1Ph, which may be via R^○Substitution; -CH ═ CHPh, which may be via R^○Substitution; - (CH)₂)_0-4O(CH₂)_0-1-pyridyl, which may be via R^○Substitution; -NO₂；-CN；-N₃；-(CH₂)_0-4N(R^○)₂；-(CH₂)_0-4N(R^○)C(O)R^○；-N(R^○)C(S)R^○；-(CH₂)_0-4N(R^○)C(O)NR^○ ₂；-N(R^○)C(S)NR^○ ₂；-(CH₂)_0-4N(R^○)C(O)OR^○；-N(R^○)N(R^○)C(O)R^○；-N(R^○)N(R^○)C(O)NR^○ ₂；-N(R^○)N(R^○)C(O)OR^○；-(CH₂)_0-4C(O)R^○；-C(S)R^○；-(CH₂)_0-4C(O)OR^○；-(CH₂)_0-4C(O)SR^○；-(CH₂)_0-4C(O)OSiR^○ ₃；-(CH₂)_0-4OC(O)R^○；-OC(O)(CH₂)_0-4SR-、SC(S)SR^○；-(CH₂)_0-4SC(O)R^○；-(CH₂)_0-4C(O)NR^○ ₂；-C(S)NR^○ ₂；-C(S)SR^○；-SC(S)SR^○、-(CH₂)_0-4OC(O)NR^○ ₂；-C(O)N(OR^○)R^○；-C(O)C(O)R^○；-C(O)CH₂C(O)R^○；-C(NOR^○)R^○；-(CH₂)_0-4SSR^○；-(CH₂)_0-4S(O)₂R^○；-(CH₂)_0-4S(O)₂OR^○；-(CH₂)_0-4OS(O)₂R^○；-S(O)₂NR^○ ₂；-(CH₂)_0-4S(O)R^○；-N(R^○)S(O)₂NR^○ ₂；-N(R^○)S(O)₂R^○；-N(OR^○)R^○；-C(NH)NR^○ ₂；-P(O)₂R^○；-P(O)R^○ ₂；-OP(O)R^○ ₂；-OP(O)(OR^○)₂；SiR^○ ₃；-(C_1-4Straight or branched chain alkylene) O-N (R)^○)₂(ii) a Or- (C)_1-4Straight or branched chain alkylene) C (O) O-N (R)^○)₂Wherein each isR^○Can be substituted and independently hydrogen, C as defined below_1-6Aliphatic radical, -CH₂Ph、-O(CH₂)_0-1Ph、-CH₂A 5-6 membered saturated, partially unsaturated or aryl ring- (5-6 membered heteroaromatic ring) or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring R's despite the above definitions^○Together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

R^○(or by two independently occurring R^○A ring formed together with the intervening atoms) are independently halogen, - (CH)₂)_0-2R^●- (halogeno radical R)^●)、-(CH₂)_0-2OH、-(CH₂)_0-2OR^●、-(CH₂)_0-2CH(OR^●)₂(ii) a -O (halo R)^●)、-CN、-N₃、-(CH₂)_0-2C(O)R^●、-(CH₂)_0-2C(O)OH、-(CH₂)_0-2C(O)OR^●、-(CH₂)_0-2SR^●、-(CH₂)_0-2SH、-(CH₂)_0-2NH₂、-(CH₂)_0-2NHR^●、-(CH₂)_0-2NR^● ₂、-NO₂、-SiR^● ₃、-OSiR^● ₃、-C(O)SR^●、-(C_1-4Straight OR branched chain alkylene) C (O) OR^●or-SSR^●Wherein each R is^●Unsubstituted or substituted with one or more halogens only when preceded by "halo", and is independently selected from C_1-4Aliphatic radical, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R^○Suitable divalent substituents on the saturated carbon atom of (a) include ═ O and ═ S.

Saturation of "optionally substituted" radicalsSuitable divalent substituents on carbon atoms include the following: is one of O, S and NNR^* ₂、＝NNHC(O)R^*、＝NNHC(O)OR^*、＝NNHS(O)₂R^*、＝NR^*、＝NOR^*、-O(C(R^* ₂))_2-3O-or-S (C (R)^* ₂))_2-3S-, wherein R^*Selected from hydrogen, C which may be substituted as defined below, at each occurrence_1-6An aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bound to adjacent substitutable carbons of the "optionally substituted" group include: -O (CR)^* ₂)_2-3O-, wherein R^*Selected from hydrogen, C which may be substituted as defined below, at each occurrence_1-6An aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

R^*Suitable substituents on the aliphatic radical of (A) include halogen, -R^●- (halogeno radical R)^●)、-OH、-OR^●-O (halo R)^●)、-CN、-C(O)OH、-C(O)OR^●、-NH₂、-NHR^●、-NR^● ₂or-NO₂Wherein each R is^●Unsubstituted or substituted by one or more halogen(s) only if preceded by "halo", and is independently C_1-4Aliphatic radical, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include

Each of whichIndependently hydrogen, C which may be substituted as defined below_1-6Aliphatic, unsubstituted-OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring, despite the above definitions

Together with their intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic radical of (A) are independently halogen, -R^●- (halogeno radical R)^●)、-OH、-OR^●-O (halo R)^●)、-CN、-C(O)OH、-C(O)OR^●、-NH₂、-NHR^●、-NR^● ₂or-NO₂Wherein each R is^●Unsubstituted or substituted by one or more halogen(s) only if preceded by "halo", and is independently C_1-4Aliphatic radical, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in journal of pharmacy (j. pharmaceutical Sciences), 1977, 66, 1-19, by s.m. berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids (e.g. hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids) or organic acids (e.g. acetic, oxalic, maleic, tartaric, citric, succinic or malonic acids), or by using other methods used in the art (e.g. ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, salts of benzoic acid, bisulfates, and salts of benzoic acid, salts of butyric acid, salts of cinnamic acid, persulfa, Phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, R and of each asymmetric centerS configuration, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having hydrogen replaced by deuterium or tritium or carbon replaced by deuterium or tritium¹³C or¹⁴C-enriched carbon-substituted compounds of the present structures are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the invention.

3. Description of illustrative embodiments:

in certain embodiments, the present invention provides AHR inhibitors. In some embodiments, such compounds include compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from:

each R¹Independently selected from R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂；

Each R is independently hydrogen, deuterium, or an optionally substituted group selected from: c_1-6Aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; having 1-2 substituents independently selected from nitrogen, oxygen or sulfurA 4-8 membered saturated or partially unsaturated monocyclic heterocycle of a heteroatom, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

two R on the same carbon^xTogether form ═ O or ═ S; or:

two R on the same carbon^yTogether form ═ O or ═ S;

each of m and n is independently 1, 2, 3, 4, or 5;

In some embodiments, the present invention provides AHR inhibitors, such compounds including those of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from:

each p is independently 0, 1 or 2, where valency permits;

each R¹Independently selected from R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂；

two R on the same carbon^xTogether form ═ O or ═ S; or:

two R on the same carbon^yTogether form ═ O or ═ S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring C is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, the invention provides compounds of formula I or formula I', with the proviso that when ring a isWhen ring B is not

And/or ring C is not

And/or R¹Is not that

When L is¹Is not-NHCH₂CH₂-。

In some embodiments, the present invention provides a compound of formula I or formula I', with the proviso that the compound is not:

in some embodiments, the provided compound is not

In some embodiments, the provided compound is notIn some embodiments, the provided compound is notIn some embodiments, the provided compound is not

In some embodiments, the provided compound is not

As generally defined above, R¹Is R, -C (O) OR, -SO₂R、-C(O)N(R)₂or-SO₂RN(R)₂. In some embodiments, R¹Is hydrogen. In some embodiments, R¹Is R. In some embodiments, R¹is-C (O) R. In some embodiments, R¹is-C (O) OR. In some embodiments, R¹is-SO₂And R is shown in the specification. In some embodiments, R¹is-C (O) N (R)₂. In some embodiments, R¹is-SO₂RN(R)₂. In some embodiments, R¹Is hydrogen. In some embodiments, R¹Is deuterium. In some embodiments, R¹Is selected from C_1-6Optionally substituted groups of aliphatic groups. In some embodiments, R¹Selected from those depicted in table 1 below.

As generally defined above, each R^xIndependently R, halogen, cyano, nitro, -OR, -SR, -N (R)₂、-N(R)C(O)R、-C(O)N(R)₂、-C(O)N(R)OR、-N(R)C(O)N(R)₂、-N(R)C(O)OR、-OC(O)N(R)₂、-N(R)SO₂R、-SO₂RN(R)₂-C (O) R, -C (O) OR, -OC (O) R, -C (O) OR, -S (O) R OR-SO₂R, or two R on the same carbon^xTogether form ═ O or ═ S. In some embodiments, each R is^XAre the same. In some embodiments, each R is^XAre different. In some embodiments, R^XIs hydrogen. In some embodiments, R^XIs R. In some embodiments, R^XIs halogen. In some embodiments, R^XIs cyano. In some embodiments, R^XIs nitro. In some embodiments, R^Xis-OR. In some embodiments, R^Xis-SR. In some embodiments, R^Xis-N (R)₂. In some implementationsIn the examples, R^Xis-N (R) C (O) R. In some embodiments, R^Xis-C (O) N (R)₂. In some embodiments, R^Xis-C (O) N (R) OR. In some embodiments, R^Xis-N (R) C (O) N (R)₂. In some embodiments, R^Xis-N (R) C (O) OR. In some embodiments, R^Xis-OC (O) N (R)₂. In some embodiments, R^Xis-N (R) SO₂And R is shown in the specification. In some embodiments, R^Xis-SO₂RN(R)₂. In some embodiments, R^Xis-C (O) R. In some embodiments, R^Xis-C (O) OR. In some embodiments, R^Xis-CO (O) R. In some embodiments, R^Xis-S (O) R. In some embodiments, R^Xis-SO₂And R is shown in the specification. In some embodiments, two R on the same carbon^xTogether form ═ O or ═ S. In some embodiments, R^XIs hydrogen. In some embodiments, R^XIs deuterium. In some embodiments, R^xIs selected from C_1-6Optionally substituted groups of aliphatic groups. In some embodiments, R^xSelected from those depicted in table 1 below.

As generally defined above, each R^yIndependently R, halogen, cyano, nitro, -OR, -SR, -N (R)₂、-N(R)C(O)R、-C(O)N(R)₂、-C(O)N(R)OR、-N(R)C(O)N(R)₂、-N(R)C(O)OR、-OC(O)N(R)₂、-N(R)SO₂R、-SO₂RN(R)₂-C (O) R, -C (O) OR, -OC (O) R, -C (O) OR, -S (O) R OR-SO₂R, or two R on the same carbon^yTogether form ═ O or ═ S. In some embodiments, each R is^yAre the same. In some embodiments, each R is^yAre different. In some embodiments, R^yIs hydrogen. In some embodiments, R^yIs R. In some embodiments, R^yIs halogen. In some embodiments, R^yIs cyano. In some embodiments, R^yIs nitro. In some embodiments, R^yis-OR. In some embodiments, R^yis-SR. In some embodiments, R^yis-N (R)₂. In some embodiments, R^yis-C (O) N (R) OR. In some embodiments, R^yis-N (R) C (O) R. In some embodiments, R^yis-C (O) N (R)₂. In some embodiments, R^yis-N (R) C (O) N (R)₂. In some embodiments, R^yis-N (R) C (O) OR. In some embodiments, R^yis-OC (O) N (R)₂. In some embodiments, R^yis-N (R) SO₂And R is shown in the specification. In some embodiments, R^yis-SO₂RN(R)₂. In some embodiments, R^yis-C (O) R. In some embodiments, R^yis-C (O) OR. In some embodiments, R^yis-CO (O) R. In some embodiments, R^yis-S (O) R. In some embodiments, R^yis-SO₂And R is shown in the specification. In some embodiments, two R on the same carbon^yTogether form ═ O or ═ S. In some embodiments, R^yIs hydrogen. In some embodiments, R^yIs deuterium. In some embodiments, R^yIs selected from C_1-6Optionally substituted groups of aliphatic groups. In some embodiments, R^ySelected from those depicted in table 1 below.

As generally defined above, each R^zIndependently R, halogen, cyano, nitro, -OR, -SR, -N (R)₂、-N(R)C(O)R、-C(O)N(R)₂、-C(O)N(R)OR、-N(R)C(O)N(R)₂、-N(R)C(O)OR、-OC(O)N(R)₂、-N(R)SO₂R、-SO₂RN(R)₂-C (O) R, -C (O) OR, -OC (O) R, -C (O) OR, -S (O) R OR-SO₂And R is shown in the specification. In some embodiments, R^zIs hydrogen. In some embodiments, R^zIs R. In some embodiments, R^zIs halogen. In some embodiments, R^zIs cyano. In some embodiments, R^zIs nitro. In some embodiments, R^zis-OR. In some embodiments, R^zis-SR. In some embodiments, R^zis-N (R)₂. In some embodiments, R^zis-C (O) N (R) OR. In some embodiments, R^zis-N (R) C (O) R. In some embodiments, R^zis-C (O) N (R)₂. In some embodiments, R^zis-N (R) C (O) N (R)₂. In some embodiments, R^zis-N (R) C (O) OR. In some embodiments, R^zis-OC (O) N (R)₂. In some embodiments, R^zis-N (R) SO₂And R is shown in the specification. In some embodiments, R^zis-SO₂RN(R)₂. In some embodiments, R^zis-C (O) R. In some embodiments, R^zis-C (O) OR. In some embodiments, R^zis-CO (O) R. In some embodiments, R^zis-S (O) R. In some embodiments, R^zis-SO₂And R is shown in the specification. In some embodiments, R^zIs hydrogen. In some embodiments, R^zIs deuterium. In some embodiments, R^zIs selected from C_1-6Optionally substituted groups of aliphatic groups. In some embodiments, R^zSelected from those depicted in table 1 below.

As generally defined above, p is 0, 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is selected from those groups depicted in table 1 below.

As generally defined above, n is 1, 2, 3, 4 or 5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is selected from those groups depicted in table 1 below.

As generally defined above, m is 1, 2, 3, 4 or 5. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is selected from those groups depicted in table 1 below.

As generally defined above, ring B is phenyl, a 7-10 membered bicyclic moiety unsaturated or aromatic carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 12-15 membered moiety unsaturated or aromatic tricyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 7-10 membered bicyclic moiety unsaturated or aromatic carbocyclic ring. In some embodiments, ring B is a 12-15 membered partially unsaturated or aromatic tricyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is phenyl. In some embodiments, ring B is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl or pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or pyrido [2, 3-B ] -1, 4-oxazin-3 (4H) -one. In some embodiments, ring B is selected from those depicted in table 1 below.

As generally defined above, ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring C is phenyl. In some embodiments, ring C is a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring C is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl or pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or pyrido [2, 3-b ] -1, 4-oxazin-3 (4H) -one. In some embodiments, ring C is selected from those depicted in table 1 below.

As generally defined above, L¹Is a covalent bond or optionally substituted C_1-6A linear or branched divalent hydrocarbon chain, wherein L¹Optionally containing methylene units of-Cy-, -O-, -S-, -NR-, -C (O) O-, -OC (O) -, -C (O) N (R) -, -N (R) C (O) -, -SO₂-、-N(R)SO₂-or-SO₂N (R) -S substitution. In some embodiments, L¹Is a covalent bond. In some embodiments, L¹Is optionally substituted C_1-6A linear or branched divalent hydrocarbon chain. In some embodiments, L¹is-Cy-. In some embodiments, L¹Is phenylene, heterocyclylene, heteroarylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or oxetane. In some embodiments, L¹is-NR-. In some embodiments, L¹is-N (CH)₂)₂-. In some embodiments, L¹Selected from those depicted in table 1 below.

In some embodiments, -Cy-is phenylene, heterocyclylene, heteroarylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and oxetane. In some embodiments, -Cy-is selected from:

wherein X is a heteroatom selected from nitrogen, oxygen or sulfur. In some embodiments, -Cy-is selected from those depicted in table 1 below.

In some embodiments, the present invention provides a compound selected from any one of formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, I-l, I-m, I-n, I-o, and I-p:

or a pharmaceutically acceptable salt thereof; wherein each variable is as defined herein and as described in the examples above for formula I and formula I' or in the examples herein, alone or in combination.

In some embodiments, the present invention provides a compound selected from any one of formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-j, II-k, II-l, II-m, II-n, II-o, and II-p:

In some embodiments, the present invention provides a compound selected from any one of formulas III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, III-j, III-k, III-l, III-m, III-n, III-o, III-p, III-q, III-r, III-s, III-t, III-u, III-v, III-w, III-x, III-y, III-z, III-aa, III-bb, III-cc, III-dd, III-ee, III-ff, III-gg, III-hh, III-ii, III-jj, and III-kk:

In some embodiments, the present invention provides a compound selected from any one of formulas IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, IV-l, IV-m, IV-n, IV-o, IV-p, and IV-q:

In some embodiments, the present invention provides a compound selected from any one of formulas V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, and V-l:

In some embodiments, the present invention provides a compound selected from any one of formulas VI-a, VI-b, VI-c, VI-d, VI-e, and VI-f:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; wherein each variable is as defined herein and as described in the examples above for formula I and formula I' or in the examples herein, alone or in combination.

In some embodiments, the present invention provides a compound selected from any one of formulas VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, and VII-g:

In some embodiments, the present invention provides a compound selected from any one of formulas VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, and VIII-f:

In some embodiments, the present invention provides a compound selected from any one of formulas IX-a, IX-b, and IX-c:

In some embodiments, the present invention provides a compound selected from any one of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h, and X-i:

In some embodiments, the invention provides a compound selected from any one of formulas XI-a, XI-b, XI-c, XI-d, XI-e, XI-f, XI-g, XI-h, and XI-i:

In some embodiments, the present invention provides a compound selected from any one of formulas XII-a, XII-b and XI-c:

In some embodiments, the invention provides compounds of formula I and formula I', with the proviso that when ring a is

When ring B is not

And/or ring C is not

And/or R¹Is not that

In some embodiments, the present invention provides compounds of formula I and formula I', with the proviso that L¹Is not-NHCH₂CH₂-. In some embodiments, the invention provides compounds of formula I and formula I', with the proviso that when ring a is

When L is¹Is not-NHCH₂CH₂-。

Exemplary compounds of the invention are set forth in table 1 below:

TABLE 1 exemplary Compounds of formula I

In certain embodiments, the present invention provides any compound selected from those depicted in table 1 above, or a pharmaceutically acceptable salt thereof.

4. Use, formulation and administration and pharmaceutically acceptable compositions

According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, or salt of an ester thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the compositions of the present invention is effective to measurably inhibit AHR in a biological sample or patient. In certain embodiments, the amount of the compound in the compositions of the invention is effective to measurably inhibit AHR in a biological sample or patient. In certain embodiments, the compositions of the present invention are formulated for administration to a patient in need thereof. In some embodiments, the compositions of the present invention are formulated for oral administration to a patient.

As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles which may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

By "pharmaceutically acceptable derivative" is meant any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention, or an inhibitory active metabolite or residue thereof.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) are suitable for the preparation of injectables, as are natural pharmaceutically-acceptable oils (e.g., olive oil or castor oil, especially the polyoxyethylated versions thereof). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (e.g., Tween, Span, and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. The materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, especially when the target of treatment includes diseases of the region or organ accessible by topical application, including the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application to the lower intestinal tract can be achieved in the form of a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

For topical application, the provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micron-sized suspensions in pH adjusted isotonic sterile saline, or preferably as solutions in pH adjusted isotonic sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in the form of an ointment (e.g., petrolatum).

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the invention are administered in the presence of food.

The amount of a compound of the invention that can be combined with a carrier material to produce a composition in a single dosage form will depend on the host treated, the particular mode of administration. Preferably, the provided compositions should be formulated such that a daily dose of between 0.01-100mg per kg body weight of the inhibitor can be administered to a patient receiving these compositions.

It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease undergoing therapy. The amount of the compound of the invention in the composition will also depend on the particular compound in the composition.

Use of compounds and pharmaceutically acceptable compositions

The activity of a compound for use as an AHR inhibitor in the present invention can be assayed in vitro or in vivo. In vivo assessment of the efficacy of the compounds of the invention may be performed using animal models of obesity or metabolic syndrome, such as rodent or primate animal models. Cell-based assays can be performed using, for example, cell lines isolated from tissues expressing AHR. Furthermore, biochemical or mechanistic analysis such as transcription analysis using purified proteins, northern blot (northern blot), RT-PCR, and the like can be performed. In vitro assays include assays that determine the cellular morphology, protein expression and/or cytotoxicity, enzyme inhibitory activity and/or subsequent functional outcome of cells treated with compounds of the invention. An alternative in vitro assay quantifies the ability of an inhibitor to bind to a protein or nucleic acid molecule within a cell. Inhibitor binding can be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/target molecule complex and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which the novel inhibitor is incubated with purified protein or nucleic acid that binds to a known radioligand. The detailed conditions for analyzing the compounds used as AHR inhibitors in the present invention are set forth in the examples below. The above mentioned analyses are exemplary and not intended to limit the scope of the invention. Those skilled in the art will appreciate that modifications can be made to the routine analysis to develop equivalent analyses to achieve the same results.

As used herein, the terms "treatment", "treating" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, the treatment may be administered after one or more symptoms have occurred. In other embodiments, the treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, e.g., to prevent or delay their recurrence.

According to the methods of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of a metabolic disorder or condition, cancer, bacterial infection, fungal infection, parasitic infection (e.g., malaria), autoimmune disorder, neurodegenerative or neurological disorder, schizophrenia, bone-related disorder, liver disease, or cardiac disorder.

In some embodiments, a compound or composition can be administered using any amount and any route of administration effective to treat or reduce the severity of an AHR-associated disease according to the methods of the present invention.

The precise amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. For ease of administration and uniformity of dosage, it is preferred to formulate the compounds of the invention in unit dosage form. As used herein, the expression "unit dosage form" refers to a physically discrete unit of medicament suitable for the patient to be treated. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dose for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound used; the specific composition used; the age, weight, overall health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors as are well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), bucally (e.g., by oral or nasal spray), etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at dosage levels of from about 0.01mg to about 50mg and preferably from about 1mg to about 25mg per kg of subject body weight per day, one or more times a day to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporation of sterilizing agents, in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium at the point of use.

In order to prolong the effect of the compounds of the invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. The rate of absorption of the compound is then dependent on the rate of dissolution, which in turn is dependent on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by embedding the compounds in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (for example cocoa butter, polyethylene glycol or a suppository wax) which are solid at ambient temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) a dissolution inhibitor, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell layers such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract, or optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols.

The active compounds may also be present in microencapsulated form together with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell layers such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As is common practice, such dosage forms may also contain, in addition to inert diluents, other substances such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract, or optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of controlled delivery of compounds to the body. Such dosage forms may be manufactured by dissolving or dispensing the compound in an appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Use and method of treatment

According to one embodiment, the present invention relates to a method of inhibiting AHR in a biological sample comprising the step of contacting the biological sample with a compound of the invention or a composition comprising the compound.

As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of enzymes in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and biological target identification.

Another embodiment of the present invention is directed to a method of inhibiting AHR in a patient comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

The compounds provided are AHR inhibitors and are therefore useful for treating one or more conditions associated with AHR activity. Thus, in certain embodiments, the present invention provides a method for treating an AHR-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

As used herein, the term "AHR-mediated" disorder, disease, and/or condition, as used herein, means any disease or other deleterious condition for which AHR or a mutant thereof is known to function. Thus, another embodiment of the invention relates to treating or lessening the severity of one or more diseases in which AHR or mutants thereof are known to play a role.

AHR mediated disorders are well established in the art. The relationship between AHR and AHR-mediated disorders, diseases and/or conditions as described herein is well established in the relevant art. See, for example: wuteff (Uyttenhove), et al, Evidence of tumor immune resistance mechanism based on degradation of tryptophan by indoleamine 2, 3-dioxygenase (Evidence for an effective immune resistance function mechanism on tryptophan degradation byindole 2, 3-dioxygenase)' Nature Medicine (Nature Medicine), Vol. 9 (10) 2003, 1038; muley et al, Nature & reviews of friend relationships of AH RECEPTOR ligands in cancer (AH RECEPTOR LIGANDS IN CANCER: FRIEND AND FOE): cancer (nat. rev. cancer)2014 12 months, volume 14 (12), page 801-; moen (Moon) et al, "Targeting the indoleamine 2, 3-dioxide pathway (Targeting the indole 2, 3-dioxygenase pathway in Cancer") in Cancer, "journal of Cancer immunotherapy (j. immunological therapy of Cancer"), volume 3, 2015, page 51; shiitake (Ishida), et al, Activation of arene receptors promotes invasion of renal clear cell carcinoma and causes poor prognosis and smoking (Activation of aryl hydrocarbon receptor promoters invasion of clear cell renal cell carcinoma) 'journal of international cancer (int.J.cancer)' 2015, 7 th, 15 th, 137 th, 310 th page; shitian et al, Activation of the arene receptor pathway enhances cancer cell invasion by upregulating MMP expression and leads to poor prognosis of upper urinary tract epithelial cancers (Activation of the aryl hydrocarbon receptor pathway cancer by regulating the MMP expression and is associated with a pore diagnosis in an upper urinary tract cancer), "Carcinogenesis (Carcinogenesis)' Vol.31 (2) at 2.2010, p.287 and 295. Su (Su) et al, a predictive value of nuclear translocation of arene receptors for non-small cell lung cancerer.) anticancer study (anticancer Res.) in 9 months of 2013, Vol.33 (9), p.3953-3961; peng (Peng), et al, activation of the arene receptor pathway may enhance gastric cancer Cell invasion by c-Jun dependent induction of matrix metalloproteinase-9 (Aryl hydrocarbon receptor activity enhancement of gastric cancer Cell invasion a c-Jun-dependent inhibition of matrix metalloproteinase-9), BMC Cell Biol (BMC Cell Biol.) 2009, Vol.4, 16; pages 10-27; gold (Jin) et al, "Activation of arene receptors during fungal Infection reduces dendritic Cell Function (Aryl Hydrocarbon Receptor Activation reduction Cell Function Infection) in toxicological sciences (ToxicolSci.) at 8 months 2010, vol. 116 (2), page 514-522; hede (Head), et al, modulators of The presence of arene receptors to prevent viral immunity (The aryl hydrocarbon receptor a modulator of anti-viral immunity), biochem (biochem. pharmacol.) 2009, vol.2, 15; stage 77 (4), pages 642-53; gold et al, aromatic receptors during viral infection of the respiratory tract at CD11c⁺The role in the function of cells is newly elucidated (News in the role of the aryl hydro carbon receptor in the function of CD11c⁺cells reduction respiratory viral infection, "journal of immunology in europe (eur.j. immune.) -2014 at 6 months, volume 44 (6), pages 1685-98; raney et al, aromatic hydrocarbon receptor and kynurenine: recent developments in autoimmune disease research (Aryl carbohydrate receptors and kynurenines: receptor activities in autoimmune disease research), advanced immunologic Front of the year (Front Immunol.) 2014, month 10, 29, 5, p 551; eseh (Eser), et al, The arene receptor in immunity (Trends in Immunology), Vol.30, No. 9.

In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions, wherein the disorder, disease, or condition is a proliferative disease, such as cancer, an inflammatory disorder, or a viral infection.

In certain embodiments, the invention provides a method of treating cancer or another proliferative disorder comprising administering to a patient having cancer or another proliferative disorder a compound or composition of the invention. In certain embodiments, the methods of treating cancer or another proliferative disorder comprise administering to a mammal compounds and compositions of the present invention. In certain embodiments, the mammal is a human.

As used herein, the terms "inhibiting cancer" and "inhibiting cancer cell proliferation" refer to inhibiting the growth, division, maturation or survival of cancer cells and/or causing cancer cell death, individually or in whole with other cancer cells, by cytotoxicity, nutrient depletion or induction of apoptosis.

Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and for which the methods described herein are useful include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

In some embodiments, the cancer treated by the compounds or compositions of the invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, renal cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. In certain embodiments, the cancer is Primary Effusion Lymphoma (PEL).

The compounds of the invention are useful for treating proliferative diseases selected from: benign or malignant tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, carcinomas; sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer (in particular colon cancer or colorectal adenoma) or tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, tumorsNeoplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, Hodgkins and non-Hodgkins lymphomas, Waldenstrom's macroglobulinemia (II)macroglobulinemia), breast cancer, follicular cancer, undifferentiated tumors, papillary carcinoma, seminoma, melanoma, MYD 88-driven disorders, DLBCL, ABC DLBCL, IL-1-driven disorders, and mild or indolent multiple myeloma or leukemia.

In some embodiments, the cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., hodgkin's disease or non-hodgkin's disease), waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, e.g., sarcomas and carcinomas (e.g., fibrosarcoma, sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mucinous sarcoma, and mucinous sarcoma, Mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal tumor, wilms' tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibroma, meningioma, melanoma, neuroblastoma, cervical adenocarcinoma, bladder adenocarcinoma, and bladder adenocarcinoma, Neuroblastoma and retinoblastoma).

In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-hairy cell astrocytoma, grade II-low-grade astrocytoma, grade III-pleomorphic astrocytoma, or grade IV-Glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brain stem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a sub-ependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a Primary Neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type more common in children than in adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile hairy cell astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primary neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a pediatric or pediatric patient.

In another embodiment, cancers include (without limitation): mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid, carcinoma of the parathyroid, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, carcinoma of the testis, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphomas, carcinoma of the bladder, carcinoma of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenal cortex carcinoma, cancer of the gallbladder, multiple myeloma, cancer of the head or, Cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; ewing's sarcoma; thyroid cancer polymorphous; adrenocortical adenoma; pancreatic cancer; pancreatic ductal or pancreatic cancer; gastrointestinal/Gastric (GIST) cancer; lymphoma; squamous Cell Carcinoma of Head and Neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1 associated Malignant Peripheral Nerve Sheath Tumor (MPNST); waldenstrom's macroglobulinemia; or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), cholangiohepatoma, soft tissue and synovial sarcoma, rhabdomyosarcoma, osteosarcoma, thyroid carcinoma polymorphous, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic carcinoma, glioma, neurofibroma-1 associated Malignant Peripheral Nerve Sheath Tumor (MPNST), waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors typically contain abnormal tissue masses that generally do not include cysts or fluid regions. In some embodiments, the cancer is selected from renal cell carcinoma or renal carcinoma; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal carcinoma or carcinoma; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or Small Cell Lung Cancer (SCLC); ovarian, epithelial, ovarian or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; ewing's sarcoma; thyroid cancer polymorphous; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal or pancreatic cancer; gastrointestinal/Gastric (GIST) cancer; lymphoma; squamous Cell Carcinoma of Head and Neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1 associated Malignant Peripheral Nerve Sheath Tumor (MPNST); waldenstrom's macroglobulinemia; or medulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colon carcinoma, rectal carcinoma, anal carcinoma, ovarian epithelial carcinoma, ovarian carcinoma, fallopian tube carcinoma, papillary serous cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), cholangiohepatoma, soft tissue and synovium sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, thyroid carcinoma of the polymorphic type, adrenocortical carcinoma, pancreatic ductal carcinoma, pancreatic carcinoma, glioma, brain carcinoma, neurofibroma-1-associated Malignant Peripheral Nerve Sheath Tumor (MPNST), waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), cholangiohepatoma, soft tissue and synovial sarcoma, rhabdomyosarcoma, osteosarcoma, thyroid carcinoma polymorphous, adrenocortical adenoma, pancreatic cancer, pancreatic duct cancer, pancreatic cancer, glioma, neurofibroma-1 associated Malignant Peripheral Nerve Sheath Tumor (MPNST), waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is ovarian cancer or an ovarian carcinoma. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine serous papillary carcinoma (UPSC). In some embodiments, the cancer is cholangiohepatoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is Malignant Peripheral Nerve Sheath Tumor (MPNST). In some embodiments, the cancer is neurofibroma-1 associated MPNST. In some embodiments, the cancer is waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

In some embodiments, the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, atypical teratoid/rhabdoid tumors, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, bone carcinoma, brain tumor, astrocytoma, brain and spinal cord tumors, brainstem glioma, central nervous system atypical teratoid/rhabdoid tumors, central nervous system embryonic tumors, breast carcinoma, bronchial tumor, Burkitt Lymphoma (Burkitt Lymphoma), carcinoid tumors, cancers of unknown primary origin, central nervous system cancer, cervical carcinoma, childhood cancer, chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon carcinoma, colorectal carcinoma, craniopharyngioma, cutaneous T-cell Lymphoma, cervical cancer, and cervical cancer, Ductal Carcinoma In Situ (DCIS), embryonal tumors, endometrial carcinoma, ependymoma, esophageal carcinoma, sensitive neuroblastoma, Ewing's Sarcoma, extracranial germ Cell tumor, extragonadal germ Cell tumor, extrahepatic bile duct Cancer, eye Cancer, osteochondral histiocytoma, gallbladder Cancer, gastric Cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ Cell tumor, ovarian germ Cell tumor, gestational trophoblastic tumor, glioma, hairy Cell leukemia, head and neck Cancer, heart Cancer, hepatocellular carcinoma, histiocytosis, Langerhans Cell carcinoma (Langerhans Cell Cancer), Hodgkin's lymphoma, hypopharynx Cancer, intraocular melanoma, islet Cell tumor, Kaposi's Sarcoma (Kaposi Saroma), kidney Cancer, Langerhans Cell histiocytosis, laryngeal carcinoma, oral Cancer, leukemia, lip and lip Cancer, and lip Cancer, Liver cancer, Lobular Carcinoma In Situ (LCIS), lung cancer, lymphoma, AIDS-related lymphoma, macroglobulinemia, male breast cancer, medulloblastoma, melanoma, Merkel Cell Carcinoma (Merkel Cell Carcinoma), malignant mesothelioma, occult primary metastatic squamous neck cancer, mid-line cancer involving the NUT gene, oral cancer, multiple endocrine tumor syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myelodysplastic neoplasms, Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), myeloma, multiple myeloma, chronic myeloproliferative disorder, nasal cavity cancer, nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small Cell lung cancer, oral cancer, lip cancer, oropharyngeal cancer, pharyngeal cancer, cervical cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus cancer, nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, mesodifferentiated pineal parenchymal tumor, pineal cytoma, pituitary tumor, plasma cell tumor, pleuropulmonoblastoma, breast cancer, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, clear cell renal cell carcinoma, renal pelvis cancer, ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, Sezary Syndrome (Sezandrome), skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, occult primary germ layer neck cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), gastric cancer, supratentorial primary extraneural tumor, T cell lymphoma, testicular cancer, thyroid cancer, cervical cancer, Laryngeal cancer, thymoma, thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, Triple Negative Breast Cancer (TNBC), gestational trophoblast tumor, primary poorly-focused childhood abnormal cancer, urinary tract cancer, uterine sarcoma, waldenstrom's macroglobulinemia, or wilms' tumor.

The compounds according to the invention are useful for the treatment of inflammatory or obstructive airways diseases, reducing for example tissue damage, airway inflammation, bronchial hyperreactivity, remodelling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of any type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood to encompass treatment of subjects exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", e.g. less than 4 or 5 years of age, which is an established patient category of major medical problems and is now often identified as incipient or early asthmatics.

The prophylactic efficacy of asthma treatment will be manifested in a reduction in the frequency or severity of symptomatic attack, e.g. acute asthma or bronchoconstrictor attack, improved lung function or improved airway hyperreactivity. It may further be manifested in a reduced need for other symptomatic therapies, such as therapies for or intended to limit or halt the onset of symptoms at their onset, for example anti-inflammatory or bronchodilatory agents. Prophylactic benefit for asthma may be particularly evident in subjects prone to "early onset". "morning attacks" are a recognized asthma syndrome, common to a substantial percentage of asthmatic patients, and characterized by asthma attacks, for example, between about 4 and 6 am, i.e., asthma attacks at a time point that is typically quite distant from any previously administered symptomatic asthma therapy.

The compounds of the invention may be useful in other inflammatory or obstructive airways diseases and conditions to which the invention is applicable and which include Acute Lung Injury (ALI), adult/Acute Respiratory Distress Syndrome (ARDS), chronic obstructive lung, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema and exacerbation of airways hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and resulting from repeated inhalation of dust) of any type or genesis including, for example, aluminosis, anthracosis, asbestosis, chalicosis, eyelash fallout, siderosis, silicosis, tobacco poisoning and cotton scurf.

With respect to anti-inflammatory activity, particularly with respect to inhibition of eosinophil activation, the compounds of the present invention may also be useful in the treatment of eosinophil-related disorders, such as hypereosinophilia, particularly eosinophil-related disorders of the respiratory tract (e.g., pathological eosinophil infiltration into lung tissue), including hypereosinophilia, as it affects the respiratory tract and/or lung; and eosinophil-related disorders of the respiratory tract, such as those associated with or concomitant with Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-StraussSyndrome), eosinophilic granuloma, and eosinophil-related disorders affecting the respiratory tract resulting from drug reactions.

The compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus paraneoplastic, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic skin conditions.

The compounds of the invention may also be used to treat other diseases or conditions, such as those with an inflammatory component, for example to treat eye diseases and conditions, such as ocular allergy, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having an autoimmune component or cause, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, wegener's granulomatosis (wegenerrgranolamatosis), dermatomyositis, chronic active hepatitis, myasthenia gravis, stevens-Johnson syndrome, idiopathic steatorrhea, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), large bowel emergency, celiac disease, periodontal disease, hyaline periostitis, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves ' disease, sarcoidosis, alveolitis, and the like, Chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, dry eye and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptotropin-related periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, chronic kidney disease, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, chronic inflammatory bowel disease, chronic inflammatory bowel, Mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, pigment incontinence, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, anaphylaxis, systemic anaphylaxis, sinusitis, ocular allergy, silica-induced disease, COPD (injury, airway inflammation, bronchial hyperreactivity, remodeling, or reduced disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in combination with systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, Lichen planus, type 1 diabetes or type 2 diabetes.

In some embodiments, the inflammatory disease treatable according to the methods of the present invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, Systemic Juvenile Idiopathic Arthritis (SJIA), cryptotropin-associated periodic syndrome (CAPS), and osteoarthritis.

In some embodiments, the inflammatory disease treatable according to the methods of the invention is selected from TH 17-mediated diseases. In some embodiments, the TH 17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including crohn's disease or ulcerative colitis).

In some embodiments, the inflammatory disease treatable according to the methods of the invention is selected from sjogren's syndrome; allergic disorders; osteoarthritis; eye diseases such as ocular allergy, conjunctivitis, dry eye and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis.

In some embodiments, the inflammatory disease treatable according to the methods of the invention is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus paraneoplastic, epidermolysis bullosa acquisita, and other inflammatory or allergic skin conditions.

In certain embodiments, the provided compounds are useful for treating viral infections, diseases, or conditions. In some embodiments, the invention provides a method of treating a viral disease selected from retroviral diseases such as HIV-1, HIV-2, human T cell leukemia virus-I (HTLV-I), HTLV-II, HTLV-III, Simian Immunodeficiency Virus (SIV), lymphadenopathy-associated virus (LAV-2), simian T-lymphotropic virus-I (STLV-I), STLV-II, STLV-III, simian B-lymphotropic virus (SBL) virus, Gibbon Ape Leukemia Virus (GALV), Bovine Leukemia Virus (BLV), Equine Infectious Anemia Virus (EIAV), feline leukemia virus (FELV), murine leukemia virus (MuLV), Avian Leukemia Virus (ALV); other viral infections, such as hepadnaviridae (hepatitis B); herpesviridae (herpes simplex type I, herpes simplex type II, varicella zoster, ebeltan-barvirus (Epstein-Barr virus) and cytomegalovirus); parvoviridae (human parvovirus B-19); papovaviridae (human papilloma virus types 1 to 60, JC and BK viruses); poxviruses (variola major, variola minor, pox sores, monkeypox, cowpox, paravaccinia or milker nodavirus, parapoxvirus or ORF virus, molluscum contagiosum) and cancers, lymphomas and other leukemias.

Combination therapy

Depending on the particular condition or disease to be treated, additional therapeutic agents typically administered to treat the condition may be administered in combination with the compounds and compositions of the present invention. As used herein, an additional therapeutic agent that is typically administered to treat a particular disease or condition is referred to as "appropriate for the disease or condition being treated.

In certain embodiments, the provided compounds or compositions thereof are administered to a patient in need thereof in combination with another anti-cancer agent, cytotoxin, or chemotherapeutic agent.

In certain embodiments, anti-cancer or chemotherapeutic agents used in combination with the compounds or compositions of the present invention include, but are not limited to, metformin (metformin), phenformin (phenformin), buforminBiguanide (buformin), imatinib (imatinib), nilotinib (nilotinib), gefitinib (gefitinib), sunitinib (sunitinib), carfilzomib (carfilzomib), salinomycin A (salinosporamide A), retinoic acid (retinic acid), cisplatin (cispin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), mechlorethamine (mechlorethamine), cyclophosphamide (cyclophophamide), chlorambucil (chlorembucil), ifosfamide (ifosfamide), azathioprine (azathioprine), mercaptopurine (mercaptoprine), deoxyfloxuridine (doxifluridine), fluorouracil (fluroracil), gemcitabine (gemcitabine), methotrexate (methyperthyroid), thioguanine (neoguanyline), vincristine (paclitaxel), vinblastine (paclitaxel), docetaxel (paclitaxel), docetaxel (paclitaxel), paclitaxel (docetaxel (paclitaxel), paclitaxel (docetaxel (paclitaxel), paclitaxel (paclitaxel), paclitaxel (docetaxel (paclitaxel), paclitaxel (paclitaxel), paclitaxel), paclitaxel (paclitaxel), paclitaxel (paclitaxel), paclitaxel (paclitaxel), paclitaxel (paclitaxel), paclitaxel, Irinotecan (irinotecan), topotecan (topotecan), amsacrine (amsacrine), actinomycin (actinomycin), doxorubicin (doxorubicin), daunorubicin (daunorubicin), vatamicin (valrubicin), idarubicin (idarubicin), epirubicin (epirubicin), plicamycin (plicamycin), mitomycin (mitomycin), mitoxantrone (mitoxantrone), melphalan (melphalan), busulfan (busufan), capecitabine (capecitabine), pemetrexed (pemetrexed), epothilone (epothilone), 13-cis-retinoic acid, 2-CdA, 2-chlorodeoxyadenosine, 5-cytarabine (5-Azacitidine), 5-Fluorouracil (5-Fluorouracil), 5-fluoropurin (5-fluoropurin), 6-Mercaptopurine (6-Mercaptopurine (TG), Thioguanine (6-Thiopurine (TG), thiouracil (thiouracil), thiouracil (epirubicin), and mitoxantrone (mitoxan), and their derivatives thereof,Actinomycin-D (Actinomycin-D),

Aldesleukin (Aldesleukin), Alemtuzumab (Alemtuzumab), ALIMTA, Alitretinoin (alitretinin),

All-trans retinoic acid, α interferon, Altretamine (Altretamine), methotrexate (Amethopterin), Amifostine (Amifostine), Aminoglutethimide (Aminoglutethimide), Anagrelide (Anagrelide), and pharmaceutically acceptable salts thereof,

Anastrozole (Anastrozole), cytarabine (Arabinosylscosine), Ara-C,

Arsenic trioxide, Arzerra^TMAsparaginase, ATRA,

Azacitidine (Azacitidine), BCG, BCNU, Bendamustine (Bendamustine), Bevacizumab (Bevacizumab), Betheruotine (Bexarotene),Bicalutamide (Bicalutamide), BiCNU,

Bleomycin (Bleomycin), Bortezomib (Bortezomib), busulfan,

C225, Calcium Leucovorin (Calcium Leucovorin),

Camptothecin-11 (Camptothecin-11), capecitabine, Carac^TMCarboplatin, Carmustine (Carmustine), Carmustine powder tablets, and mixtures thereof,

CC-5013、CCI-779、CCNU、CDDP、CeeNU、

Cetuximab (Cetuximab), chlorambucil, citral Factor (citronvorum Factor), Cladribine (Cladribine), Cortisone (Cortisone),

CPT-11、

Dacarbazine (Dacabazine), dactinomycin (Dacogen), actinomycin D (Dactinomycin), alfacabepotin (Darbetoetin Alfa), Dasatinib (Dasatinib), Daunomycin (Daunomycin), Daunomycin Hydrochloride (Daunomycin Hydrochloride), Daunomycin liposomes, Daunomycin D, dactinomycin C, Dacarbazine D, dactinomycin C, Dacarbazine D, Dacarbazine A, Dacarbazine B, dactinomycin D, dac,

Decatetron (Decadron), Decitabine (Decitabine),

Deny interleukin (Denileukin), Diffutox (Diftitox), Depocyt^TMDexamethasone (Dexamethasone), Dexamethasone Acetate (Dexamethasone Acetate), Dexamethasone sodium phosphate, dexanazoxanone (Dexasone), Dexrazoxane (Dexrazoxane), DHAD, DIC, Diodex, docetaxel, and combinations thereof,

Doxorubicin, liposomal doxorubicin, droxa^TM、DTIC、

Eligard^TM、Ellence^TM、Eloxatin^TM、Epirubicin, Epoetin Alfa (Epoetin Alfa), Erbitux (Erbitux), Erlotinib (Erlotinib), Erwinia L-asparaginase (Erwinia L-asparaginase), Estramustine (Estramustine), Yidaole (Ethylol),

Etoposide, etoposide phosphate,

Everolimus (Everolimus),

Exemestane (Exemestane),Filgrastim (Filgrastim), Floxuridine (Floxuridine),Fludarabine (Fludarabine),

Fluorouracil, fluorouracil (cream), flumethyltestosterone (fluoxymestrone), Flutamide (Flutamide), folinic acid, flutolanil, flutol,

Fulvestrant (Fulvestrant), G-CSF, gefitinib, gemcitabine, Gemtuzumab ozogamicin (Gemtuzumab), ozogamicin (ozogamicin), Gemzar Gleevec^TM、Powder tablet, GM-CSF, Goserelin (Goserelin), granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, and,

Haixi Qu (Hexadrol),

Hexamethylmelamine (Hexamethelmenamine), HMM,Hydrocort

Hydrocortisone (Hydrocortisone), Hydrocortisone sodium phosphate, Hydrocortisone sodium succinate, Hydrocortisone phosphate, Hydroxyurea (Hydroxyurea), bumuzumab (Ibritumomab), bumuzumab, tezetan (Tiuxetan),

Idarubicin

IFN- α, ifosfamide, IL-11, IL-2, imatinib mesylate (Imatinibmesylate), Imidazole Carboxamide (Imidazole Carboxamide), interferon α, interferon α -2b (PEG conjugate), Interleukin-2 (Interleukin-2), Interleukin-11, Intron

(Interferon α -2b),

Irinotecan, Isotretinoin (Isotretinoin), Ixabepilone (Ixabepilone), Ixempra^TM、

Lapatinib (Lapatinib), L-asparaginase, LCR, Lenalidomide (Lenalidomide), Letrozole (Letrozole), leucovorin, leukerin (Leukeran), Leukene^TMLeuprolide, Leurocristine and Leustatin^TMLiposome Ara-C, Liquid

Lomo (r) particlesStatin (Lomustine), L-PAM, L-Sarcolysin (L-Sarcolysin),Lupron

Maxidex, Mechlorethamine hydrochloride,

Megestrol (Megestrol), Megestrol Acetate (Megestrol Acetate), melphalan, mercaptopurine, Mesna (Mesna), Mesnex^TMMethotrexate, methotrexate sodium, Methylprednisolone,

Mitomycin, mitomycin-C, mitoxantrone, mitomycin-C, mitoxantrone, mitoxan,

MTC、MTX、

Nitrogen mustard (Mustine),Mylocel^TM、

Nelarabine (nellabrine),Neulasta^TM、

Nilotinib, Nilutamide (Nilutamide),

Nitrogen mustard (Nitrogen mustard),

Nplate, Octreotide (Octreotide), Octreotide acetate, Ofatumumab (Ofatumumab),Onxal^TMOlporil (Opreltekin), Oprelvekin,

Oxaliplatin, paclitaxel, protein-bound paclitaxel, Pamidronate (Pamidronate), Panitumumab (Panitumumab),

Pazopanib (Pazopanib),PEG interferon, Pegasparnase, Pegfilgrastim, PEG-INTRON^TMPEG-L-asparaginase, pemetrexed, Pentostatin (pentastatin), melphalan (phenylalkane Mustard),

Prednisolone (Prednisonone), Prednisone (Prednisonone),

Procarbazine (Procarbazine),

Prolifoprospan 20, with carmustine implant,

Raloxifene (Raloxifene),

Rituximab (Rituximab),

(interferon α -2a), Romipristin (Romiplostim),

Rubimycin hydrochloride (rubidomycin hydrochloride),

Sandostatin

Sargramostim (Sargramostim),

Sorafenib (Sorafenib) and SPRYCEL^TMSTI-571, streptozotocin (Streptozocin), SU11248, sunitinib, and pharmaceutically acceptable salts thereof,

Tamoxifen (Tamoxifen),Temozolomide (Temozolomide), Temsirolimus (Temsirolimus), teniposide, TESPA, Thalidomide (Thalidomide),

Thioguanine (Thioguanine), Thioguanine

Thiophosphoramides,

Thiotepa (Thiotepa),

Topotecan, Toremifene (Tormedifene),

Tositumomab (Tositumomab), Trastuzumab (Trastuzumab),

Tretinoin (Tretinoin) and Trexall^TM、

TSPA、

VCR、Vectibix^TM、

Viadur^TM、

Vinblastine, Vinblastine Sulfate, Vincasar

Vincristine, vinorelbine tartrate, VLB, VM-26, Vorinostat, VP-16, and,

Zevalin^TM、

Zoledronic acid, Zollinza, Zolinza,

Or a combination of any of the above.

In certain embodiments, the immunooncology agent may be administered with a compound as described herein for treating a proliferative disorder as described herein. As used herein, the term "immunooncology agent" refers to an agent effective to enhance, stimulate and/or up-regulate an immune response in a subject. In some embodiments, administration of an immunooncology agent with a compound as described herein has a synergistic effect in treating cancer.

In some embodiments, the compounds as described herein are administered sequentially prior to administration of the immunooncology agent. In some embodiments, a compound as described herein is administered concurrently with an immunooncology agent. In some embodiments, a compound as described herein is administered sequentially after administration of an immunooncology agent.

In some embodiments, a compound as described herein may be co-formulated with an immunooncology agent.

The immunooncology agent may be, for example, a small molecule drug, an antibody, or a biomolecule or small molecule. Examples of bioimmune-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

In some embodiments, the immunooncology agent is (i) an agonist that stimulates (including co-stimulates) a receptor or (ii) an antagonist that inhibits (including co-inhibits) a signal on a T cell, both of which cause an expansion of an antigen-specific T cell response.

An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1(PD-L1), B1-DC (PD-L1), B1-H1 (ICOS-L), B1-H1 (VISTA) and another family of membrane-bound ligands where B1-1 binds to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the homologous TNF family, which includes CD1 and CD40 1, OX-40 1, CD27 1, CD30 1, 4-1BBL, CD137 (CD 137-1 BB), TRAIL/KR 1-1/1, TRAVEL/TRAVEL 1, TNFAVEL/TRAVEL, TNFAVEL/TRAVEL, TRAVEL.

In some embodiments, the immunooncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

In some embodiments, a combination of a compound as described herein and an immunooncology agent may stimulate a T cell response. In some embodiments, the immunooncology agent is: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) a protein that stimulates T cell activation, such as agonists of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD 28H.

In some embodiments, the immunooncology agent is an antagonist of an inhibitory receptor on an NK cell or an agonist of an activating receptor on an NK cell. In some embodiments, the immunooncology agent is an antagonist of KIR, such as rituximab (lirilumab).

In some embodiments, the immunooncology agent is an agent that inhibits or depletes macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008(WO 11/140249; WO 13169264; WO 14/036357).

In some embodiments, the immunooncology agent is selected from the group consisting of an agonist that engages a positive co-stimulatory receptor, a blocker, antagonist that attenuates signaling through the inhibitory receptor, and one or more agents that increase the systemic frequency of anti-tumor T cells, an agent that overcomes different immunosuppressive pathways within the tumor microenvironment (e.g., blocks inhibitory receptor engagement (e.g., PD-L1/PD-1 interaction), depletes or inhibits tregs (e.g., using an anti-CD 25 monoclonal antibody (e.g., daclizumab)) or depletes through ex vivo anti-CD 25 beads), inhibits a metabolic enzyme such as IDO or reverses/prevents T cell energy or depletion), and triggers innate immune activation and/or inflammation at the tumor site.

In some embodiments, the immunooncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is yerboy (ipilimumab) or tremelimumab (tremelimumab).

In some embodiments, the immunooncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immunooncology agent is an antibody, or antigen binding portion thereof, that specifically binds to a programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012/145493). In some embodiments, the immunooncology agent may be pidilizumab (pidilizumab) (CT-011). In some embodiments, the immunooncology agent is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

In some embodiments, the immunooncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG 7446; WO2010/077634), de wagauumab (durvalumab) (MEDI4736), BMS-936559(WO2007/005874), and MSB0010718C (WO 2013/79174).

In some embodiments, the immunooncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016(WO10/19570, WO14/08218) or IMP-731 or IMP-321(WO08/132601, WO 009/44273).

In some embodiments, the immunooncology agent is a CD137(4-1BB) agonist. In some embodiments, the CD137(4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is Urelumab (urelumab) or PF-05082566(WO 12/32433).

In some embodiments, the immunooncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166(WO 11/028683).

In some embodiments, the immunooncology agent is an IDO antagonist. In some embodiments, the IDO antagonist is INCB-024360(WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indomethamide (indoximod), or NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO 12/142237).

In some embodiments, the immunooncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, the immunooncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888(WO 06/029879).

In some embodiments, the immunooncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immunooncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or daclizumab (dacetuzumab).

In some embodiments, the immunooncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varolimumab (varliumab).

In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11/109400).

In some embodiments, the immunooncology agent is abamectin (abagomab), adalimumab (adezelimumab), aftuzumab (afutuzumab), alemtuzumab, maamplex (anatomamafenatox), aprezumab (apolizumab), atelizumab (atezolimab), avilatumab (avelumab), brimomab (blinatumomab), BMS-936559, catomoximab (cataxomab), dewazumab, empatastat (epacadostat), epratuzumab (epatuzumab), indomomab, oxotuzumab (inozumab ozogamicin), itumumab (intelumumab), ipilimumab, isatuximab (isatuximab), ranibizumab (lambrolizumab), MED14736, MPDL3280A, nivolumab, obinutuzumab (obinutuzumab), olaratuzumab (ocatatuzumab), olaratuzumab, olaratumab (olaratumab), palivizumab, pidilizuzumab, rituximab, tixizumab (ticilimumab), samuzumab (salizumab), or tremelimumab.

In some embodiments, the immunooncology agent is an immunostimulant. For example, antibodies that block the inhibition axis of PD-1 and PD-L1 may release activated tumor-reactive T cells and have been shown in clinical trials to induce a durable anti-tumor response, increasing the number of tumor tissue structures, including some tumor types that have not conventionally been considered sensitive to immunotherapy. See, e.g., Okazaki (Okazaki, T.) et al (2013) natural immunology (nat. immunol.)14, 1212-; crepe (Zou) et al (2016) science, transmutation medicine (sci. trans. med.) 8. anti-PD-1 antibody nivolumab (Baishi-Myers Squibb company, also known as ONO-4538 and MDX1106 and BMS-936558) have been shown to improve overall survival in RCC patients undergoing disease progression during or after anti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents for use in the invention include pomalidomide (pomalidomide) (A)

The Seal gene (Celgene)); lenalidomide (A)

Seier gene); ingenol mebutate (ingenol mebutate) (ii)Rio pharmaceuticals (LEO Pharma)).

In some embodiments, the immunooncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from the group consisting of Spiroleucet-T (sipuleucel-T) (II)

Dandelion (Dendreon)/vesuah (valant pharmaceuticals)) approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone refractory) prostate cancer; and ralimogen laherparepvec (a)

Bowei (BioVex)/ann in (Amgen), previously known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous, and nodular lesions in melanoma. In some embodiments, the immunooncology agent is selected from an oncolytic viral therapy, such as pexabexadiol divaricatepvec (PexaVec/JX-594, selajen (SillaJen)/formerly jenirex Biotherapeutics), a thymidine kinase (TK-) deficient vaccinia virus engineered to express GM-CSF, against hepatocellular carcinoma (NCT02562755) and melanoma (NCT 00429312)) (ii) a Parylene (pelareoreep) (ii)Oncolytic biotechnology (Oncolytics Biotech)), a variant of the respiratory tract orphan virus (reovirus) that does not replicate in non-RAS activated cells in a number of cancers including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic cancer (NCT00998322) and non-small cell lung cancer (NCT 00861627), Anderson (enadenoviridi) (NG-348, Pistoseous Euros (PsiOxus), formerly ColoAd1), an adenovirus engineered to express full-length CD7 and antibody fragments specific for the T cell receptor CD3 protein, in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors such as colorectal cancer, head and neck cell carcinoma and salivary gland carcinoma (NCT 0260263636), an adenovirus (COS-360102) (Corgtakura), a previous engineered adenovirus expressing NINGT adenovirus (NCT-365631), a homolog adenovirus, Cokura-transfected human ovarian cancer (GLOBTARG) expressing a glycoprotein, RGE-GCG-GCS-354331), a homolog adenovirus (NCT-3631), a homolog adenovirus (NCT-365631), a homolog adenovirus expressing a homolog adenovirus, a homolog adenovirus expressing a gene expressing.

In some embodiments, the immunooncology agent is selected from the group consisting of JX-929 (Styrax/formerly Jenrey biotherapeutics), a TK-and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase that is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil, TG01 and TG02 (Tager/formerly Oxcos), peptide-based immunotherapeutics targeting difficult-to-treat RAS mutations, and TILT-123(TILT biotherapeutics), an engineered adenovirus called Ad 5/3-E2F-delta 24-hTNF α -IRES-hIL20, and VSV-GP (Viratherapeutics), a Vesicular Stomatitis Virus (VSV) engineered to express Glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express CD8 designed to produce antigen specificity⁺Antigens of T cell responses.

In some embodiments, the immunooncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such chimeric antigen receptors are referred to as CAR-T cells.

CARs have been constructed consisting of a single chain variable fragment (scFv) derived from a binding domain derivable from a natural ligand, from a monoclonal antibody specific for a cell surface antigen, fused to an endodomain that is the functional terminus of a T Cell Receptor (TCR), such as the CD 3-zeta signaling domain from the TCR capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs connect to endogenous signaling pathways in effector cells and generate an activation signal similar to the activation signal elicited by the TCR complex.

For example, in some embodiments, the CAR-T cell is one of the CAR-T cells described in U.S. patent 8,906,682 (month 6; incorporated herein by reference in its entirety), which discloses a CAR-T cell engineered to comprise an extracellular domain having an antigen binding domain (e.g., a domain that binds to CD 19) fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta). When expressed in T cells, the CAR is capable of redirecting antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently over 200 clinical trials employing CAR-T in various indications are progressing. [ https: gov/ct 2/results? term ═ chimeric + antigen + receptors & pg ═ 1 ].

In some embodiments, the immunostimulant is an activator of retinoic acid receptor-associated orphan receptor gamma (ROR γ). ROR γ T is a transcription factor that plays a role in the differentiation and maintenance of the type 17 effector subpopulations of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of the innate immune cell subpopulations (e.g., NK cells) expressing IL-17. In some embodiments, the activator of ROR γ t is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT 02929862).

In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that was studied for B-cell, follicular and other lymphomas (NCT 02254772). Agonists or activators of TLR8 useful in the present invention include motolimod (VTX-2337, wittig pharmaceuticals (VentiRxPharmaceuticals)), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT 02431559).

Other immunooncology agents that may be used in the present invention include Ulvacizumab (BMS-663513, Behcet Shi Guibao Co., Ltd.), an anti-CD 137 monoclonal antibody; (ii) palimumab (CDX-1127, seides medicine (CelldexTherapeutics)), an anti-CD 27 monoclonal antibody; BMS-986178 (Behcet, S.C.), an anti-OX 40 monoclonal antibody; rirelumab (IPH2102/BMS-986015, Einet pharmaceuticals (Innate Pharma), Bezish Shi Guibao Co.), an anti-KIR monoclonal antibody; molizumab (IPH2201, einite, AstraZeneca), an anti-NKG 2A monoclonal antibody; andriximab (andedecaliximab) (GS-5745, gillidd science, inc. (Gilead Sciences)), an anti-MMP 9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

In some embodiments, the immunostimulant is selected from the group consisting of elotuzumab (elotuzumab), mifamurtide (mifamurtide), an agonist or activator of toll-like receptors, and an activator of ROR γ t.

In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested clinically as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT 02689453). in some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). in some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15(hetIL-15, Novartis/adriam (admone)), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed with a soluble IL-15 binding protein IL-15 receptor α chain (IL 15: sIL-15RA), which has been tested in phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT 0252268). in some embodiments, the recombinant human interleukin NM 12 (IL-12) is new drug No. 5, No. IL-15, No. 5.

In some embodiments, the immunooncology agent is selected from jie rui L adams et al, large opportunities for small molecules in immunooncology (Big opportunities in immunooncology), Cancer Therapy (Cancer Therapy) 2015, volume 14, page 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immunooncology agent is selected from the examples described in table 1 of jerry-L-adams et al. In some embodiments, the immunooncology agent is an immunooncology target-targeting small molecule selected from the group consisting of small molecules targeting immunooncology targets listed in table 2 of jerry L adams et al. In some embodiments, the immunooncology agent is a small molecule agent selected from the small molecule agents listed in table 2 of jerry L adams et al.

In some embodiments, the immunooncology agent is selected from Peter L. Toogood, Small molecule immunooncology therapeutics, Small molecule immunooncology agents, Bioorganic and Medicinal Chemistry Letters 2018, Vol.28, p.319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immunooncology agent is an agent that targets a pathway as described in peterkin old.

In some embodiments, the immunooncology agent is selected from Sandra L ross (Sandra L ross) et al, bispecific T cell engaging molecules

The antibody construct may mediate bystander tumor cell killing (Bispecific T cell engage

Inorganic constraints located by transmitter concrete), U.S. public science library, complex (PLoS ONE)12 (8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immunooncology agent is a bispecific T cell engaging molecule

An antibody construct. In some embodiments, bispecific T cell engaging moleculesThe antibody construct was a CD19/CD3 bispecific antibody construct. In some embodiments, bispecific T cell engaging molecules

The antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, bispecific T cell engaging molecules

The antibody construct activates T cells. In some embodiments, bispecific T cell engaging molecules

The antibody construct activates T cells and releases cytokines that induce upregulation of intercellular adhesion molecule 1(ICAM-1) and FAS on bystander cells. In some embodiments, bispecific T cell engaging molecules

The antibody construct activates T cells, inducing bystander cell lysis. In some casesIn the examples, the bystander cells are in a solid tumor. In some embodiments, lysed bystander cells are in proximity

Activated T cells. In some embodiments, the bystander cells comprise Tumor Associated Antigen (TAA) -negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the immunooncology agent is an antibody that blocks the PD-L1/PD1 axis and/or CTLA 4. In some embodiments, the immunooncology agent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the immunooncology agent is a bispecific antibody construct or a Chimeric Antigen Receptor (CAR) directly linking a T cell to a tumor-associated surface antigen (TAA).

In certain embodiments, a combination of 2 or more therapeutic agents may be administered along with a compound of the invention. In certain embodiments, a combination of 3 or more therapeutic agents may be administered with a compound of the invention.

Other examples of agents that may also be combined with the inhibitors of the invention include (but are not limited to): vitamins and nutritional supplements, cancer vaccines, neutropenia therapy (e.g., G-CSF, filgrastim, lengerstim), thrombocytopenia therapy (e.g., blood transfusions, erythropoietin), PI3 kinase (PI3K) inhibitors, MEK inhibitors, mTOR inhibitors, CPT1 inhibitors, AMPK activators, PCSK9 inhibitors, SREBP site 1 protease inhibitors, HMG CoA-reductase inhibitors, anti-emetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergics), Alzheimer's disease therapy (e.g., G-CSF, filgrastim, lenstim), and combinations thereof

And

) (ii) a Parkinson's disease therapy, e.g. L-DOPA/carbidopa (carbidopa), entacapone (entacapone), ropinirole (roprole), pramipexole (pramipex)ole), bromocriptine (bromocriptine), pergolide (pergolide), trihexyphenidyl (trihexyphenyle) and amantadine (amantadine), agents for the treatment of Multiple Sclerosis (MS), for example β interferon (e.g. β interferon

And)、

and mitoxantrone; asthma therapies, e.g. albuterol and

agents for the treatment of schizophrenia such as repaglinide (zyprexa), risperidone (risperdal), selexicam (seroquel) and haloperidol (haloperidol), anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine, immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine, neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole (riluzole) and antiparkinsonism agents, agents for the treatment of cardiovascular diseases such as β -blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins, fibrates of cellulose esters, antidiabetics, cholesterol absorption inhibitors, bile acid chelators and hepatopathies, agents for the treatment of corticosteroids such as corticotropin, antiviral agents and glitazone (glitazone), agents for the treatment of leukemia and glitazone, agents for the treatment of leukemia, glitazone, antimycotinate (glitazone), agents for the treatment of leukemia and glitazone), agents for the treatment of leukemia (e, glitazone), agents for the treatment of leukemia, and hypo, for the treatment of leukemia, for the conditions of leukemia such as glitazone, for the treatment of leukemia, for the diseasetolbutamide), cyclazamide (acetohexamide), tolazamide (tolazamide), chlorpropamide (chlorpropamide), glipizide (glipizide), glyburide (glyburide), glimepiride (glipiride), gliclazide (gliclazide), meglitinide (meglitinide), meglitinide (repaglinide), nateglinide (nateglinide)), α -glucosidase inhibitors (miglitol), acarbose (acarbose), insulinotropic mimetics (exenatide), liraglutide (liraglutide), tallutide (tasaglutide), peplopeptide analogues, DPP-4 inhibitors (vildagliptin), sitagliptin (sitagliptiline), saratinxa (gliptin), gliclatin (gliadine), insulin analogs (insulin), and insulin analogs).

In certain embodiments, a compound of the invention or a pharmaceutically acceptable composition thereof is administered in combination with an antisense agent, a monoclonal or polyclonal antibody, or an siRNA therapeutic.

In another embodiment, the invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of the invention and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin (aspirin), ibuprofen (ibuprofen), naproxen (naproxen), etodolac (etodolac)

And celecoxib (celecoxib), colchicine (colchicine)

Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat

SulfasalazineAntimalarial drugs, e.g. hydroxychloroquine (hydroxychloroquine)

And chloroquinine (chloroquine)

Methotrexate (MTX)Gold salts, e.g. gold thioglucoside

Gold thiomalate

And auranofin (auranofin,

) D-penicillamine (a)

) AzathioprineCyclophosphamideChlorambucilCyclosporine (cyclosporine,) Leflunomide (leflunomide,

) (ii) a And "anti-TNF" agents, such as etanercept (etanercept,

) Infliximab (infliximab,

) Golimumab (golimumab,

) Pegylated certolizumab pegol (certolizumab pegol,

) And adalimumab (adalimumab,

) (ii) a An "anti-IL-1" agent, such as anakinra (anakinra,

) And linaglicept (rilonacept,

) Kana mab (canakinumab,

) (ii) a anti-Jak inhibitors, such as tofacitinib; antibodies, e.g. rituximab

An "anti-T cell" agent, such as abatacept (abatacept,) (ii) a "anti-IL-6" agents, e.g. tositumumab (tocilizumab)

Diclofenac (diclofenac), cortisone, hyaluronic acid: (A)

Or) (ii) a Monoclonal antibodies, such as, for example, tanizumab; anticoagulants, e.g. heparin (A), (B)

) And warfarin (warfarin,) (ii) a Antidiarrheal agents, such as diphenoxylate (diphenoxylate,

) And loperamide (loperamide,

) (ii) a Bile acid binders, such as cholestyramine, alosetron (aloetron,

) Lubiprostone (lubiprostone)

Laxatives (laxatives), e.g. magnesium oxide emulsions, polyethylene glycols

And

anticholinergics or antispasmodics, such as bicyclovine (dicyclomine,

)、

β -2 agonists, such as salbutamol (albuterol,

HFA、

HFA), levalbuterol (levalbuterol,

) Metaproterenol (metaproterenol,

) Pirbuterol acetate (pirbuterol acetate,

) And terbutaline sulfate (terbutaline sulfate,) Salmeterol xinafoate (salmeterol xinafoate,

) And formoterol (formoterol,

) (ii) a Anticholinergics, such as ipratropium bromide (ipratropium bromide,) And tiotropium (tiotropium,) (ii) a Inhaled corticosteroids, such as beclomethasone dipropionate (beclomethasone dipropionate,

and

) Triamcinolone acetonide (triamcinolone acetonide,) Mometasone (mometasone,) Budesonide (budesonide,

) And flunisolide (flunisolide,)、

cromolyn sodium saltMethylxanthines, e.g. theophylline (A)

) And aminophylline (aminophylline); IgE antibodies, e.g. omalizumab

Nucleoside reverse transcriptase inhibitors, such as zidovudine (zidovudine,

) Abacavir (abacavir,

) Abacavir/lamivudine (abacavir/lamivudine)

Abacavir/lamivudine/zidovudine

Didanosine (didanosine)Emtricitabine (emtricitabine,

) Lamivudine, lamivudine

Lamivudine/zidovudine

Stavudine (stavudine)

And zalcitabine (zalcitabine,

) (ii) a Non-nucleoside reverse transcriptase inhibitors, such as delavirdine (delavirdine,) Efavirenz (efavirenz)

Nevirapine (nevirapine,

) And etravirine (etravirine,) (ii) a Nucleotide inversionA transcriptase inhibitor, such as tenofovir (tenofovir,

) (ii) a Protease inhibitors, such as amprenavir (amprenavir,

) Atazanavir (atazanavir,

) Darunavir (darunavir,) Fosamprenavir (fosamprenavir,

) Indinavir (indinavir,

) Lopinavir (lopinavir), ritonavir (ritonavir,

) Nelfinavir (nelfinavir,

) Ritonavir, ritonavir

Saquinavir (saquinavir,

) And tipranavir (tipranavir,

) (ii) a Entry inhibitors, such as enfuvirtide (enfuvirtide,

) And maraviroc (maraviroc,

) (ii) a Integrase inhibitors, such as raltegravir (raltegravir,

) Doxorubicin, doxorubicin

Vincristine

Bortezomib

And dexamethasone

And lenalidomideOr any combination thereof.

In some embodiments, the provided compounds are administered in combination with antiviral agents including, for example, acyclovir (acyclovir), penciclovir (penciclovir), cidofovir (cidofovir), idoxuridine (idoxuridine), zidovudine, ribavirin (ribavarin), amantadine, foscarnet (foscamet), didanosine, acyclovir, ganciclovir (ganciclovir), cidofovir, zalcitabine, rimantadine (rimatadine), kalalovir (calaciclovir), famciclovir (famciclovir), abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir (tenofovir), cerclabine, zidovudine-lamivudine, trizir (zivudine, lamivudine), zivudine (epivudine), uvivelvudine (epvirolavir), uviorevudine (efavir), valvirucine (efavir), valvirenz (efavir), valvirdine (valvirdine, valvirenz (valvirdine), valvirdine (valvirvudine), virvudine (efavir (valvirvudine), virvudine, valvirvudine, valvir, Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir and tipranavir. In some embodiments, the antiviral agent is an anti-influenza agent, including, for example, rimantadine, amantadine, oseltamivir (oseltamivir), and zanamivir (zanamivir).

Those additional agents may be administered separately from the compositions containing the compounds of the present invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be provided simultaneously, sequentially, or separated from each other by a period of time (typically within 5 hours of each other).

As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the present invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both the provided compound and the additional therapeutic agent (in those compositions comprising the additional therapeutic agent as described above) that can be combined with the carrier material to produce a single dosage form will depend on the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dose of between 0.01 and 100mg of a compound of the invention per kg of body weight per day can be administered.

In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compound of the invention may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than that required in monotherapy utilizing only the therapeutic agent. In the composition, additional therapeutic agents may be administered at a dose between 0.01-100 μ g per kg body weight per day.

The amount of additional therapeutic agent present in the compositions of the present invention will be up to the amount normally administered in compositions comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the disclosed compositions will preferably range from about 50% to 100% of the amount typically present in compositions comprising the agent as the sole therapeutically active agent.

In one embodiment, the invention provides a composition comprising a compound of the invention and one or more additional therapeutic agents. The therapeutic agent may be administered in conjunction with the compound of the invention, or may be administered before or after administration of the compound of the invention. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of the invention can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours prior to the therapeutic agent. In other embodiments, the compound of formula I' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

In some embodiments, the present invention provides a pharmaceutical agent comprising at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Examples of the invention

As depicted in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. It is to be understood that while general methods depict the synthesis of certain compounds of the invention, the following general methods and other methods known to those of ordinary skill in the art are applicable to all compounds as described herein and to subclasses and classes of each of these compounds.

Example 1A

DRE-luciferase reporter gene assay

AHR binds to a Dioxin Response Element (DRE) upstream of its activated gene. One measure of AHR activity is the activation of a reporter gene, such as luciferase, downstream of one or more DRE elements. Luciferase activity will reflect activation and inhibition of AHR in cells expressing his reporter.

Murine Hepa1-6 or Hepa-1c1c7 or other murine cell lines stably or transiently transfected with DRE-luciferase reporter genes were plated in medium (96-well, 384-well or other plates) and in CO₂Incubate overnight at 37 ℃ in an incubator. Similarly, human HepG2 or other human cell lines stably or transiently transfected with DRE-luciferase reporter gene were plated in medium in plates (96-well, 384-well or other plates) and in CO₂Incubate overnight at 37 ℃ in an incubator.

The following day, an AHR activating ligand such as TCDD, kynurenine, ITE (methyl 2- (1H-indol-3-ylcarbonyl) -4-thiazolecarboxylate), VAF347, BNF (β -naphthoflavone), FICZ (6-formylindolo (3, 2-b) carbazole or other AHR ligands were added with or without AHR antagonists.

Cells were incubated for 4 hours, 15 hours or 24 hours or another time point and then lysed to determine luciferase activity as a readout for AHR activation or inhibition. Luciferase is measured using a commercial kit such as the Promega luciferase kit or any kit or reagent that provides a luciferin substrate to measure luciferase activity. The level of luciferase with only the added activated ligand is the maximum signal, while the luciferase without the ligand is the minimum signal. IC (integrated circuit)₅₀Values were determined as the concentration that inhibited half of the luciferase activity. Compounds analyzed and their IC₅₀The values are shown in table 2 below.

In some embodiments, the compound has an IC of 5-20 μ M₅₀. In some embodiments, the IC of the compound₅₀Less than or equal to 5 mu M. In some embodiments, the IC of the compound₅₀Less than or equal to 1 mu M. In some embodiments, the IC of the compound₅₀Less than or equal to 0.1 mu M. In some embodiments, the IC of the compound₅₀Less than or equal to 0.01 mu M. In some embodiments, the IC of the compound₅₀≤0.001μM。

The activity of certain compounds of the invention as obtained by the above assay is set forth in table 2 below.

In Table 2, IC50 values are reported as A, B, C and D, where A represents IC50 < 0.5. mu.M; b represents an IC50 of between 0.5 and 1.0 μ M; and C represents IC50 between 1.0 and 1.5 μ Μ; and D represents IC50 > 1.5. mu.M.

₅₀TABLE 2 IC values of selected compounds analyzed according to example 1A

Compound (I)	IC₅₀
		I-1	C
I-2	A
		I-3	C
I-4	A
		I-5	D
I-6	A
		I-7	A
I-9	C
		I-19	B

Example 1B

DRE-luciferase reporter gene assay (alternative method)

Murine Hepa1-6 or Hepa-1c1c7 or other murine cell lines stably or transiently transfected with DRE-luciferase reporter genes were plated in medium in plates (96-well, 384-well or other plates) and in CO₂Incubations were carried out overnight at 37 ℃ in an incubator, or compounds and agonists were added while plating. Similarly, human HepG2 or other human cell lines stably or transiently transfected with DRE-luciferase reporter gene were plated in medium in plates (96-well, 384-well or other plates) and in CO₂Incubations were carried out overnight at 37 ℃ in an incubator, or compounds and agonists were added while plating.

AHR activating ligands such as TCDD, kynurenine, ITE (methyl 2- (1H-indol-3-ylcarbonyl) -4-thiazolecarboxylate), VAF347, BNF (β -naphthoflavone), FICZ (6-formylindolo (3, 2-b) carbazole or other AHR ligands are added with or without AHR antagonists, either while plating the cells or after overnight incubation.

Cells were incubated for 4 hours, 15 hours or 24 hours or another time point and then lysed to determine luciferase activity as a readout for AHR activation or inhibition. Luciferase is measured with a commercial kit such as the Promega luciferase kit or any kit or reagent that provides a luciferin substrate to measure luciferase activity. The level of luciferase with only added activating ligand is the maximum signal, and that without ligandLuciferase is the minimal signal. IC (integrated circuit)₅₀Values were determined as the concentration that inhibited half of the luciferase activity. Compounds analyzed and their IC₅₀The values are shown in table 3 below.

The activity of certain compounds of the invention as obtained by the above assay is set forth in table 3 below.

In Table 3, IC₅₀The values are reported as A, B, C and D, where A represents IC₅₀Less than 0.5. mu.M; b represents IC₅₀Between 0.5 and 1.0 μ M; and C represents IC₅₀Between 1.0 and 1.5 μ M; and D represents IC₅₀＞1.5μM。

₅₀TABLE 3 IC values of selected compounds analyzed according to example 1B

Example 1C

Study of mouse pharmacokinetics

Formulations of the compounds set forth in table 4 were administered to CD-1 mice either intravenously or orally via gavage. Typically, at 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, and 24 hours post-administration, blood was collected and processed into plasma by centrifugation, and stored at-80 ℃ until analysis.

An internal standard was added to each sample followed by protein precipitation with acetonitrile. The pellet was filtered through a petri (phre) phospholipid removal filter plate and the sample was analyzed by LC/MS. Standard curves were made in plasma, typically 1.0ng/mL to 3000ng/mL, and processed in the same manner as the samples. Sample analysis is typically performed on a suitable LC/MS system equipped with an analytical UPLC column and is performed at 30-95% ACN containing 0.1% formic acid (v/v): the compound was eluted from the analytical column under a gradient of water containing 0.1% formic acid (v/v). Mass spectrometric detection of test compounds and internal standards was performed in positive ion mode by MRM. The pharmacokinetics of each compound was analyzed by non-compartmental analysis by phoenix winnonlin software (Pharsight, st. louis, MO) by st louis). The results are summarized in table 4 below.

TABLE 4 pharmacokinetic data for mice according to example 1C

Example 1D

In vitro mouse liver S9 metabolic stability analysis

CD-1 mouse liver S9 was purchased from Corning (Corning) or SinuoTech Inc. (XenoTech LLC) or Bairui Bio Inc. (BiorecamationIVT, LLC) or prepared tin-free (Wuxi). When cells were used and stored in a freezer at-80 ℃, β -Nicotinamide Adenine Dinucleotide Phosphate (NADP), glucose 6-phosphate (G6P), glucose 6-phosphate dehydrogenase from yeast (G6PDH), uridine 5 '-glucuronic acid trisodium diphosphate (UDPGA), and 3' -adenosine 5 '-phosphosulfate 5' -phosphate lithium salt hydrate (PAPS) were purchased from Sigma (Sigma).

Compounds were diluted in DMSO to prepare 10mM stock solutions. mu.L of this stock solution (10mM, DMSO) was diluted with 45. mu.L of DMSO and 450. mu.L of 50% methanol/water to prepare an intermediate stock solution (100. mu.M, 45% MeOH, 10% DMSO). The final stock solution (10 μ M, 4.5% MeOH, 1% DMSO) was prepared by diluting 50 μ L of the intermediate stock solution with 450 μ L of 100mM phosphate buffer. Add 10 μ L of the final stock solution to a 90 μ L liver S9 system (final concentration 1 μ M, 0.45% MeOH, 0.1% DMSO).

Test compounds were incubated with 1 μ M liver S9 (pooled from multiple donors) in the presence of 1mg/mL S9 protein NADPH regeneration system, UDPGA and PAPS at 37 ℃. Time samples (0 and 60 minutes) were removed and immediately mixed with cold acetonitrile containing an Internal Standard (IS). Samples were analyzed by LC/MS and the disappearance of test compounds was assessed based on the peak area ratio of analyte/IS (no standard curve). All samples were injected and analyzed using LC-MS/MS. The analyte/internal standard peak area ratio was converted to percent remaining (remaining%) using the following equation: the remaining% at 60 minutes IS ═ (peak area ratio of analyte to IS at 60 minutes/peak area ratio of analyte to IS at t of 0) × 100%. The results are summarized in table 5 below.

TABLE 5 mouse stability data according to example 1D

Example 1E

In vivo mouse liver and spleen Cyp1a1 modulation assay

Female C57BL/6 mice weighing about 18-20g were purchased from Shanghai Lingchang Biological technology Co., Ltd or other certified supplier for 6-8 weeks of age and used in the study. Animal husbandry, breeding and health conditions all meet animal welfare guidelines. VAG539(30mg/kg, po) was used as an AHR agonist and test compounds were formulated in a suitable vehicle, typically 0.5% methylcellulose.

C57BL/6 mice (each group n-3) were treated with either AHR agonist alone or with AHR agonist and test compound. Animals were sacrificed 4 or 10 hours post treatment, then their livers and spleens were collected and subsequently analyzed by qPCR. The fold induction of normalized cyp1a1 was determined by comparing mCYP1a1 and mGAPDH counts (ct) according to: normalized multiple 2^-ΔΔCt. Percent inhibition was calculated according to:

the results are summarized in table 6 below.

TABLE 6 Cyp1a1 inhibition data according to example 1E

Example 1F

T cell study Using I-70

After PBMCs were isolated from human donor blood via ficoll density gradient centrifugation, human T cells were isolated by CD3 negative selection. One million T cells were activated with 25 μ L of CD3/CD28 tetramer (Stemcell) for 24 hours in the presence or absence of I-70, after which the medium was removed and stored at-80 ℃ for subsequent cytokine analysis. The cells were then washed 2 times with PBS and RNA was isolated following the manufacturer's instructions for RNAeasy mini kit (Qiagen).

RNA was converted to cDNA using a VILO-IV RT master mix (Thermofeisher) and q-RT-PCR was performed to determine the levels of IL-22(Hs01574154_ m1), Cyp1a1(Hs01054797_ g1) and GAPDH (Hs00266705_ g 1). Data were analyzed using ddCT method, where each sample was first normalized to GAPDH housekeeping gene, followed by normalization to control treatment. The expression levels of IL22 and cyp1a1 RNA were inhibited by treatment with I-70, as shown in FIG. 1.

Cytokine levels were determined using the mesoscale discovery (MSD) platform (K15067L-2) and MSD analysis software according to the manufacturer's instructions. Under I-70 treatment, IL-22 protein levels were reduced and proinflammatory IL-2 protein levels were increased, as shown in FIG. 2.

CD3/CD28 activated T cells were AHR activated as measured by gene expression and cytokine production. Treatment with AHR inhibitors inhibited cyp1a1 and IL22 gene expression and cytokine IL-22 production. AHR inhibition also increases the production of the proinflammatory cytokine IL-2.

Example 1G

I-70 and checkpoint inhibitor anti-PD-1 efficacy studies in Balb/c mice in the mouse colorectal cancer model CT26

CT26 is a murine colon cancer cell line obtained from ATCC. CT26 cells were cultured in RPMI supplemented with 10% FBS. Mu.l of PBS was added at 5X 10⁵Individual CT26 cells were implanted subcutaneously into 6-8 week old female Balb/c mice. Dosing for efficacy studies was initiated 4 days after implantation: the AHR antagonist was administered orally at 10mg/kg per day (QD) over a 3 week period. anti-PD-1 (Behcel corporation (BioXcell) RMP1-14) was administered twice a week at 10mg/kg Intraperitoneally (IP) for a total of five doses. Tumors were monitored by caliper measurements every 2-3 days and body weight was measured three times per week.

Tumor growth was inhibited by the AHR antagonist I-70 alone or in combination with anti-PD-1, as shown in figure 3. Tumor growth inhibition was statistically significant compared to vehicle with I-70 as the single agent, where p-value was 0.0166. In addition, tumor growth inhibition in the combination group was significant compared to anti-PD-1 alone, with a p-value of 0.0420. The p-value was determined by Student T-test analysis (Student's T-test analysis).

Example 1H

Efficacy study of I-70 and checkpoint inhibitor anti-PD-1 in mouse melanoma model B16-IDO in C57BL/6 mice

B16-IDO is a murine melanoma Cell line (Holmgaard, 2015 Cell Reports) engineered to overexpress IDO 1. B16-IDO cells were cultured in DMEM supplemented with 10% FBS. 50 μ l of PBS 2X 10⁵Individual B16-IDO cells were implanted intradermally into 6-8 week old female C57BL/6 mice. Dosing for efficacy studies began 7 days post-implantation: AHR antagonist I-70 was administered orally at 10mg/kg per day (QD) for 2 weeks. anti-PD-1 (baccil RMP1-14) was administered Intraperitoneally (IP) at 250 micrograms/mouse every 3 days for a total of five doses. Tumors were monitored by caliper measurements every 2-3 days and body weight was measured three times per week.

Tumor growth was inhibited by the AHR antagonist I-70 alone or in combination with anti-PD-1, as shown in figure 4. Tumor growth inhibition was statistically significant with a p-value < 0.001 using I-70 as the single agent compared to vehicle. In addition, tumor growth inhibition in the combination group was significant compared to anti-PD-1 alone, with p values < 0.03. The p-value was determined by student T-test analysis.

Example 2

AHR dependent gene expression

Murine Hepa1-6 or Hepa-1c1c7 or other murine cell lines were plated in medium (6-well, 12-well or other plates) and in CO₂Incubate overnight at 37 ℃ in an incubator; or human HepG2 or other human cell lines plated in medium in plates (6-well, 12-well or other plates) and in CO₂Incubate overnight at 37 ℃ in an incubator.

The next day, AHR activating ligands such as TCDD, kynurenine, ITE (methyl 2- (1H-indol-3-ylcarbonyl) -4-thiazolecarboxylate), VAF347, BNF (β -napthoflavone), ICZ (6-formylindolo (3, 2-b) carbazole or other AHR ligands are added with or without AHR antagonists the cells are incubated for 4 hours, 15 hours or 24 hours or at another point in time and then lysed to collect RNA the gene expression can be determined via an RNA isolation kit such as qiagen, or any other RNA isolation method, RNA is collected by quantitative RT-PCR using probes for specific genes including housekeeping genes such as Gapdh, β -or other genes for standardized constitutive expression, the AHR dependent genes to be examined include, but are not limited to, cyp1a1, cyp1b1, actin, IDO1, IDO2, cox2, IL2, cyclosporin a, sirna 1, MMP 23, myc-493c-493.

Example 3

AHR-dependent gene expression is measured in a tissue sample, such as a tumor or liver, RNA may be extracted from the tissue via methods such as RNA isolation kits, such as Qiagen, or any other RNA isolation method known to one of ordinary skill in the art RNA extraction may be performed from cells that are total or sorted for a particular cell population, such as tumor cells, tumor-associated T cells, tumor-associated bone marrow cells, or other cells, gene expression is determined by quantitative RT-PCR using probes for specific genes including housekeeping genes, such as Gapdh, β -actin, or other genes for normalized constitutive expression.

Example 4

Synthesis I-5

The synthesis scheme is as follows:

step 1: n- (2- (1H-indol-3-yl) ethyl) -2-chlorothieno [2, 3-d]Pyrimidin-4-amines

To 2, 4-dichlorothiopheneAnd [2, 3-d ]]To a solution of pyrimidine (200mg, 975.31. mu. mol, 1 eq) in i-PrOH (15mL) was added DIPEA (630.24mg, 4.88mmol, 849.38. mu.L, 5.0 eq) and 2- (1H-indol-3-yl) ethylamine (203.14mg, 1.27mmol, 1.3 eq). The mixture was stirred at 50 ℃ for 3 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. Subjecting the reaction mixture to hydrogenation with H₂O (15mL) was diluted and extracted with DCM (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (b) ((b))

12g

Silica flash column, eluent 20-30% EtOAc/PE gradient, 50mL/min) to afford 2-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Thieno [2, 3-d ]]Pyrimidin-4-amine (260mg, 774.90. mu. mol, 79.4% yield).¹H NMR(400MHz，CD₃OD)δppm 7.67(d，J＝7.9Hz，1H)，7.40-7.35(m，2H)，7.31(d，J＝8.2Hz，1H)，7.10-7.05(m，2H)，7.00-6.93(m，1H)，3.86-3.79(m，2H)，3.11(t，J＝7.4Hz，2H)；ES-LCMS m/z 329.0，331.0[M+H]⁺。

Step 2: n- (2- (1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) thieno [2, 3-d]Pyrimidine-4-amine (I-5)

To 2-chloro-N- [2- (1H-indol-3-yl) ethyl]Thieno [2, 3-d ]]Pyrimidin-4-amine (100mg, 298.04. mu. mol, 1 eq.) in 1, 4-dioxane (3mL) and H₂To a solution in O (1mL) were added (5-fluoro-3-pyridyl) boronic acid (75.59mg, 536.47. mu. mol, 1.8 equiv.), Cs₂CO₃(291.32mg, 894.11. mu. mol, 3.0 equiv.) and Pd (dppf) Cl₂(32.71mg, 44.71. mu. mol, 0.15 equiv.). The mixture was stirred under microwave at 120 ℃ for 1 hour. LC-MS showed complete consumption of the starting material andone major peak with the desired MS is detected. The reaction mixture was filtered. The filtrate is treated with H₂O (15mL) was diluted and extracted with EtOAc (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (HCl conditions; column: Philomenax Kinetex XB-C18150mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -75%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Thieno [2, 3-d ]]Pyrimidin-4-amine (54.40mg, 109.05 μmol, 36.59% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm9.19(s，1H)，8.84(s，1H)，8.58(d，J＝9.3Hz，1H)，7.63-7.57(m，2H)，7.54(d，J＝5.7Hz，1H)，7.19(d，J＝7.7Hz，1H)，7.02-6.90(m，3H)，4.08(t，J＝6.8Hz，2H)，3.19(t，J＝6.7Hz，2H)；ES-LCMS m/z 390.0[M+H]⁺。

Example 5

Synthesis I-4

The synthesis scheme is as follows:

step 1: 2, 4-dichloro-7-isopropyl-7H-pyrrolo [2, 3-d]Pyrimidines

2, 4-dichloro-7H-pyrrolo [2, 3-d)]Pyrimidine (1g, 5.32mmol, 1 equiv.), 2-bromopropane (3.27g, 26.59mmol, 2.50mL, 5.0 equiv.), and K₂CO₃A mixture of (3.68g, 26.59mmol, 5 equiv.) in DMSO (20mL) was degassed and N added₂Purifying 3 times, and mixing the mixture with N₂Stirring at 10-20 deg.C for 48 hr under atmosphere. TLC (PE/EA: 3/1, R)_f0.50) meansIndicating that the starting material was consumed and that a major new spot with greater polarity was detected. Subjecting the reaction mixture to hydrogenation with H₂O (50mL) was diluted and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 4/1, TLC: PE/EtOAc: 3/1, R_f0.50) to yield the product 2, 4-dichloro-7-isopropyl-pyrrolo [2, 3-d) as a white solid]Pyrimidine (650mg, 2.71mmol, 50.99% yield, 96% purity).¹H NMR(400MHz，CDCl₃)δppm 7.33(d，J＝3.7Hz，1H)，6.62(d，J＝3.5Hz，1H)，5.20-5.01(m，1H)，1.53(d，J＝6.8Hz，6H)；ES-LCMS m/z 230.0，232.0[M+H]⁺。

Step 2: 2-chloro-N- [2- (1H-indol-3-yl) ethyl]-7-isopropyl-pyrrolo [2, 3-d]Pyrimidin-4-amines

2, 4-dichloro-7-isopropyl-pyrrolo [2, 3-d)]A mixture of pyrimidine (100mg, 417.22. mu. mol, 1 eq), 2- (1H-indol-3-yl) ethylamine (100mg, 620. mu. mol, 1.2 eq) and DIEA (161.77mg, 1.25mmol, 218.02. mu.L, 3 eq) in i-PrOH (5mL) was degassed and N-PrOH (5mL) was used₂And purifying for 3 times. Then the mixture is added to N₂Stirred at 50 ℃ for 11 hours under an atmosphere. LC-MS showed 15% starting material remaining. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 3/1, R_f0.28) to yield the product 2-chloro-N- [2- (1H-indol-3-yl) ethyl as a pale red oil]-7-isopropyl-pyrrolo [2, 3-d]Pyrimidin-4-amine (120mg, 315.39 μmol, 75.59% yield, 93% purity).¹H NMR(400MHz，CDCl₃)δppm 8.06(s，1H)，7.69(d，J＝7.9Hz，1H)，7.41(d，J＝7.9Hz，1H)，7.26-7.20(m，1H)，7.18-7.13(m，1H)，7.09(d，J＝2.4Hz，1H)，6.96(d，J＝3.5Hz，1H)，6.23(s，1H)，5.22(s，1H)，5.03(d，J＝6.8，13.5Hz，1H)，3.99(q，J＝6.6Hz，2H)，3.17(t，J＝6.6Hz，2H)，1.46(d，J＝6.8Hz，6H)；ES-LCMS m/z353.8，354.9[M+H]⁺。

Step 3: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-7-isopropyl-pyrrolo [2, 3-d]Pyrimidine-4-amine (I-4)

2-chloro-N- [2- (1H-indol-3-yl) ethyl]-7-isopropyl-pyrrolo [2, 3-d]Pyrimidin-4-amine (80mg, 210.26 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (44.44mg, 315.39 μmol, 1.5 eq), Pd (dppf) Cl₂(15.38mg, 21.03. mu. mol, 0.1 equiv.) and Cs₂CO₃(205.52mg, 630.78. mu. mol, 3 equivalents) of 1, 4-dioxane (2mL) and H₂O (0.5mL) was placed in a microwave tube. Reaction mixture with N₂Bubbled for 3 minutes, then sealed and heated under microwave at 110 ℃ for 30 minutes. LC-MS showed that 90% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: DC/Philomo KinetexXB-C18150 mm X30 mm, 5 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 47% to 77% per flow rate over 10 minutes: 25mL/min) and then lyophilized to give 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-7-isopropyl-pyrrolo [2, 3-d]Pyrimidin-4-amine (51.57mg, 120.95. mu. mol, 57.52% yield, 97.21% pure, 3HCl salt).¹H NMR(400MHz，DMSO-d₆)δppm 9.41(s，1H)，8.72(s，1H)，8.50(d，J＝8.6Hz，1H)，8.09(s，1H)，7.64(d，J＝7.7Hz，1H)，7.40(s，1H)，7.35(d，J＝8.2Hz，1H)，7.23(s，1H)，7.07(t，J＝7.4Hz，1H)，7.02-6.93(m，1H)，6.69(s，1H)，5.06(s，1H)，3.89(s，1H)，3.80-3.77(m，2H)，3.20-3.00(m，2H)，1.48(d，J＝6.6Hz，6H)；ES-LCMS m/z 414.9[M+H]⁺。

Example 6

Synthesis of I-3

The synthesis scheme is as follows:

step 1: n- (2- (1H-indol-3-yl) ethyl) -7-bromo-2-chlorothieno [3, 2-d]Pyrimidin-4-amines

To 7-bromo-2, 4-dichloro-thieno [3, 2-d ]]To a solution of pyrimidine (100mg, 352.16. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (84.63mg, 528.24. mu. mol, 1.5 eq) in i-PrOH (3mL) was added DIEA (136.54mg, 1.06mmol, 184.02. mu.L, 3 eq). The mixture was stirred at 50 ℃ for 3 hours. LC-MS showed no starting material remaining and 93% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM/MeOH ═ 1/0 to 100/1, TLC: PE/EtOAc ═ 3/1, R_f0.42) to yield 7-bromo-2-chloro-N- [2- (1H-indol-3-yl) ethyl as a gray solid]Thieno [3, 2-d]Pyrimidin-4-amine (140mg, 339.94 μmol, 96.53% yield, 99% purity).¹H NMR(400MHz，CDCl₃)δppm 8.11(s，1H)，7.69-7.66(m，2H)，7.43(d，J＝8.2Hz，1H)，7.25-7.23(m，1H)，7.18-7.14(m，1H)，7.09(d，J＝2.2Hz，1H)，5.25(s，1H)，4.01(q，J＝6.4Hz，2H)，3.18(t，J＝6.5Hz，2H)；ES-LCMS m/z 406.9，408.9[M+H]⁺。

Step 2: n- (2- (1H-indol-3-yl) ethyl) -2-chloro-7- (prop-1-en-2-yl) thieno [3, 2-d]Pyrimidin-4-amines

The compound containing 7-bromo-2-chloro-N- [2- (1H-indol-3-yl) ethyl]Thieno [3, 2-d]Pyrimidin-4-amine (120mg, 291.38 μmol, 1 eq), 2-isopropenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaboroPentane (39.17mg, 233.10. mu. mol, 0.8 eq.), Pd (dppf) Cl₂(42.64mg, 58.28. mu. mol, 0.2 equiv.) and Cs₂CO₃(284.81mg, 874.14. mu. mol, 3.0 equiv.) of 1, 4-dioxane (5mL) and H₂O (1mL) was placed in a microwave tube. N for the pipe₂Purge for 3 minutes, then seal and heat at 80 ℃ for 10 minutes under microwave. LC-MS showed most of the starting material was consumed and 68% of the desired compound was detected. The combined reaction mixture is washed with H₂O (20mL) was diluted and extracted with EtOAc (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.45) to yield the product N- (2- (1H-indol-3-yl) ethyl) -2-chloro-7- (prop-1-en-2-yl) thieno [3, 2-d) as a pale yellow oil]Pyrimidin-4-amine (95mg, 73.85% yield, 98% purity);¹HNMR(400MHz，CDCl₃)δppm 8.10(s，1H)，7.69(d，J＝7.8Hz，1H)，7.51(s，1H)，7.42(d，J＝8.0Hz，1H)，7.26-7.22(m，1H)，7.20-7.13(m，1H)，7.09(d，J＝2.3Hz，1H)，6.37(s，1H)，5.38(s，1H)，5.11(s，1H)，4.00(q，J＝6.4Hz，2H)，3.18(t，J＝6.7Hz，2H)，2.21(s，3H)；ES-LCMSm/z 369.0，371.0[M+H]⁺。

step 3: n- (2- (1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -7- (prop-1-en-2-yl) thieno [3, 2-d]Pyrimidin-4-amines

2-chloro-N- [2- (1H-indol-3-yl) ethyl]-7-isopropenyl-thieno [3, 2-d]Pyrimidin-4-amine (95mg, 252.38 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (53.34mg, 378.58 μmol, 1.5 eq), Pd (dppf) Cl₂(18.47mg, 25.24. mu. mol, 0.1 equiv.) and Cs₂CO₃(246.69mg, 757.15. mu. mol, 3 equivalents) of 1, 4-dioxane (2mL) and H₂O (0.5mL) was placed in a microwave tube. Sealing pipe N₂Purging for 3 minutes, followed by heating at 110 ℃ for 30 minutes under microwave. LC-MS displayMost of the starting material was consumed and 85% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.44) to yield the product 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl ester as an oil]-7-isopropenyl-thieno [3, 2-d]Pyrimidin-4-amine (85mg, 188.00 μmol, 74.49% yield, 95% purity).¹H NMR(400MHz，CDCl₃)δppm 9.59(s，1H)，8.55(d，J＝2.6Hz，1H)，8.48(d，J＝10.1Hz，1H)，8.07(s，1H)，7.69(d，J＝7.9Hz，1H)，7.56(s，1H)，7.42(d，J＝7.9Hz，1H)，7.26-7.22(m，1H)，7.20-7.15(m，1H)，7.11(s，1H)，6.70(s，1H)，5.46(s，1H)，5.06(s，1H)，4.14(q，J＝6.5Hz，2H)，3.26(t，J＝6.5Hz，2H)，2.30(s，3H)；ES-LCMS m/z 430.0[M+H]⁺。

Step 4: n- (2- (1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -7-isopropylthieno [3, 2-d]Pyrimidine-4-amine (I-3)

To 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl under N2]-7-isopropenyl-thieno [3, 2-d]To a solution of pyrimidin-4-amine (50mg, 110.59 μmol, 1 eq) in MeOH (20mL) and THF (2mL) was added Pd/C (10%, 50 mg). The suspension is degassed under vacuum and treated with H₂And purifying for 3 times. Mixing the mixture in H₂(15psi) at 10-15 deg.C for 0.5 hours. LC-MS showed no starting material remaining and 95% of the desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: DC/Feilomen Kinetex XB-C18150mm X30 mm, 5 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 62% to 92%/flow rate over 10 min: 25mL/min) and then lyophilized to give 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-7-isopropyl-thieno [3, 2-d]Pyrimidin-4-amine (40.32mg, 74.05. mu. mol, 66.96% yield, 99.34% purity, 3 HC)l salt). 1H NMR (400MHz, DMSO-d)₆)δppm 10.85(s，1H)，9.46(s，1H)，8.69(d，J＝2.8Hz，1H)，8.42(d，J＝10.0Hz，1H)，8.19(t，J＝5.6Hz，1H)，7.77(s，1H)，7.64(d，J＝8.0Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.22(d，J＝2.0Hz，1H)，7.07(t，J＝7.4Hz，1H)，6.99-6.95(m，1H)，3.93-3.87(m，2H)，3.46-3.41(m，1H)，3.12(t，J＝7.4Hz，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 432.0[M+H]⁺。

Example 7

Synthesis of I-2

The synthesis scheme is as follows:

step 1: 2-formyl-3-methylbutyronitrile

At-78 ℃ under N₂n-BuLi (2.5M, 10.10mL, 1.05 equiv.) was added dropwise to a mixture of diisopropylamine (2.43g, 24.06mmol, 3.40mL, 1 equiv.) in THF (20 mL). The mixture was stirred at-78 ℃ for 10 minutes, then warmed to 0 ℃ and stirred for 1 hour. The mixture was cooled to-78 ℃, 3-methylbutanenitrile (2g, 24.06mmol, 2.53mL, 1 eq) dissolved in THF (15mL, anhydrous) was added dropwise and stirred at-78 ℃ for 10 min. A solution of ethyl formate (1.87g, 25.26mmol, 2.03mL, 1.05 equiv.) in THF (15mL, anhydrous) was added dropwise and stirred at-78 deg.C for 40 minutes, then the mixture was warmed to 5-14 deg.C for 16 hours. TLC (PE/EA: 3/1, R)_f0.34) indicates that a primary new blob is detected. The reaction mixture was quenched by addition of 1N HCl solution (50mL) at-78 deg.C and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residueIt was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 1/4, TLC: PE/EtOAc: 3/1, R_f0.34) to yield 2-formyl-3-methyl-butyronitrile (2g, 16.20mmol, 67.32% yield, 90% purity) as a pale yellow oil.¹H NMR(400MHz，CDCl₃)δppm9.57(s，1H)，3.43(d，J＝4.4Hz，1H)，2.56-2.40(m，1H)，1.20(d，J＝6.8Hz，3H)，1.12(d，J＝6.8Hz，3H)。

Step 2: 4-isopropyl-1H-pyrazol-5-amine

A mixture of 2-formyl-3-methyl-butyronitrile (500mg, 4.05mmol, 1 equiv.), hydrazine hydrate (168.67mg, 5.26mmol, 190.37. mu.L, 1.3 equiv.), and AcOH (425.50mg, 7.09mmol, 405.24. mu.L, 1.75 equiv.) in EtOH (20mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirring was carried out at 80-90 deg.C (reflux) under an atmosphere for 16 hours, followed by concentration under reduced pressure. The residue was taken up in saturated NaHCO₃The solution (20mL) was diluted and extracted with DCM (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude 4-isopropyl-1H-pyrazol-5-amine (420mg, 3.02mmol, 74.58% yield, 90% purity) as a yellow solid, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.13(s，1H)，2.69(t，J＝6.9Hz，1H)，1.21(d，J＝6.8Hz，6H)。

Step 3: 3- (5-Fluoropyridin-3-yl) -3-oxopropanoic acid methyl ester

To a solution of 5-fluoropyridine-3-carboxylic acid (500mg, 3.54mmol, 1 eq) in THF (20mL) was added CDI (689.51mg, 4.25mmol, 1.2 eq). The mixture was stirred at 5-14 ℃ for 2 hours. (3-methoxy-3-oxo-propionyl) Potassium oxy (553.43mg, 3.54mmol, 1 equiv.) and MgCl were added₂(337.39mg, 3.54mmol, 1 eq.) andthe reaction was stirred at 5-14 ℃ for 16 hours. TLC (PE/EA: 1/1, R)_f0.58) indicates that the starting material is consumed and one major new spot with greater polarity is detected. The reaction mixture was diluted with 3N HCl solution (20mL) and extracted with EtOAc (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 1/4, TLC: PE/EtOAc: 1/1, R_f0.58) to yield 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (175mg, 843.21 μmol, 23.80% yield, 95% purity) as a white solid and 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (175mg, 843.21 μmol, 23.80% yield, 95% purity) as a white solid.¹H NMR(400MHz，CDCl₃)δppm 12.48(s，1H)，8.97(s，1H)，8.82(s，1H)，8.70(d，J＝2.6Hz，1H)，8.56(d，J＝2.6Hz，1H)，7.96(d，J＝2.2，8.6Hz，1H)，7.86-7.73(m，1H)，5.75(s，1H)，4.04(s，2H)，3.84(s，3H)，3.78(s，3H)；ES-LCMS m/z 198.1[M+H]⁺。

Step 4: 5- (5-Fluoropyridin-3-yl) -3-isopropylpyrazolo [1, 5-a]Pyrimidin-7-ols

To a solution of 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (200mg, 963.67 μmol, 1 eq) in AcOH (5mL) was added 4-isopropyl-1H-pyrazol-5-amine (134.03mg, 963.67 μmol, 1 eq). The mixture was stirred at 120 ℃ for 0.5 hour. LCMS showed complete consumption of the starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give the crude product 5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-ol (300mg, 639.05 μmol, 66.31% yield, 58% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.79(m，1H)，8.63-8.67(m，1H)，8.09-8.06(m，1H)，7.87(m，1H)，6.06(m，1H)，3.26-3.25(m，1H)，2.75-2.70(m，1H)，1.30(d，J＝6.8Hz，3H)，1.15-1.09(m，3H)；ES-LCMS m/z 567.0[2M+Na]⁺。

Step 5: 7-chloro-5- (5-fluoropyridin-3-yl) -3-isopropylpyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-fluoropyridin-3-yl) -3-isopropylpyrazolo [1, 5-a]Pyrimidin-7-ol (300mg, 639.05. mu. mol, 1 eq.) in POCl₃(4.95g, 32.28mmol, 3mL, 50.52 equiv.) the solution was stirred at 110 ℃ for 3 hours. LC-MS showed no starting material remaining and 67% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure, then diluted with DCM (20mL × 2) and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 2/5, TLC: PE/EtOAc: 1/1, R_f0.64) to yield the product 7-chloro-5- (5-fluoropyridin-3-yl) -3-isopropylpyrazolo [1, 5-a) as a yellow solid]Pyrimidine (140mg, 385.25 μmol, 60.28% yield, 80% purity).¹H NMR(400MHz，CDCl₃)δppm 9.10(s，1H)，8.61-8.60(m，1H)，8.22-8.14(m，2H)，7.41-7.27(m，1H)，3.47-3.38(m，1H)，1.48-1.44(m，6H)；ES-LCMS m/z 291.0，293.0[M+H]⁺。

Step 6: n- (2- (1H-indol-3-yl) ethyl) -5- (5-fluoropyridin-3-yl) -3-isopropylpyrazolo [1, 5-a]Pyrimidine-7-amine (I-2)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (80mg, 220.14. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (52.90mg, 330.21. mu. mol, 1.5 eq) in i-PrOH (3mL) was added DIEA (85.36mg, 660.42. mu. mol, 115.03. mu.L, 3.0 eq). The mixture was stirred at 50 ℃ for 3 hours. LCMS showed no starting material remaining and 92% of desired compound was detected. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic condition and apparatus: DC/Feilomen Kinetex XB-C18150mm X30 mm, 5 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 47% to 57%/flow rate over 10 min: 25mL/min) and then lyophilized to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (88.45mg, 168.66 μmol, 76.61% yield, 99.89% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝2.2Hz，1H)，8.34(s，1H)，8.15(s，1H)，7.55(d，J＝8.6Hz，1H)，7.43(d，J＝7.9Hz，1H)，7.07(d，J＝8.2Hz，1H)，6.94(s，1H)，6.86(t，J＝7.2Hz，1H)，6.72(t，J＝7.4Hz，1H)，5.71(s，1H)，3.95(t，J＝5.7Hz，2H)，3.17-3.12(m，3H)，1.26(d，J＝6.8Hz，6H)；ES-LCMS m/z 415.2[M+H]⁺。

Example 8

Synthesis I-10

The synthesis scheme is as follows:

step 1: n- [2- (2-nitroanilino) ethyl]Carbamic acid tert-butyl ester

To a solution of 1-fluoro-2-nitro-benzene (10g, 70.87mmol, 7.46mL, 1 eq.) and tert-butyl N- (2-aminoethyl) carbamate (11.35g, 70.87mmol, 11.13mL, 1 eq.) in DMF (50mL) was added K₂CO₃(15.67g, 113.39mmol, 1.6 equiv.). The mixture was stirred at 70 ℃ for 18 hours. TLC (PE/EtOAc ═ 5/1, R_f0.69) showed most of the starting material consumed. Subjecting the mixture to hydrogenation with H₂O (100mL) was diluted and extracted with EtOAc (100 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure. Coarse materialSilica gel column chromatography (PE/EtOAc: 1/0 to 5/4, TLC: PE/EtOAc: 5/1, R)_f0.69) to yield N- [2- (2-nitroanilino) ethyl group as orange solid]Tert-butyl carbamate (19g, 67.54mmol, 95.3% yield, 100% purity).¹H NMR(400MHz，CDCl₃)δppm8.19(d，J＝8.8Hz，1H)，7.47-7.43(m，1H)，6.95(d，J＝8.4Hz，1H)，6.69-6.65(m，1H)，3.50-3.43(m，4H)，1.46(s，9H)；ES-LCMS m/z 304.0[M+Na]⁺。

Step 2: n- [2- (2-Aminoanilino) ethyl]Carbamic acid tert-butyl ester

In N₂N- [2- (2-nitroanilino) ethyl group under atmosphere]To a solution of tert-butyl carbamate (5g, 17.77mmol, 1 eq) in MeOH (50mL) was added Pd/C (10%, 500 mg). The suspension is degassed and treated with H₂And purifying for 3 times. Mixing the mixture in H₂(15psi) at 2-9 deg.C for 18 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give crude N- [2- (2-aminoanilino) ethyl ] as a dark red oil]Tert-butyl carbamate (4.4g, 17.51mmol, 98.50% yield, crude) was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 6.70-6.67(m，2H)，6.62(d，J＝7.6Hz，1H)，6.56(t，J＝7.2Hz，1H)，3.29-3.26(m，2H)，3.18-3.17(m，2H)，1.42(s，9H)；ES-LCMS m/z 252.2[M+H]⁺。

Step 3: n- [2- (2-oxo-3H-benzimidazol-1-yl) ethyl]Carbamic acid tert-butyl ester

To the N- [2- (2-aminoanilino) ethyl group]To a solution of tert-butyl carbamate (2g, 7.96mmol, 1 eq) in THF (20mL) was added CDI (1.55g, 9.55mmol, 1.2 eq). The mixture was stirred at 80 ℃ for 2hThen (c) is performed. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The mixture was diluted with EtOAc (50mL), washed with citric acid solution (aq, 20 mL. times.2) over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 5/4, TLC: PE/EtOAc: 1/1, R_f0.31). The resulting yellowish oil was diluted with 1N HCl solution (5mL), filtered and the solid collected. The solid was wet-milled with isopropyl ether (20mL), filtered and the product N- [2- (2-oxo-3H-benzimidazol-1-yl) ethyl was collected as a white solid]Tert-butyl carbamate (1.63g, 5.73mmol, 72.0% yield, 97.52% purity).¹H NMR(400MHz，CD₃OD)δppm 7.13-7.01(m，4H)，3.93(t，J＝6.0Hz，2H)，3.35-3.31(m，2H)，1.29，1.17(s，9H)；ES-LCMS m/z 300.1[M+H]⁺。

Step 4: 3- (2-aminoethyl) -1H-benzimidazol-2-one

To N- [2- (2-oxo-3H-benzimidazol-1-yl) ethyl at 0 DEG C]To a solution of tert-butyl carbamate (646.02mg, 2.27mmol, 1 eq) in DCM (10mL) was added HCl/1, 4-dioxane (4M, 5.00mL, 8.80 eq) dropwise. After the addition, the mixture was stirred at 4-12 ℃ for 1 hour. LC-MS showed most of the starting material consumption. The reaction mixture was concentrated under reduced pressure to give crude 3- (2-aminoethyl) -1H-benzimidazol-2-one (400mg, 1.87mmol, 82.4% yield, HCl salt) as a white solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.18-7.17(m，1H)，7.11-7.08(m，3H)，4.19-4.16(m，2H)，3.31-3.28(m，2H)；ES-LCMS m/z 178.1[M+H]⁺。

Step 5: 3- [2- [ (2-chloro-9-isopropyl-purin-6-yl) amino group]Ethyl radical]-1H-benzimidazol-2-one

To a solution of 2, 6-dichloro-9-isopropyl-purine (200mg, 827.24 μmol, 1 eq) in isopropanol (10mL) was added DIEA (427.65mg, 3.31mmol, 576.35 μ L, 4.0 eq) and 3- (2-aminoethyl) -1H-benzimidazol-2-one (265.13mg, 1.24mmol, 1.5 eq, HCl). The mixture was stirred at 50 ℃ for 5 hours. LC-MS showed most of the starting material consumption. The reaction mixture was concentrated under reduced pressure to remove isopropanol. The residue is washed with H₂O (20mL) was diluted and extracted with DCM/isopropanol (20mL × 3, v/v ═ 3/1). The combined organic layers were passed over anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. The residue was chromatographed over silica gel (DCM/MeOH-1/0 to 10/1, TLC: DCM/MeOH-10/1, R_f0.15) to give 3- [2- [ (2-chloro-9-isopropyl-purin-6-yl) amino group as a white solid]Ethyl radical]-1H-benzimidazol-2-one (280mg, 730.45 μmol, 88.3% yield, 97% purity);¹H NMR(400MHz，CD₃OD)δppm8.14(s，1H)，7.28(d，J＝7.2Hz，1H)，7.06-6.97(m，3H)，4.78-4.75(m，1H)，4.22(t，J＝6.0Hz，2H)，3.97(t，J＝6.0Hz，2H)，1.62(d，J＝6.4Hz，6H)；ES-LCMS m/z 372.1，374.0[M+H]⁺。

step 6: 3- [2- [ [2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-yl ] amine]Amino group]Ethyl radical]-1H-benzimidazol-2-one (I-10)

To 3- [2- [ (2-chloro-9-isopropyl-purin-6-yl) amino group]Ethyl radical]-1H-benzimidazol-2-one (100mg, 260.88 μmol, 1 eq) and (5-fluoro-3-pyridinyl) boronic acid (73.52mg, 521.75 μmol, 2 eq) in 1, 4-dioxane (2mL) and H₂Pd (dppf) Cl was added to a solution of O (0.5mL)₂(9.54mg, 13.04. mu. mol, 0.05 eq.) and Cs₂CO₃(255.00mg, 782.63. mu. mol, 3 equiv.). Mixing the mixture with N₂Purify for 3 minutes and stir at 120 ℃ for 0.5 hour under microwave. LC-MS showed most of the starting material was consumed and the desired compound was detected. The reaction mixture was subjected to reduced pressureAnd (5) concentrating. The residue was diluted with EtOAc/MeOH/THF (10mL/10mL/10mL) and stirred for 5 min, filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: DC/Philomo KinetexXB-C18150 mm X30 mm, 5 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 20% to 50% per flow rate over 12 minutes: 25mL/min) and then lyophilized to give 3- [2- [ [2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-yl ] as a pale yellow solid]Amino group]Ethyl radical]-1H-benzimidazol-2-one (11.08mg, 21.29 μmol, 8.16% yield, 97.1% purity, 2HCl salt, yield 10.85 mg).¹H NMR(400MHz，CD₃OD)δppm 9.51-9.27(m，2H)，9.15-8.90(m，2H)，7.23(d，J＝7.8Hz，1H)，6.92(t，J＝7.8Hz，1H)，6.75(t，J＝7.5Hz，1H)，6.63(d，J＝7.8Hz，1H)，5.19-4.97(m，1H)，4.30-4.15(m，4H)，1.67(d，J＝6.8Hz，6H)；ES-LCMSm/z 433.1[M+H]⁺。

Example 9

Synthesis I-19

The synthesis scheme is as follows:

step 1: n- (2- (1H-indol-3-yl) ethyl) -7-bromo-2-chloropyrrolo [2, 1-f][1，2，4]Triazine-4-amines

To 7-bromo-2, 4-dichloro-pyrrolo [2, 1-f][1，2，4]To a solution of triazine (100mg, 374.66. mu. mol, 1 eq) in i-PrOH (3mL) was added DIEA (242.10mg, 1.87mmol, 326.29. mu.L, 5.0 eq) and 2- (1H-indole)-3-yl) ethylamine (78.03mg, 487.06 μmol, 1.3 equiv). The mixture was stirred at 50 ℃ for 1.5 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. Subjecting the reaction mixture to hydrogenation with H₂O (15mL) was diluted and extracted with DCM (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (b) ((b))

Silica flash column, eluent 20-25% ethyl acetate/petroleum ether gradient, 55mL/min) to obtain 7-bromo-2-chloro-N- [2- (1H-indol-3-yl) ethyl as a white solid]Pyrrolo [2, 1-f][1，2，4]Triazin-4-amine (140mg, 354.78 μmol, 94.7% yield).¹H NMR(400MHz，CDCl₃)δppm 8.08(s，1H)，7.66(d，J＝7.7Hz，1H)，7.42(d，J＝8.2Hz，1H)，7.26-7.23(m，1H)，7.19-7.14(m，1H)，7.09(d，J＝2.2Hz，1H)，6.59(d，J＝4.6Hz，1H)，6.40(br s，1H)，5.55(m，1H)，3.99(q，J＝6.2Hz，2H)，3.17(t，J＝6.6Hz，2H)；ES-LCMS m/z 389.9，392.0[M+H]⁺。

Step 2: n- (2- (1H-indol-3-yl) ethyl) -2-chloro-7- (prop-1-en-2-yl) pyrrolo [2, 1-f][1，2，4]Triazine-4-amines

To the reaction solution of 7-bromo-2-chloro-N- [2- (1H-indol-3-yl) ethyl]Pyrrolo [2, 1-f][1，2，4]Triazin-4-amine (90mg, 228.07 μmol, 1 eq.) in 1, 4-dioxane (2mL) and H₂To a solution of O (0.5mL) was added 2-isopropenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane (38.33mg, 228.07. mu. mol, 1.0 eq.), Pd (dppf) Cl₂(33.38mg, 45.61. mu. mol, 0.2 eq.) and Cs₂CO₃(222.93mg, 684.22. mu. mol, 3.0 equiv.). The mixture was stirred at 80 ℃ for 30 minutes under microwave. LCMS showed 67% desired product was found. The reaction mixture was filtered and the filtrate was taken up with H₂O (15mL) was diluted, followed by extraction with EtOAc (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (b) ((b))

12g

Purifying with silica gel flash column, eluent of 10-13% ethyl acetate/petroleum ether gradient, 50mL/min) to obtain colorless oily 2-chloro-N- [2- (1H-indol-3-yl) ethyl]-7-isopropenyl-pyrrolo [2, 1-f][1，2，4]Triazin-4-amine (65mg, 144.10. mu. mol, 63.2% yield).¹H NMR(400MHz，CDCl₃)δppm 8.08(br s，1H)，7.67(d，J＝7.7Hz，1H)，7.41(d，J＝8.2Hz，1H)，7.26-7.23(m，1H)，7.20-7.14(m，1H)，7.09(d，J＝2.2Hz，1H)，6.58(d，J＝4.6Hz，1H)，6.36(br s，1H)，6.25(s，1H)，5.50(br s，1H)，5.35(s，1H)，4.02-3.96(m，2H)，3.16(t，J＝6.5Hz，2H)，2.20(s，3H)；ES-LCMS m/z 352.0，354.0[M+H]⁺。

Step 3: n- (2- (1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -7- (prop-1-en-2-yl) pyrrolo [2, 1-f][1，2，4]Triazine-4-amines

To 2-chloro-N- [2- (1H-indol-3-yl) ethyl]-7-isopropenyl-pyrrolo [2, 1-f][1，2，4]Triazin-4-amine (65mg, 144.10 μmol, 1 eq) in 1, 4-dioxane (3mL) and H₂To a solution in O (1mL) was added (5-fluoro-3-pyridyl) boronic acid (30.46mg, 216.15. mu. mol, 1.5 eq.), Pd (dppf) Cl₂(15.82mg, 21.62. mu. mol, 0.15 eq.) and Cs₂CO₃(140.85mg, 432.31. mu. mol, 3.0 equiv.). The mixture was stirred under microwave at 110 ℃ for 0.5 hour. LCMS showed about 72% desired product detected. The reaction mixture is filtered andh for filtrate₂O (15mL) was diluted, followed by extraction with EtOAc (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc ═ 1.5/1, R)_f0.6) to yield 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-7-isopropenyl-pyrrolo [2, 1-f][1，2，4]Triazin-4-amine (40mg, 76.61. mu. mol, 53.2% yield).¹H NMR(400MHz，CDCl₃)δppm 9.29(s，1H)，8.38(d，J＝2.9Hz，1H)，8.23-8.16(m，1H)，8.05(br s，1H)，7.55(d，J＝7.7Hz，1H)，7.30-7.27(m，1H)，7.30-7.24(m，1H)，7.14-7.09(m，1H)，7.07-7.02(m，1H)，6.95(d，J＝2.2Hz，1H)，6.54(d，J＝4.6Hz，1H)，6.34-6.23(m，2H)，5.45(t，J＝5.6Hz，1H)，5.27(s，1H)，3.95(q，J＝6.5Hz，2H)，3.09(t，J＝6.6Hz，2H)，2.15(s，3H)；ES-LCMS m/z 413.1[M+H]⁺。

Step 4: n- (2- (1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -7-isopropylpyrrolo [2, 1-f][1，2，4]Triazine-4-amine (I-19)

To 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]-7-isopropenyl-pyrrolo [2, 1-f][1，2，4]To a solution of triazin-4-amine (30mg, 57.46 μmol, 1 eq) in MeOH (8mL) was added Pd/C (10%, 40 mg). The suspension is degassed under vacuum and treated with H₂Purifying several times, and then adding the mixture in H₂(15psi) at 20 ℃ for 0.5 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Kinetex XB-C18150mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 75% -95%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a white solid]-7-isopropyl-pyrrolo [2, 1-f][1，2，4]Triazin-4-amines (6.75)mg, 12.89 μmol, 17.72% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.05(s，1H)，8.76(br s，1H)，8.42(d，J＝8.8Hz，1H)，7.63(d，J＝7.3Hz，1H)，7.23(d，J＝7.7Hz，1H)，7.06-6.97(m，3H)，6.92(d，J＝4.0Hz，1H)，6.54(d，J＝4.0Hz，1H)，4.01(t，J＝7.1Hz，2H)，3.55(d，J＝7.0，14.1Hz，1H)，3.17(t，J＝6.8Hz，2H)；ES-LCMS m/z 415.1[M+H]⁺。

Example 10

Synthesis I-22

Step 1: 2- (chloromethyl) imidazo [1, 2-a]Pyridine compound

To a solution of pyridin-2-amine (5g, 53.13mmol, 1 equiv.) in DME (10mL) was added 1, 3-dichloropropan-2-one (13.49g, 106.25mmol, 2 equiv.). The mixture was stirred at 20 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (50mL) and then stirred at 90 ℃ for 16 h. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was concentrated and the residue was hydrolyzed with saturated sodium carbonate solution (100 mL). The reaction mixture was extracted with DCM (60 mL. times.3), combined, and passed through Na₂SO₄Drying, filtering, and concentrating under reduced pressure to give 2- (chloromethyl) imidazo [1, 2-a]Pyridine (8.85g, crude), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.14(d，J＝6.8Hz，1H)，7.70-7.59(m，2H)，7.26-7.20(m，1H)，6.85(t，J＝6.8Hz，1H)，4.79(s，2H)；ES-LCMS m/z 167.2，169.5[M+H]⁺。

Step 2: 2-imidazo [1, 2-a ]]Pyridin-2-ylacetonitrile

2- (chloromethyl) imidazo [1, 2-a]A mixture of pyridine (3g, 18.01mmol, 1 equiv.) and KCN (1.52g, 23.41mmol, 1.3 equiv.) in DMSO (50mL) was degassed and treated with N₂And purifying for 3 times. Then the mixture is added to N₂Stirred under an atmosphere at 80 ℃ for 16 hours. LC-MS showed 27% starting material remaining and 17% of the desired compound was detected. The reaction mixture was quenched with water (200mL) followed by extraction with EtOAc (100 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica chromatography (DCM/MeOH ═ 1/0 to 10/1, TLC: DCM/MeOH ═ 10/1, R_f0.49) to give 2-imidazo [1, 2-a) as a yellow solid]Pyridin-2-ylacetonitrile (200mg, 890.75. mu. mol, 5.0% yield, 70% purity).¹H NMR(400MHz，DMSO-d₆)δppm 8.59-8.49(m，1H)，7.92(s，1H)，7.55-7.49(m，1H)，7.28-7.11(m，1H)，6.92-6.85(m，1H)，4.12(s，3H)；ES-LCMS m/z 158.1[M+H]⁺。

Step 3: 2-imidazo [1, 2-a ]]Pyridin-2-ylethylamine

To 2-imidazo [1, 2-a ]]Pyridine-2-ylacetonitrile (100mg, 445.37. mu. mol, 1 eq.) in THF (5mL) was added BH₃-Me₂S (10M, 445.37. mu.L, 10 equiv.). The mixture was stirred at 80 ℃ for 2 hours until LC-MS showed complete consumption of the starting material and the desired MS was detected. The reaction mixture was quenched with MeOH at 10 deg.C, followed by stirring for 1 hour at 80 deg.C. The resulting mixture was concentrated under reduced pressure to give 2-imidazo [1, 2-a as a white solid]Pyridin-2-ylethylamine (71.8mg, crude) was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.82-8.61(m，1H)，8.21-8.06(m，1H)，8.02-7.61(m，2H)，7.52-7.21(m，1H)，3.61-3.38(m，2H)，3.35-3.28(m，2H)；ES-LCMS m/z 162.1[M+H]⁺。

Step (ii) of4: 2- (5-fluoro-3-pyridinyl) -N- (2-imidazo [1, 2-a)]Pyridin-2-ylethyl) -9-isopropyl-purin-6-amine (I-22)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 164.55 μmol, 1 eq) in i-PrOH (5mL) was added DIEA (106.33mg, 822.73 μmol, 143.31 μ L, 5 eq) and 2-imidazo [1, 2-a ]]Pyridin-2-ylethylamine (71.8mg, 445.40 μmol, 2.71 eq). The mixture was stirred at 90 ℃ for 16 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenetdoor Kinetex XB-C18150mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 10% -38%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- (2-imidazo [1, 2-a) as a yellow solid]Pyridin-2-ylethyl) -9-isopropyl-purin-6-amine (22.38mg, 41.71 μmol, 25.4% yield, 98% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.62(s，1H)，9.36(s，1H)，9.18-8.90(m，2H)，8.71(d，J＝6.2Hz，1H)，8.17(s，1H)，7.96-7.76(m，2H)，7.43(t，J＝6.8Hz，1H)，5.16(s，1H)，4.30(s，2H)，3.43(t，J＝6.4Hz，2H)，1.75(d，J＝6.8Hz，6H)；ES-LCMS m/z 417.1[M+H]⁺。

Example 11

Synthesis of I-20

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-2-iodo-pyrimidine

To a solution of 4, 6-dichloropyrimidin-2-amine (5g, 30.49mmol, 1 eq) in acetonitrile (40mL) was added CH₂I₂(8.98g, 33.54mmol, 2.71mL, 1.1 equiv.) and isoamyl nitrite (17.86g, 152.45mmol, 20.53mL, 5.0 equiv.). The mixture was stirred at 80 ℃ for 3.5 hours. LCMS showed complete consumption of starting material and a major peak was detected. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The residue was diluted with EtOAc (50mL) and Na₂SO₃The solution (50 mL. times.2) was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 100/1 to 10/1, TLC: PE/EtOAc: 3/1, R_f0.90) to yield 4, 6-dichloro-2-iodo-pyrimidine as a white solid (6.32g, 22.60mmol, 74.1% yield, 98.3% purity).¹H NMR(400MHz，CD₃OD)δppm 7.79-7.76(m，1H)；ES-LCMS m/z 274.7，276.8[M+H]⁺。

Step 2: 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine

4, 6-dichloro-2-iodo-pyrimidine (500mg, 1.79mmol, 1 eq.), 5-fluoro-3-pyridinyl) boronic acid (251.96mg, 1.79mmol, 1 eq.), and Na were added₂CO₃(568.55mg, 5.36mmol, 3.0 equiv.) and Pd (dppf) Cl₂(130.84mg, 178.81. mu. mol, 0.1 eq.) of 1, 4-dioxane (6mL) and water (1.2mL) were placed in a microwave tube. The sealed tube was heated at 80 ℃ for 30 minutes under microwave. LCMS showed 53% desired compound detected. The reaction mixture was diluted with EtOAc (30mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.80) to yield 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine as a white solid (165mg, 676.08 μmol, 37.8% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 9.36(s，1H)，8.67(d，J＝2.9Hz，1H)，8.52-8.44(m，1H)，7.76(s，1H)；ES-LCMS m/z 243.9，245.9[M+H]⁺。

Step 3: 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amines

To a solution of 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine (165mg, 676.08 μmol, 1.0 eq) in i-PrOH (10mL) was added DIEA (262.13mg, 2.03mmol, 353.28 μ L, 3.0 eq) and 2- (1H-indol-3-yl) ethylamine (108.32mg, 676.08 μmol, 1.0 eq). The mixture was stirred at 50 ℃ for 3 hours. LCMS showed 88% desired compound detected. The reaction mixture was concentrated to give 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ester as a brown oil]Pyrimidin-4-amine (240mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 9.31-9.23(m，1H)，8.86-8.20(m，2H)，8.11(s，1H)，7.92(s，1H)，7.57(dd，J＝7.8，11.8Hz，1H)，7.42-7.29(m，1H)，7.26-7.17(m，1H)，7.13-6.93(m，2H)，6.55(s，1H)，3.83-3.70(m，2H)，3.04-2.95(m，2H)；ES-LCMS m/z 368.0，369.0[M+H]⁺。

Step 4: 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl]-N4-isopropyl-pyrimidine-4, 6-diamine (I-20)

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amine (60mg, 140.62. mu. mol, 1.0 equiv.), propan-2-amine (1.03g, 17.46mmol, 1.5mL, 124.16 equiv.), and DIEA (90.87mg, 703.10. mu. mol, 122.46. mu.L, 5.0 equiv.) were placed in a microwave tube in i-PrOH (3 mL). The sealed tube was heated at 125 ℃ for 6 hours under microwave. LCMS showed 66% desired compound detected. The reaction mixture was concentrated under reduced pressure to remove i-PrOH. The residue is passed throughPreparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 10min) and lyophilizing the desired fractions to give 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl ] as a yellow solid]-N4-isopropyl-pyrimidine-4, 6-diamine (19.11mg, 38.19 μmol, 27.16% yield, 99.90% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm8.99(s，1H)，8.75(d，J＝2.6Hz，1H)，8.18(s，1H)，7.62(d，J＝7.9Hz，1H)，7.31(s，1H)，7.17-6.98(m，4H)，3.73(s，2H)，3.13(t，J＝6.4Hz，3H)，1.21(s，6H)；ES-LCMS m/z391.3[M+H]⁺。

Example 12

Synthesis I-15

The synthesis scheme is as follows:

step 1: 1-imidazo [1, 2-a ]]pyridin-3-yl-N, N-dimethyl-methylamines

Imidazo [1, 2-a)]A mixture of pyridine (500mg, 4.23mmol, 1 eq), N-methyl methylamine (414.16mg, 5.08mmol, 1.2 eq, HCl) and HCHO (412.16mg, 5.08mmol, 378.13. mu.L, 37% in water, 1.2 eq) in N-BuOH (5mL) was degassed and treated with N₂And purifying for 3 times. Then the mixture is added to N₂Stirred at 120 ℃ for 3 hours under an atmosphere. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 1-imidazo [1, 2-a ] as a yellow solid]pyridin-3-yl-N, N-dimethyl-methylamine (742mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.85(d，J＝6.8Hz，1H)，8.27(d，J＝6.8Hz，1H)，7.85-7.73(m，2H)，7.68(s，1H)，4.41(s，2H)，2.64(s，6H)；ES-LCMS m/z176.2[M+H]⁺。

Step 2: 2-imidazo [1, 2-a ]]Pyridin-3-ylacetonitrile

To 1-imidazo [1, 2-a ]]To a solution of pyridin-3-yl-N, N-dimethyl-methylamine (742.00mg, 4.23mmol, 1 eq) in THF (6mL) was added dimethyl sulfate (534.10mg, 4.23mmol, 401.58 μ L, 1 eq) dropwise. The resulting mixture was heated at 70 ℃ for 30 minutes. The solvent was removed and the residue was dissolved in H₂O (5 mL). KCN (303.30mg, 4.66mmol, 1.1 equiv.) was added to the mixture and the mixture was heated at 110 ℃ for 3 hours. LC-MS showed 27% starting mixture remained and 33% of the desired compound was detected. The reaction mixture was purified by addition of NaHCO₃Quenched (30mL), followed by extraction with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (DCM/MeOH ═ 1/0 to 10/1, TLC: DCM/MeOH ═ 10/1, R_f0.48) to yield 2-imidazo [1, 2-a) as a yellow solid]Pyridin-3-ylacetonitrile (900mg, 50.4% yield, 87.6% purity).¹H NMR(400MHz，CDCl₃)δppm 8.39(d，J＝6.8Hz，1H)，7.63(d，J＝9.0Hz，1H)，7.58(s，1H)，7.32(ddd，J＝1.1，6.7，9.0Hz，1H)，7.06(dt，J＝0.9，6.8Hz，1H)，4.47(s，2H)；ES-LCMS m/z 158.1[M+H]⁺。

Step 3: 2-imidazo [1, 2-a ]]Pyridin-3-ylethylamine

To 2-imidazo [1, 2-a ]]Pyridin-3-ylacetonitrile (80mg, 421.70. mu. mol, 1 eq) to a solution in THF (8mL) BH was added dropwise₃-Me₂S (10M, 421.70. mu.L, 10 equiv.).The mixture was stirred at 70 ℃ for 2 hours. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was quenched by the slow addition of MeOH (20mL) and HCl/MeOH (4M, 0.1mL), followed by stirring at 70 ℃ for 3 hours. The mixture was concentrated under reduced pressure to give 2-imidazo [1, 2-a ] as a colorless oil]Pyridin-3-ylethylamine (68mg, crude) was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.48-8.43(m，1H)，7.89-7.65(m，1H)，7.69-7.44(m，1H)，7.46(s，1H)，7.26-7.17(m，1H)，3.17-3.10(m，2H)，3.09-3.01(m，2H)；ES-LCMS m/z 162.1[M+H]⁺。

Step 4: 6-chloro-9-isopropyl-purin-2-amine

To a solution of 6-chloro-9H-purin-2-amine (27g, 159.22mmol, 1 eq) in DMSO (220mL) was added K₂CO₃(66.02g, 477.67mmol, 3 equiv.) and 2-bromopropane (97.92g, 796.12mmol, 74.75mL, 5 equiv.). The mixture was stirred at 15 ℃ for 88 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was quenched by the addition of water (1000mL) followed by extraction with EtOAc (500 mL. times.3). The combined organic layers were washed with water (100 mL. times.2), brine (100mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue as a yellow solid. To the residue was added PE/EtOAc (5/1, 500mL), followed by stirring at 15 ℃ for 2 h. The slurry was filtered and the filter cake was rinsed with PE (30mL × 2). The solid was collected and dried in vacuo to give crude 6-chloro-9-isopropyl-purin-2-amine (28g, 130.97mmol, 82.2% yield, 99% purity) as a light yellow solid, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.84(s，1H)，5.20(s，2H)，4.74-4.64(m，1H)，1.57(d，J＝6.8Hz，6H)；ES-LCMS m/z 212.0，214.0[M+H]⁺。

Step 5: 6-chloro-2-iodo-9-isopropyl-purine

To 6-chloro-9-isopropyl-purin-2-amine (10g, 46.78mmol, 1 eq.), I₂(11.87g, 46.78mmol, 1 equiv.), CuI (8.91g, 46.78mmol, 1 equiv.), and CH₂I₂(125.28g, 467.75mmol, 37.73mL, 10 equiv.) to a mixture of THF (400mL) was added isoamyl nitrite (16.44g, 140.33mmol, 18.89mL, 3 equiv.). The mixture was stirred at 70 ℃ for 3 hours. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc (100mL × 2). The filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (300mL) and Na₂SO₃(100mL), brine (100mL), washed over Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.58) to yield 6-chloro-2-iodo-9-isopropyl-purine as a yellow solid (12.5g, 31.39mmol, 67.1% yield, 81% purity).¹HNMR(400MHz，CDCl₃)δppm 8.09(s，1H)，4.98-4.82(m，1H)，1.63(d，J＝7.0Hz，6H)；ES-LCMSm/z 322.8，324.8[M+H]⁺。

Step 6: 6-chloro-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purine

Containing 6-chloro-2-iodo-9-isopropyl-purine (3g, 8.28mmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (1.17g, 8.28mmol, 1 eq), Pd (dppf) Cl₂(302.86mg, 413.91. mu. mol, 0.05 eq.) and Cs₂CO₃(2.70g, 8.28mmol, 1 equiv.) of 1, 4-dioxane (50mL) and H₂O (10mL) degassed and then N₂The mixture was heated at 80 ℃ for 16 hours. LCMS showed complete consumption of the starting material. The reaction mixture is poured into H₂O (100mL), followed by extraction with EtOAc (80 mL. times.3). The organic phase was washed with brine (30mL) and over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.58) to yield 6-chloro-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purine as a yellow solid (1.71g, 5.63mmol, 68.0% yield, 96% purity).¹H NMR(400MHz，CDCl₃)δppm 9.54(s，1H)，8.58(d，J＝2.8Hz，1H)，8.48(td，J＝2.1，9.5Hz，1H)，8.21(s，1H)，5.10-4.93(m，1H)，1.73(d，J＝6.8Hz，6H)；ES-LCMS m/z292.0，294.0[M+H]⁺。

Step 7: 2- (5-fluoro-3-pyridinyl) -N- (2-imidazo [1, 2-a)]Pyridin-3-ylethyl) -9-isopropyl-purin-6-amine (I-15)

To 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 164.55 μmol, 1 eq.) and 2-imidazo [1, 2-a ]]To a solution of pyridin-3-ylethylamine (68mg, 421.83 μmol, 2.56 equivalents) in i-PrOH (5mL) was added DIEA (106.33mg, 822.73 μmol, 143.31 μ L, 5 equivalents). The mixture was stirred at 95 ℃ for 16 hours. LC-MS showed complete consumption of the starting material and the desired MS was detected (M/z ═ M/2+ H). The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Pheroma Kinetex XB-C18150mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 7% -37%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- (2-imidazo [1, 2-a) as a yellow solid]Pyridin-3-ylethyl) -9-isopropyl-purin-6-amine (34.09mg, 63.53 μmol, 38.6% yield, 98% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.50(s，1H)，9.33(s，1H)，9.03-8.88(m，3H)，8.00(s，1H)，7.96-7.88(m，1H)，7.86-7.79(m，1H)，7.54(t，J＝6.8Hz，1H)，5.21-5.07(m，1H)，4.32(t，J＝6.2Hz，2H)，3.58(t，J＝6.3Hz，2H)，1.74(d，J＝6.6Hz，6H)；ES-LCMS m/z 416.9[M+H]⁺。

Example 13

Synthesis of I-1

The synthesis scheme is as follows:

step 1: 3-isopropyl-4-nitro-1H-pyrazole-5-carboxylic acid

Fuming HNO at 0 ℃ over 5 minutes₃(700.00mg, 11.11mmol, 0.5mL, 1.71 equiv.) and fuming H₂SO₄(1.88g, 18.76mmol, 1.02mL, 98% purity, 2.89 equiv.) to the stirred solution in an ice bath was added 3-isopropyl-1H-pyrazole-5-carboxylic acid (1g, 6.49mmol, 1 equiv.) portionwise. After the addition, the mixture was stirred at this temperature for 1 hour, followed by stirring at 100 ℃ for 6 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The mixture was poured into ice water (30g), the white precipitate was filtered and dried to give 3-isopropyl-4-nitro-1H-pyrazole-5-carboxylic acid (700mg, 3.20mmol, 49.36% yield, 91.1% purity) as a white solid.¹H NMR(400MHz，CD₃OD)δppm3.56(spt，J＝7.0Hz，1H)，1.35(d，J＝7.1Hz，6H)；ES-LCMS m/z 200.1[M+H]⁺。

Step 2: 3-isopropyl-4-nitro-1H-pyrazole-5-carboxamide

To a solution of 3-isopropyl-4-nitro-1H-pyrazole-5-carboxylic acid (700mg, 3.20mmol, 1 eq) in DCM (15mL) and DMF (0.1mL) was added oxalyl chloride (1.22g, 9.61mmol, 840.83 μ L, 3 eq) dropwise over 5 min. After the addition, the mixture was stirred at 15 ℃ for 1 hour, followed by concentration of the resulting mixture. The residue was dissolved in THF (10mL) and cooledTo 0 ℃. Dropwise addition of NH₃·H₂O (9.75g, 77.90mmol, 10.71mL, 28% purity, 24.33 equiv.). After the addition, the mixture was stirred at 15 ℃ for 1 hour. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (50mL) and extracted with EtOAc (50mL × 2). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave 3-isopropyl-4-nitro-1H-pyrazole-5-carboxamide (0.6g, 2.91mmol, 90.96% yield, 96.2% purity) as a white solid.¹HNMR(400MHz，CD₃OD)δppm 3.68-3.60(m，1H)，1.34(d，J＝6.8Hz，6H)；ES-LCMS m/z 199.1[M+H]⁺。

Step 3: 4-amino-3-isopropyl-1H-pyrazole-5-carboxamide

In N₂To a mixture of 3-isopropyl-4-nitro-1H-pyrazole-5-carboxamide (600mg, 2.91mmol, 1 eq) in MeOH (20mL) was added Pd/C (10%, 0.1g) next. The suspension is degassed under vacuum and treated with H₂The purification is carried out for several times. Mixing the mixture in H₂(15psi) at 15 ℃ for 3 hours. TLC (PE/EA: 1/1, R)_f0.1) showed complete consumption of the starting material. The reaction mixture was filtered and the filtrate was concentrated to give 4-amino-3-isopropyl-1H-pyrazole-5-carboxamide (500mg, 2.68mmol, 91.86% yield, 90% purity) as an off-white solid.¹H NMR(400MHz，CD₃OD)δppm 3.02(spt，J＝7.0Hz，1H)，1.27(d，J＝7.1Hz，6H)；ES-LCMS m/z 169.1[M+H]⁺。

Step 4: 3-isopropyl-1, 4-dihydropyrazolo [4, 3-d]Pyrimidine-5, 7-diones

To 4-amino-3-isopropyl-1H-pyrazole-5-carboxamide (500mg, 2.68mmol, 1)Eq) to a solution in DMF (10mL) CDI (477.20mg, 2.94mmol, 1.1 eq) was added and the mixture was stirred at 80 ℃ for 12 h. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated to give 3-isopropyl-1, 4-dihydropyrazolo [4, 3-d as a brown solid]Pyrimidine-5, 7-dione (550mg, crude).¹H NMR(400MHz，CD₃OD)δppm 3.22-3.13(m，1H)，1.30(d，J＝6.8Hz，6H)；ES-LCMS m/z 195.1[M+H]⁺。

Step 5: 5, 7-dichloro-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidines

3-isopropyl-1, 4-dihydropyrazolo [4, 3-d)]Pyrimidine-5, 7-dione (500mg, 2.57mmol, 1 eq) in POCl₃The solution in (10mL) was stirred at 100 ℃ for 2 hours. LC-MS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50mL), adjusted to pH 8 and extracted with EtOAc (50 mL. times.2). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (b) ((b))

Silica flash column, eluent 0-30% ethyl acetate/petroleum ether gradient, 15mL/min) to obtain 5, 7-dichloro-3-isopropyl-1H-pyrazolo [4, 3-d) as a white solid]Pyrimidine (110mg, 442.22. mu. mol, 17.18% yield, 92.9% purity).¹H NMR(400MHz，CDCl₃)δppm 10.39(br s，1H)，3.51(spt，J＝6.9Hz，1H)，1.47(d，J＝6.8Hz，6H)；ES-LCMS m/z 231.3，233.3[M+H]⁺。

Step 6: 5-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidin-7-amines

To 5, 7-dichloro-3-isopropyl-1H-pyrazolo [4, 3-d]To a solution of pyrimidine (110mg, 442.22. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (85.02mg, 530.67. mu. mol, 1.2 eq) in i-PrOH (5mL) was added DIEA (171.46mg, 1.33mmol, 231.08. mu.L, 3 eq). The mixture was stirred at 8 ℃ for 16 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 5-chloro-N- [2- (1H-indol-3-yl) ethyl ] as a brown solid]-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidin-7-amine (160mg, 392.29 μmol, 88.71% yield, 87% purity).¹H NMR(400MHz，CD₃OD)δppm 7.67(br s，1H)，7.35(d，J＝8.0Hz，1H)，7.14-7.08(m，2H)，7.04-6.98(m，1H)，3.94(q，J＝6.2Hz，2H)，3.43(brs，1H)，3.17(t，J＝7.2Hz，2H)，1.39(s，6H)；ES-LCMS m/z 355.2，357.1[M+H]⁺。

Step 7: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidine-7-amine (I-1)

In N₂Down to 5-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidin-7-amine (80mg, 196.15. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (33.17mg, 235.38. mu. mol, 1.2 eq), Cs₂CO₃(159.77mg, 490.37. mu. mol, 2.5 equiv.) in a mixture of 1, 4-dioxane (2mL) and water (0.5mL) Pd (dppf) Cl was added₂(7.18mg, 9.81. mu. mol, 0.05 eq.). Subjecting the mixture to microwave at N₂Then stirred at 120 ℃ for 30 minutes. LC-MS showed 82.5% product detected. The reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (20mL) and extracted with DCM (20mL × 2). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying and filteringAnd concentrated under reduced pressure to give a residue which is purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 40% -70%, 10 min). The desired fractions were lyophilized to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a yellow solid]-3-isopropyl-1H-pyrazolo [4, 3-d]Pyrimidin-7-amine (66.84mg, 123.15 μmol, 62.78% yield, 96.7% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm8.93(s，1H)，8.74(d，J＝2.6Hz，1H)，8.01(d，J＝8.8Hz，1H)，7.55(d，J＝7.9Hz，1H)，7.16(d，J＝7.9Hz，1H)，7.04(s，1H)，6.94(t，J＝7.7Hz，1H)，6.88-6.81(m，1H)，4.18(t，J＝6.6Hz，2H)，3.57(d，J＝7.0，13.9Hz，1H)，3.21(t，J＝6.6Hz，2H)，1.44(d，J＝7.1Hz，6H)；ES-LCMS m/z 415.9[M+H]⁺。

Example 14

Synthesis I-9

The synthesis scheme is as follows:

step 1: n, N-dimethyl-1- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) methylamines

To 1H-pyrrolo [2, 3-c ]]To a solution of pyridine (900mg, 7.62mmol, 1 eq) in N-BuOH (15mL) was added HCHO (680.06mg, 8.38mmol, 623.91. mu.L, 37% in water, 1.1 eq) and N-methylmethylamine hydrochloride (695.78mg, 8.53mmol, 1.12 eq). The mixture was stirred at 120 ℃ for 3 hours. TLC (DCM/MeOH ═ 10/1, R)_f＝0.06)Indicating complete consumption of starting material and detection of a major new spot. The reaction mixture was concentrated under reduced pressure to give N, N-dimethyl-1- (1H-pyrrolo [2, 3-c) as a yellow oil]Pyridin-3-yl) methylamine (1.85g, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm8.83(d，J＝1.1Hz，1H)，8.22(d，J＝5.7Hz，1H)，7.97(s，1H)，7.91(d，J＝0.7Hz，1H)，4.56(s，2H)，2.87(s，6H)；ES-LCMS m/z176.2[M+H]⁺。

Step 2: 2- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) acetonitrile

To N, N-dimethyl-1- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) methylamine (2.75g, 8.55mmol, 1 equiv) to a solution in THF (20mL) was added dimethyl sulfate (1.08g, 8.55mmol, 810.81 μ L, 1.0 equiv) dropwise. The resulting mixture was stirred at 70 ℃ for 30 minutes. The THF was removed and the residue was dissolved in water (15 mL). KCN (612.44mg, 9.40mmol, 1.1 equiv.) was added to the mixture and the mixture was stirred at 110 ℃ for 3 hours. LCMS showed complete consumption of the starting material and one major peak with the desired MS was detected. The reaction mixture was diluted with water (40mL) and extracted with EtOAc (45 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give 2- (1H-pyrrolo [2, 3-c) as a yellow solid]Pyridin-3-yl) acetonitrile (417.0mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.70(s，1H)，8.13(d，J＝5.8Hz，1H)，7.67(d，J＝5.8Hz，1H)，7.58(s，1H)，4.01(s，2H)；ES-LCMS m/z 158.1[M+H]⁺。

Step 3: 2- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) ethylamine

To 2- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) acetonitrile (417.0mg, 2.65mmol, 1 eq) in THF (20mL) was added BH₃-Me₂S (10M, 2.65mL, 10 equiv.). The mixture was stirred at 70 ℃ for 2 hours. LCMS showed complete consumption of starting material and a major peak was detected. MeOH (50mL) was added dropwise to the reaction mixture and it was stirred at 70 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give 2- (1H-pyrrolo [2, 3-c) as a yellow solid ]Pyridin-3-yl) ethylamine (423.9mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm8.71-8.59(m，1H)，8.08-8.00(m，1H)，7.73-7.64(m，1H)，7.63-7.53(m，1H)，3.09-2.92(m，4H)；ES-LCMS m/z 162.1[M+H]⁺。

Step 4: 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) ethyl]Purine-6-amine (I-9)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (49.35mg, 148.88. mu. mol, 1.0 equiv) in i-PrOH (5mL) was added DIEA (57.72mg, 446.64. mu. mol, 77.79. mu.L, 3.0 equiv) and 2- (1H-pyrrolo [2, 3-c ] o]Pyridin-3-yl) ethylamine (72.00mg, 446.64. mu. mol, 3.0 equiv). The mixture was stirred at 50 ℃ for 15 hours. LCMS showed 71% desired compound detected. The reaction mixture was concentrated under reduced pressure to remove i-PrOH. The residue was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [2, 3-c) as a yellow solid]Pyridin-3-yl) ethyl]Purin-6-amine (11.84mg, 21.76 μmol, 14.62% yield, 96.66% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.54(s，1H)，9.36(s，1H)，9.05-8.98(m，2H)，8.96(s，1H)，8.27-8.22(m，1H)，8.21-8.16(m，2H)，5.15(td，J＝6.7，13.6Hz，1H)，4.21(t，J＝6.4Hz，2H)，3.39(t，J＝6.7Hz，2H)，1.74(d，J＝6.8Hz，6H)；ES-LCMS m/z 417.0[M+H]⁺。

Example 15

Synthesis I-11

The synthesis scheme is as follows:

step 1: n- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -9-isopropyl-9H-purin-6-amine (I-11)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 150.83 μmol, 1 eq) in i-PrOH (2mL) was added DIEA (97.47mg, 754.17 μmol, 131.36 μ L, 5 eq) and 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (45.29mg, 150.83 μmol, 1 eq, oxalic acid). The mixture was stirred at 50 ℃ for 16 hours. LCMS showed 65% desired compound detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 10min) to yield N- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -2- (5-fluoropyridin-3-yl) -9-isopropyl-9H-purin-6-amine (53.81mg, 36.8% yield, 100% purity, 3HCl salt) as a light yellow solid.¹H NMR(400MHz，CD₃OD)δppm 9.36(s，1H)，8.85(s，1H)，8.76(s，1H)，8.61(d，J＝8.8Hz，1H)，6.95(d，J＝7.3Hz，1H)，6.49(t，J＝10.2Hz，1H)，5.11-4.99(m，1H)，4.03(s，2H)，3.08(t，J＝6.5Hz，2H)，2.31(s，3H)，1.70(d，J＝6.8Hz，6H)；ES-LCMS m/z466.0[M+H]⁺。

Example 16

Synthesis I-14

The synthesis scheme is as follows:

step 1: (2- (1H-indol-3-yl) ethyl) carbamic acid tert-butyl ester

To a solution of 2- (1H-indol-3-yl) ethylamine (2.8g, 17.48mmol, 1 eq) in anhydrous DCM (30mL) was added TEA (5.31g, 52.44mmol, 7.30mL, 3 eq) and (Boc)₂O (4.58g, 20.98mmol, 4.82mL, 1.2 equiv). The mixture was stirred at 15 ℃ for 3 hours. LCMS showed complete consumption of the starting material and one major peak with the desired MS was detected. Addition of H₂O (20mL), and the mixture was extracted with DCM (20 mL. times.3). The combined organic layers were washed with brine (20 mL. times.2) and dried over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 2/1, R_f0.45) to yield tert-butyl (2- (1H-indol-3-yl) ethyl) carbamate (3.55g, 13.50mmol, 77.2% yield, 99% purity) as a yellow solid.¹H NMR(400MHz，CDCl₃)δppm 8.13(br s，1H)，7.61(d，J＝7.9Hz，1H)，7.35(d，J＝8.2Hz，1H)，7.24-7.16(m，1H)，7.16-7.08(m，1H)，7.00(s，1H)，4.59(br s，1H)，3.47(q，J＝6.4Hz，2H)，2.96(t，J＝6.8Hz，2H)，1.46(s，9H)；ES-LCMS m/z 283.0[M+Na]⁺。

Step 2: (2- (1-methyl-1H-indol-3-yl) ethyl) carbamic acid tert-butyl ester

N- [2- (1H-indole) at 0 ℃ over 5 minutes-3-yl) ethyl]To a solution of tert-butyl carbamate (1.5g, 5.70mmol, 1 equiv.) in THF (30mL) was added NaH (456.30mg, 11.41mmol, 60% purity, 2.0 equiv.). After addition, the mixture was stirred at this temperature for 20 minutes, followed by dropwise addition of MeI (809.67mg, 5.70mmol, 355.12. mu.L, 1.0 equiv.) at 0 ℃. The resulting mixture was stirred at 10 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.49) indicates complete consumption of starting material and formation of two new spots. The reaction mixture was quenched by the addition of water (50mL) at 10 ℃ followed by extraction with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (20mL) and dried over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EA ═ 1/0 to 3/1, TLC: PE/EA ═ 3/1, R_f0.49) to yield N- [2- (1-methylindol-3-yl) ethyl ] ethyl as a colorless oil]Tert-butyl carbamate (900mg, 50.4% yield, 87.6% purity);¹H NMR(400MHz，CD₃OD)δppm 7.98(d，J＝7.8Hz，1H)，7.74-7.57(m，2H)，7.55-7.43(m，1H)，4.99(br s，1H)，4.13(s，3H)，3.89-3.81(m，2H)，3.32(t，J＝6.4Hz，2H)，1.82(s，9H)；ES-LCMS m/z 219.0[M-t-Bu+H]⁺。

step 3: 2- (1-methyl-1H-indol-3-yl) ethylamine

To N- [2- (1-methylindol-3-yl) ethyl]To a solution of tert-butyl carbamate (700mg, 2.24mmol, 1 eq) in DCM (20mL) was added HCl/MeOH (4M, 5mL, 8.95 eq). The mixture was stirred at 10 ℃ for 4 hours. TLC (EtOAc, R)_f0.0) indicates complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give crude 2- (1-methylindol-3-yl) ethylamine (500mg, crude, 2HCl) as a white solid, which was used in the next step without further purification.¹HNMR(400MHz，CD₃OD)δppm 7.58(d，J＝7.8Hz，1H)，7.36(d，J＝8.3Hz，1H)，7.20(t，J＝7.5Hz，1H)，7.14-7.04(m，2H)，3.78(s，3H)，3.27-3.19(m，2H)，3.15-3.07(m，2H)；ES-LCMSm/z 175.1[M+H]⁺。

Step 4: 2-chloro-9-isopropyl-N- (2- (1-methyl-1H-indol-3-yl) ethyl) -9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-purine (200mg, 827.24 μmol, 1 eq) in i-PrOH (10mL) was added DIEA (855.30mg, 6.62mmol, 1.15mL, 8 eq) and 2- (1-methylindol-3-yl) ethylamine (306.70mg, 992.69 μmol, 1.2 eq, 2 HCl). The mixture was stirred at 50 ℃ for 14 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove i-PrOH (10mL) and the residue was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/2, R_f0.62) to yield 2-chloro-9-isopropyl-N- [2- (1-methylindol-3-yl) ethyl as a colorless oil]Purin-6-amine (250mg, 81.9% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm8.48-8.19(m，2H)，7.73(d，J＝7.5Hz，1H)，7.37(d，J＝8.3Hz，1H)，7.25-6.94(m，3H)，4.70-4.58(m，1H)，3.77-3.64(m，5H)，3.06-2.91(m，2H)，1.50(d，J＝6.5Hz，6H)；ES-LCMSm/z 369.1，371.1[M+H]⁺。

Step 5: 2- (5-Fluoropyridin-3-yl) -9-isopropyl-N- (2- (1-methyl-1H-indol-3-yl) ethyl) -9H-purin-6-amine (I-14)

2-chloro-9-isopropyl-N- [2- (1-methylindol-3-yl) ethyl]Purine-6-amine (100mg, 271.10. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (95.50mg, 677.76. mu. mol, 2.5 eq), Pd (dppf) Cl₂(19.84mg, 27.11. mu. mol, 0.1 equiv.) and Cs₂CO₃(264.99mg, 813.31. mu. mol, 3.0 equiv.) in 1, 4-dioxane (3mL) and H₂O (0.6mL) was placed in the microwave tube. The sealed tube was heated at 120 ℃ for 30 minutes under microwave. LC (liquid Crystal)MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50mL) over SiO₂And (5) filtering. The filter cake was rinsed with EtOAc (10 mL. times.2). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 10 minutes). Lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridyl) -9-isopropyl-N- [2- (1-methylindol-3-yl) ethyl ] ethyl]Purin-6-amine (53.81mg, 36.8% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃0D)δppm 9.36(s，1H)，9.11(br s，1H)，8.84(s，1H)，8.75(d，J＝8.8Hz，1H)，7.60(d，J＝7.9Hz，1H)，7.20(d，J＝7.9Hz，1H)，7.07(t，J＝7.5Hz，1H)，7.02-6.93(m，2H)，5.09(td，J＝6.8，13.6Hz，1H)，4.16-4.10(m，2H)，3.61(s，3H)，3.20(t，J＝6.6Hz，2H)，1.72(d，J＝6.8Hz，6H)；ES-LCMS m/z 430.2[M+H]⁺。

Example 17

Synthesis I-7

The synthesis scheme is as follows:

step 1: n, N-dimethyl-1- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) methylamines

To 1H-pyrrolo [3, 2-b ]]To a solution of pyridine (500mg, 4.23mmol, 1 eq) in N-BuOH (5mL) was added HCHO (377.65mg, 4.65mmol, 346.47. mu.L, 37% in water, 1.1 eq) and N-methyl methylamine (379.43mg, 4.65mmol, 1.1 eq, HCl salt). The mixture was stirred at 120 ℃ for 3 hours. LC-MS displayThe starting material was completely consumed and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give N, N-dimethyl-1- (1H-pyrrolo [3, 2-b ] as a yellow solid]Pyridin-3-yl) methylamine (559.7mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.32(dd，J＝1.1，4.6Hz，1H)，7.80(d，J＝8.3Hz，1H)，7.56(s，1H)，7.16(dd，J＝4.8，8.3Hz，1H)，3.80(s，2H)，2.28(s，6H)；ES-LCMS m/z 176.1[M+H]⁺。

Step 2: 2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) acetonitrile

To N, N-dimethyl-1- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) methylamine (200.00mg, 1.14mmol, 1 equiv) to a solution in THF (1.5mL) was added dimethyl sulfate (143.96mg, 1.14mmol, 108.24 μ L, 1.0 equiv) dropwise. The resulting mixture was stirred at 70 ℃ for 30 minutes. The solvent was removed and the residue was dissolved in water (1.2 mL). KCN (81.76mg, 1.26mmol, 1.1 equiv.) was added to the mixture and the mixture was stirred at 110 ℃ for 3 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (15 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give 2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) acetonitrile (131.7mg, 662.72 μmol, 58.1% yield, 79.1% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.37-8.29(m，1H)，7.87-7.78(m，1H)，7.64-7.51(m，1H)，7.25-7.14(m，1H)，4.01(d，J＝0.9Hz，2H)；ES-LCMS m/z 158.1[M+H]⁺。

Step 3: 2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethylamine

To 2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) acetonitrile (131.70mg, 662.72. mu. mol, 1 eq) to a solution in THF (10mL) was added BH dropwise₃-Me₂S(1mL，10M Me₂S solution). The reaction mixture was stirred at 70 ℃ for 2 hours. LC-MS showed complete consumption of starting material and one major peak was detected. MeOH (30mL) was added dropwise and the mixture was stirred at 70 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give 2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) ethylamine (50.00mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.30(d，J＝4.6Hz，1H)，7.80(d，J＝8.2Hz，1H)，7.44(s，1H)，7.16(dd，J＝4.6，8.2Hz，1H)，3.35(s，2H)，3.03(s，2H)；ES-LCMS m/z 162.2[M+H]⁺。

Step 4: 2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethyl]Purine-6-amines

To a solution of 2, 6-dichloro-9-isopropyl-purine (76.49mg, 320.46. mu. mol, 1.2 equiv.) in i-PrOH (10mL) was added DIEA (172.57mg, 1.34mmol, 232.57. mu.L, 5.0 equiv.) and 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (50.00mg, 267.05. mu. mol, 1 eq). The mixture was stirred at 50 ℃ for 12 hours. LC-MS showed complete consumption of starting material and 55% of the desired compound was detected. The reaction mixture was concentrated and the residue was passed through preparative TLC (SiO)₂，DCM/MeOH＝10/1，R_f0.65) to yield 2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) ethyl]Purin-6-amine (25.00mg, 70.26. mu. mol, 26.3% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 8.30(dd，J＝1.3，4.8Hz，1H)，8.08(s，1H)，7.77(dd，J＝1.1，8.2Hz，1H)，7.44(s，1H)，7.14(dd，J＝4.8，8.3Hz，1H)，4.79-4.68(m，1H)，3.96-3.87(m，2H)，3.20(t，J＝6.8Hz，2H)，1.56(d，J＝6.8Hz，6H)；ES-LCMS m/z 356.1，358.1[M+H]⁺。

Step 5: 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Purine-6-amine (I-7)

2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Purin-6-amine (25.00mg, 70.26. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (24.75mg, 175.65. mu. mol, 2.5 eq), Cs₂CO₃(68.68mg, 210.78. mu. mol, 3.0 equiv.) and Pd (dppf) Cl₂(5.14mg, 7.03. mu. mol, 0.1 equiv.) in 1, 4-dioxane (2mL) and water (0.4mL) was placed in a microwave tube. The sealed tube was heated at 120 ℃ for 30 minutes under microwave. LC-MS showed complete consumption of starting material and 60% of the desired compound was detected. The reaction mixture was diluted with EtOAc (10mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Pheroma Kinetex XB-C18150 mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 5% -35%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [3, 2-b) as a white solid]Pyridin-3-yl) ethyl]Purin-6-amine (8.83mg, 16.14 μmol, 23.0% yield, 96.1% purity, 3HCl salt);¹H NMR(400MHz，CD₃OD)δppm 9.37(s，1H)，8.92(s，1H)，8.78(s，1H)，8.69(s，1H)，8.51(s，1H)，8.43(d，J＝7.3Hz，1H)，8.05(s，1H)，7.59(s，1H)，5.06(td，J＝6.8，13.6Hz，1H)，4.22(t，J＝6.4Hz，2H)，3.38(t，J＝6.8Hz，2H)，1.70(d，J＝6.8Hz，6H)；ES-LCMS m/z417.2[M+H]⁺。

example 18

Synthesis I-13

The synthesis scheme is as follows:

step 1: n- (2- (1H-benzo [ d ]]Imidazol-1-yl) ethyl) -2-chloro-9-isopropyl-9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-purine (200mg, 827.24 μmol, 1 eq) in i-PrOH (8mL) was added DIEA (106.91mg, 827.24 μmol, 144.09 μ L, 1 eq) and 2- (benzimidazol-1-yl) ethylamine (160.02mg, 992.69 μmol, 1.2 eq). The mixture was stirred at 50 ℃ for 16 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by flash silica gel column chromatography (DCM/MeOH ═ 1/0 to 10/1, TLC: DCM/MeOH ═ 10/1, R_f0.33) to yield N- [2- (benzimidazol-1-yl) ethyl as a white solid]-2-chloro-9-isopropyl-purin-6-amine (275mg, 93.4% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 7.98-7.71(m，2H)，7.54(d，J＝7.5Hz，2H)，7.38-7.18(m，2H)，6.77(br s，1H)，4.86-4.67(m，1H)，4.53(t，J＝6.0Hz，2H)，4.02(br s，2H)，1.69-1.46(m，6H)；ES-LCMS m/z 356.1，357.1[M+H]⁺。

Step 2: n- (2- (1H-benzo [ d ]]Imidazol-1-yl) ethyl) -2- (5-fluoropyridin-3-yl) -9-isopropyl-9H-purin-6-amine (I-13)

Reacting a mixture containing N- [2- (benzimidazol-1-yl) ethyl]-2-chloro-9-isopropyl-purin-6-amine (120mg, 337.24 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (95.04mg, 674.49 μmol, 2 eq), Cs₂CO₃(329.64mg, 1.01mmol, 3.0 equiv.) and Pd (dppf) Cl₂(12.34mg, 16.86. mu. mol, 0.05 eq.) of 1, 4-dioxane (5mL) and H₂O (1mL) degassed and refilled with N₂. Mixing the mixtureThe mixture was heated to 80 ℃ and held for 12 hours. LC-MS showed 58% of the desired compound. The reaction mixture is poured into H₂O (30mL), followed by extraction with EtOAc (20 mL. times.3). The combined organic phases were washed with brine (10mL) and over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 38% -68%, 10min) to yield N- [2- (benzimidazol-1-yl) ethyl as a white solid]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (31.40mg, 22.4% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm9.08(br s，1H)，8.43(d，J＝2.6Hz，1H)，8.17(s，1H)，8.15-7.95(m，2H)，7.67(d，J＝8.2Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.26(t，J＝7.7Hz，1H)，7.17-7.00(m，1H)，4.88-4.83(m，1H)，4.62(t，J＝5.4Hz，2H)，4.20(br s，2H)，1.63(d，J＝6.8Hz，6H)；ES-LCMSm/z 417.1[M+H]⁺。

Example 19

Synthesis I-8

The synthesis scheme is as follows:

step 1: 2, 6-dichloro-9-isopropyl-purine

To a solution of 2, 6-dichloro-9H-purine (20g, 105.82mmol, 1 eq) in DMSO (160mL) was added K₂CO₃(73.13g, 529.09mmol, 5 equiv.) and 2-bromopropane (65.07g, 529.09mmol, 49.67mL, 5 equiv.). The mixture was stirred at 25 ℃ for 12 hours. TLC (PE/EtOAc ═ 1/1, R_f0.45) indicates complete consumption of starting material and detection of one masterA new blob is needed. The reaction mixture was diluted with water (200mL) and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with water (80 mL. times.3) and Na₂SO₄Dried, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel column chromatography (PE/EtOAc: 5/1 to 2/1, TLC: PE/EtOAc: 1/1, R_f0.45) to yield 2, 6-dichloro-9-isopropyl-purine as a white solid (3.52g, 14.75mmol, 13.9% yield, 96.8% purity).¹H NMR(400MHz，CD₃OD)δppm 8.66(s，1H)，4.97-4.89(m，1H)，1.65(d，J＝6.8Hz，6H)；ES-LCMS m/z231.0，232.9[M+H]⁺。

Step 2: 2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-c)]Pyridin-3-yl) ethyl]Purine-6-amines

To a solution of 2, 6-dichloro-9-isopropyl-purine (148.07mg, 620.33. mu. mol, 1 eq.) in i-PrOH (10mL) was added DIEA (400.86mg, 3.10mmol, 540.24. mu.L, 5.0 eq.) and 2- (1H-pyrrolo [3, 2-c ]]Pyridin-3-yl) ethylamine (100mg, 620.33. mu. mol, 1 eq). The mixture was stirred at 50 ℃ for 12 hours. LC-MS showed complete consumption of starting material and 33% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography on silica gel (DCM/MeOH ═ 100/1 to 5/1, TLC: DCM/MeOH ═ 10/1, R_f0.68) to yield 2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-c) as a yellow solid]Pyridin-3-yl) ethyl]Purin-6-amine (74.5mg, 33.8% yield, crude); ES-LCMS M/z 356.0, 357.0[ M + H ]]⁺。

Step 3: 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [3, 2-c)]Pyridin-3-yl) ethyl]Purine-6-amine (I-8)

2-chloro-9-isopropyl-N- [2- (1H-pyrrolo [3, 2-c)]Pyridin-3-yl) ethyl]Purin-6-amine (74.5mg, 104.69. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (36.88mg, 261.72. mu. mol, 2.5 eq), Cs₂CO₃(102.33mg, 314.06. mu. mol, 3.0 equiv.) and Pd (dppf) Cl₂(7.66mg, 10.47. mu. mol, 0.1 equiv.) in 1, 4-dioxane (3mL) and water (0.6mL) was placed in a microwave tube. The sealed tube was heated at 120 ℃ for 30 minutes under microwave. LC-MS showed complete consumption of starting material and 56% of the desired compound was detected. The reaction mixture was diluted with EtOAc (15mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 15% -45%, 10min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (1H-pyrrolo [3, 2-c) as a white solid]Pyridin-3-yl) ethyl]Purin-6-amine (22.19mg, 42.20 μmol, 40.3% yield, 100% purity, 3HCl salt);¹H NMR(400MHz，CD₃OD)δppm 9.53(s，1H)，9.31(s，2H)，9.00-8.94(m，2H)，8.28(d，J＝6.5Hz，1H)，7.85(d，J＝6.8Hz，1H)，7.79(s，1H)，5.14(d，J＝6.7，13.5Hz，1H)，4.23(s，2H)，3.41(t，J＝6.7Hz，2H)，1.74(d，J＝6.8Hz，6H)；ES-LCMS m/z 417.2[M+H]⁺。

example 20

Synthesis of I-21

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine

Mixing 4, 6-dichloro-2-iodo-pyrimidine (1g, 3.58mmol, 1 eq), (5-fluoro-3-pyridyl)Boric acid (503.91mg, 3.58mmol, 1 eq.), Na₂CO₃(1.14g, 10.73mmol, 3.0 equiv.) and Pd (dppf) Cl₂(261.67mg, 357.62. mu. mol, 0.1 equiv.) in 1, 4-dioxane (14mL) and water (2.4mL) was placed in a microwave tube. The sealed tube was heated at 80 ℃ for 30 minutes under microwave. LCMS showed 58% of the desired compound was detected. The reaction mixture was diluted with EtOAc (50mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 5/1, TLC: PE/EtOAc: 3/1, R_f0.80) to yield 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine as a yellow solid (275mg, 1.13mmol, 37.8% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 9.34(t，J＝1.4Hz，1H)，8.66(d，J＝2.9Hz，1H)，8.51-8.43(m，1H)，7.75(s，1H)；ES-LCMS m/z243.9，245.9[M+H]⁺。

Step 2: 4-chloro-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidine

To a solution of i-PrOH (14.78mg, 245.85. mu. mol, 18.82. mu.L, 1 eq.) in THF (4mL) was added NaH (11.80mg, 295.02. mu. mol, 60% in mineral oil, 1.2 eq.). The mixture was stirred at 0 ℃ for 30 minutes. 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine (60mg, 245.85 μmol, 1.0 eq) was added to the above solution and the mixture was stirred at 15 ℃ for 12 hours. LCMS showed 83% of desired compound detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (30mL) and extracted with EtOAc (30mL × 3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 4-chloro-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidine (50mg, 167.92 μmol, 68.3% yield, 89.9% purity) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 9.39-9.28(m，1H)，8.68-8.58(m，1H)，8.50-8.39(m，1H)，6.85(s，1H)，5.57(m，1H)，1.44(d，J＝6.2Hz，6H)；ES-LCMS m/z 268.0，270.0[M+H]⁺。

Step 3: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-pyrimidin-4-amine (I-21)

To a solution of 4-chloro-2- (5-fluoro-3-pyridyl) -6-isopropoxy-pyrimidine (50mg, 167.92 μmol, 1.0 eq) in i-PrOH (4mL) was added DIEA (65.11mg, 503.76 μmol, 87.74 μ L, 3.0 eq) and 2- (1H-indol-3-yl) ethylamine (134.52mg, 839.60 μmol, 5 eq). The mixture was stirred at 70 ℃ for 12 hours. LCMS showed residual starting material and absence of desired compound. The reaction mixture was added to a microwave tube and heated at 125 ℃ for 3 hours under microwave. LCMS showed complete consumption of the starting material and 28% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 10min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6-isopropoxy-pyrimidin-4-amine (26.35mg, 52.45 μmol, 31.2% yield, 99.7% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.15(s，1H)，8.66(d，J＝2.4Hz，1H)，8.32(d，J＝8.8Hz，1H)，7.60(d，J＝7.7Hz，1H)，7.29(d，J＝7.9Hz，1H)，7.13-6.95(m，3H)，5.69(m，1H)，5.04(m，1H)，3.78(m，2H)，3.09(t，J＝6.8Hz，2H)，1.40-1.33(m，6H)；ES-LCMS m/z 392.1[M+H]⁺。

Example 21

Synthesis I-23

The synthesis scheme is as follows:

step 1: n- (2-bromo-4, 6-difluoro-phenyl) carbamic acid tert-butyl ester

2-bromo-4, 6-difluoro-aniline (5g, 24.04mmol, 1 eq.), Boc₂A mixture of O (15.74g, 72.11mmol, 16.57mL, 3 equivalents), DMAP (293.67mg, 2.40mmol, 0.1 equivalent) in THF (50mL) was degassed and N was used₂Purify 3 times, and then mix in N₂Stirred under an atmosphere at 70 ℃ for 16 hours. LC-MS showed complete consumption of starting material and detection of the di-BOC intermediate. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in MeOH (50mL) and K was added₂CO₃(9.97g, 72.11mmol, 3 equiv.). The mixture was stirred at 70 ℃ for 4 hours. LC-MS showed complete consumption of the intermediate and one major peak with the desired MS was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water (100mL) was added to the residue, which was extracted with EtOAc (60 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. To the residue was added n-heptane (100mL), followed by stirring at 15 ℃ for 1 hour. The slurry was filtered and the filter cake was washed with N-heptane (30mL × 2) and dried in vacuo to give tert-butyl N- (2-bromo-4, 6-difluoro-phenyl) carbamate (4.15g, 13.47mmol, 56.0% yield, 100% purity) as a white solid, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.18(td，J＝2.3，7.7Hz，1H)，6.89(dt，J＝2.8，8.9Hz，1H)，5.91(s，1H)，1.51(s，9H)；ES-LCMS m/z 251.9，253.9[M-t-Bu+H]⁺。

Step 2: n- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl]Carbamic acid tert-butyl ester

Will N- (2-bromo-4, 6-difluoro-phenyl) carbamic acid tert-butyl ester (4g, 12.98mmol, 1 equiv.), ethynyl (trimethyl) silane (2.55g, 25.96mmol, 3.60mL, 2.0 equiv.), TEA (3.94g, 38.95mmol, 5.42mL, 3.0 equiv.), CuI (247.24mg, 1.30mmol, 0.1 equiv.), and Pd (PPh)₃)₂Cl₂A mixture of (455.60mg, 649.10. mu. mol, 0.05 eq.) in DMF (80mL) was degassed and N was used₂Purify 3 times, and then mix in N₂Stirred under an atmosphere at 100 ℃ for 16 hours. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was quenched by the addition of water (300mL) and extracted with EtOAc (200 mL. times.3). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 20/1, R_f0.31) to yield N- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl group as a dark brown solid]Tert-butyl carbamate (2.05g, 5.04mmol, 38.8% yield, 80% purity).¹H NMR(400MHz，CDCl₃)δppm7.00-6.94(m，1H)，6.90-6.81(m，1H)，6.10(s，1H)，1.51(s，9H)，0.27(m，9H)；ES-LCMS m/z270.0[M-t-Bu+H]⁺。

Step 3: 5, 7-difluoro-1H-indoles

To EtOH (100mL) was added Na (791.23mg, 34.42mmol, 8 equiv.) slowly. After stirring at 15 ℃ for 1 hour, N- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl]Tert-butyl carbamate (1.75g, 4.30mmol, 1 eq.) was added to the above solution. The mixture was stirred at 85 ℃ for 16 hours. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. Water (100mL) was added to the residue and extracted with EtOAc (60 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure give a residue which is chromatographed on flash silica gel (PE/EtOAc ═ 1-0 to 10/1, TLC: PE/EtOAc-20/1, R_f0.17) to yield 5, 7-difluoro-1H-indole (410mg, 1.87mmol, 43.5% yield, 70% purity) as a black oil.¹H NMR(400MHz，CD₃OD) δ ppm 8.31(s, 1H), 7.29-7.22(m, 1H), 7.09(dd, J ═ 2.1, 9.2Hz, 1H), 6.73(ddd, J ═ 2.2, 9.4, 11.1Hz, 1H), 6.59-6.51(m, 1H); ES-LCMS: the correct quality was not found.

Step 4: 5, 7-difluoro-1H-indole-3-carbaldehyde

In N₂POCl was added dropwise to a DMF solution (10mL) at-20 deg.C over a period of 10 minutes₃(350.46mg, 2.29mmol, 212.40. mu.L, 2.0 equiv.). After stirring for 1 hour, 5, 7-difluoro-1H-indole (250mg, 1.14mmol, 1 eq) in DMF (2mL) was added to the above solution, during which time the temperature was maintained below-20 ℃. The reaction mixture was warmed to 15 ℃ and stirred for 1 hour. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was purified by addition of NaHCO₃Quench (30mL) and extract with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.40) to yield 5, 7-difluoro-1H-indole-3-carbaldehyde (200mg, 993.71 μmol, 86.9% yield, 90% purity) as a yellow solid.¹H NMR (400MHz, acetone) δ ppm 11.74(s, 1H), 10.06(d, J ═ 0.8Hz, 1H), 8.38(s, 1H), 7.74(dd, J ═ 2.3, 9.0Hz, 1H), 7.03(ddd, J ═ 2.3, 9.5, 11.3Hz, 1H); ES-LCMS M/z 182.1[ M + H ]]⁺。

Step 5: 5, 7-difluoro-3- [ (E) -2-nitrovinyl]-1H-indoles

To 5, 7-difluoroNH was added to a solution of (1H) -indole-3-carbaldehyde (200mg, 993.71. mu. mol, 1 eq.) in nitromethane (8mL)₄OAc (229.79mg, 2.98mmol, 3.0 equiv.). The mixture was stirred at 110 ℃ for 16 hours. LC-MS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was diluted with EtOAc (50mL), washed with water (10mL), brine (10mL), and Na₂SO₄Drying, filtering and concentrating under reduced pressure to give 5, 7-difluoro-3- [ (E) -2-nitrovinyl) as a brown solid]-1H-indole (160mg, 599.56 μmol, 60.3% yield, 84% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm8.23(d，J＝13.6Hz，1H)，7.74-7.58(m，2H)，7.26-7.11(m，1H)，6.91-6.75(m，1H)；ES-LCMSm/z 225.0[M+H]⁺。

Step 6: 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine

To 5, 7-difluoro-3- [ (E) -2-nitrovinyl at 0 deg.C]-1H-indole (50mg, 187.36. mu. mol, 1 equiv) to a solution in THF (5mL) LAH (1M, 936.82. mu.L, 5 equiv) was added dropwise. After the addition, the mixture was stirred at 80 ℃ for 2 hours. LC-MS showed complete consumption of starting material and one major peak with the desired MS was detected. The reaction mixture was diluted with THF (50mL) and quenched at 0 deg.C by the sequential addition of water (0.05mL), followed by 10% NaOH (0.05mL) and water (0.15 mL). After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (36mg, crude) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.18(s，1H)，7.13-7.01(m，1H)，6.73-6.67(m，1H)，2.97-2.79(m，4H)；ES-LCMSm/z 197.2[M+H]⁺。

Step 7: n- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (I-23)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 164.55 μmol, 1 eq) in i-PrOH (3mL) was added DIEA (106.33mg, 822.73 μmol, 143.30 μ L, 5 eq) and 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (35.51mg, 181.00 μmol, 1.1 eq). The mixture was stirred at 60 ℃ for 16 hours. LC-MS showed 21% starting material remaining and 66% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) _ ACN)](ii) a B%: 46% -76%, 10 minutes). The desired fractions were lyophilized to give N- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl ] as a yellow solid]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (20.82mg, 36.75 μmol, 22.3% yield, 99% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.45(s，1H)，9.20(s，1H)，8.90(s，1H)，8.83(d，J＝9.0Hz，1H)，7.24(s，1H)，7.11(d，J＝8.8Hz，1H)，6.67-6.58(m，1H)，5.11(m，1H)，4.13(s，2H)，3.17(t，J＝6.6Hz，2H)，1.73(d，J＝6.8Hz，6H)；ES-LCMS m/z 452.2[M+H]⁺。

Example 22

Synthesis I-16

The synthesis scheme is as follows:

step 1: 5-Fluoropyridine-3-carbonyl chloride

To 5-fluoropyridine-3-carboxylic acid (7g, 49.61 mmo) at 0 deg.Cl, 1 equivalent) to SOCl₂(57.40g, 482.47mmol, 35.00mL, 9.73 equiv.) DMF (0.1mL) was added. After the addition, the mixture was stirred at 50 ℃ for 2 hours. TLC (PE/EA: 1/1, R)_fMeOH added) showed complete consumption of the starting material. The mixture was concentrated to give 5-fluoropyridine-3-carbonyl chloride as a pale yellow oil (7g, crude), which was used in the next step without further purification.

Step 2: 5-fluoropyridine-3-carboxamides

At 0 ℃ under N₂Down NH₃H₂To a solution of O (31.85g, 254.47mmol, 35.00mL, 28% purity, 5.80 equiv.) in THF (10mL) was added dropwise a solution of 5-fluoropyridine-3-carbonyl chloride (7g, 43.87mmol, 1 equiv.) in THF (30 mL). The mixture was stirred at 15 ℃ for 1 hour. LCMS showed complete consumption of the starting material and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EtOAc (50mL) and extracted with EtOAc (50 mL. times.2). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave 5-fluoropyridine-3-carboxamide (6g, 42.39mmol, 96.6% yield, 99.0% purity) as an off-white solid.¹HNMR(400MHz，CD₃OD)δppm 8.87(s，1H)，8.62(d，J＝2.6Hz，1H)，8.06-8.01(m，1H)；ES-LCMSm/z 141.1[M+H]⁺。

Step 3: 5-fluoropyridine-3-carbonitriles

At 15 ℃ under N₂To a mixture of 5-fluoropyridine-3-carboxamide (6g, 42.39mmol, 1 equiv) and TEA (6.43g, 63.59mmol, 8.85mL, 1.5 equiv) in DCM (60mL) was added TFAA (13.36g, 63.59mmol, 8.85mL, 1.5 equiv) dropwise. The mixture was stirred at 15 ℃ for 12 hours. TLC (PE/EA: 1/1, R)_f0.89) indicates complete consumption of the starting material and formation of a new spot. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (

24g

Silica flash column, eluent 0-20% ethyl acetate/petroleum ether gradient, 30mL/min) to afford 5-fluoropyridine-3-carbonitrile as a white solid (4.7g, 36.57mmol, 86.3% yield, 95.0% purity).¹H NMR(400MHz，CD₃OD) delta ppm 8.82-8.71(m, 2H), 8.14-8.06(m, 1H); ES-LCMS: the correct quality was not found.

Step 4: 5-fluoro-N- (4-isopropyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine

A mixture of 5-fluoropyridine-3-carbonitrile (1.02g, 7.91mmol, 1 eq.) and 4-isopropyl-1H-pyrazol-5-amine (880.27mg, 6.33mmol, 0.8 eq.) in xylene (20mL) was stirred at 70 ℃ for 30 min. Followed by a reaction at 70 ℃ under N₂The following will react with AlMe₃(2M, 4.75mL, 1.2 equiv.) was added to the above mixture in one portion. The mixture was stirred at 100 ℃ for 15 hours. LC-MS showed 16% of the desired MS detected. The mixture was quenched with MeOH (20mL) and concentrated to give a residue which was purified by flash silica gel chromatography (R) ((R))

12g

Silica flash column, eluent 0-10% MeOH in DCM ether gradient, 30mL/min) to afford 5-fluoro-N- (4-isopropyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine as a yellow solid (600mg, 1.94mmol, 24.5% yield, 80% purity).¹H NMR(400MHz，CD₃OD)δppm 8.96(s，1H)，8.54(d，J＝2.6Hz，1H)，8.11(d，J＝9.5Hz，1H)，7.34(s，1H)，3.06(m，1H)，1.25(d，J＝6.8Hz，6H)；ES-LCMS m/z 248.1[M+H]⁺。

Step 5: 2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine-4-ols

To a mixture of 5-fluoro-N- (4-isopropyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine (100mg, 323.53 μmol, 1 eq) in 1, 4-dioxane (10mL) and THF (5mL) was added triphosgene (33.60mg, 113.24 μmol, 0.35 eq) and the mixture was then stirred at 80 ℃ for 15 hours. LC-MS showed 57.5% of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a) as a brown solid][1，3，5]Triazin-4-ol (88mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.90-8.85(m，2H)，8.18(d，J＝2.3，8.6Hz，1H)，7.66(s，1H)，3.04(d，J＝6.9，13.7Hz，1H)，1.26(d，J＝6.8Hz，6H)；ES-LCMS m/z 274.3[M+H]⁺。

Step 6: 4-chloro-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine

Reacting 2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a ] at 100 DEG C][1，3，5]Triazin-4-ol (88mg, 322.03. mu. mol, 1 equivalent) in POCl₃(8.1g, 52.83mmol, 4.91mL, 164.04 equiv.) the mixture was stirred for 2 hours. LC-MS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give a residue, which was then diluted with DCM (20mL) and extracted with DCM (20mL × 2). The combined organic layers were washed with brine (15mL) and Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (b) ((b))

12g

Silica flash column, eluent 0-15% ethyl acetate/petroleum ether gradient, 30mL/min) to obtain 4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazine (15mg, 49.78 μmol, 15.5% yield, 96.8% purity).¹H NMR(400MHz，CDCl₃)δppm 9.49(s，1H)，8.60(d，J＝2.6Hz，1H)，8.42(d，J＝9.5Hz，1H)，8.17(s，1H)，3.35(d，J＝6.7，13.9Hz，1H)，1.43(d，J＝6.8Hz，6H)；ES-LCMSm/z 292.0，294.0[M+H]⁺。

Step 7: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-8-isopropyl-pyrazolo [1, 5-a][1, 3, 51 triazin-4-amine (I-16)

4-chloro-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a ] at 50 ℃][1，3，5]A mixture of triazine (15mg, 49.78. mu. mol, 1 eq), DIEA (19.30mg, 149.33. mu. mol, 26.01. mu.L, 3 eq) and 2- (1H-indol-3-yl) ethylamine (9.57mg, 59.73. mu. mol, 1.2 eq) in i-PrOH (3mL) was stirred for 3 hours. LC-MS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenetex Kinetex XB-C18150 mm X30 mm, 5 μm; mobile phase: [ water (0.05% HCl) -ACN]；B％：55％-85％，]7min) and freeze drying the desired fractions to give 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a white solid]-8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (6.17mg, 11.70. mu. mol, 23.5% yield, 99.5% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm9.14(s，1H)，8.81(br s，1H)，8.56(d，J＝9.0Hz，1H)，7.97(s，1H)，7.69-7.63(m，1H)，7.18-7.12(m，1H)，7.00-6.94(m，3H)，4.04(t，J＝6.7Hz，2H)，3.27-3.20(m，1H)，3.17(t，J＝6.7Hz，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 416.2[M+H]⁺。

Example 23

Synthesis I-24

The synthesis scheme is as follows:

step 1: [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Morpholinyl-methanones (I-24)

To 5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (25mg, 55.60. mu. mol, 1 eq) in DCM (3mL) was added HATU (31.71mg, 83.40. mu. mol, 1.5 eq), TEA (11.25mg, 111.20. mu. mol, 15.48. mu.L, 2 eq) and morpholine (9.69mg, 111.20. mu. mol, 9.79. mu.L, 2 eq). Mixing the mixture in N₂Stirring was carried out at 25 ℃ for 12 hours under an atmosphere. The mixture was concentrated under reduced pressure, followed by addition of water (30mL) and extraction with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) followed by lyophilization to give [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Morpholinyl-methanone (8.45mg, 13.61 μmol, 24.4% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.24(s，1H)，8.66(d，J＝2.6Hz，1H)，8.55-8.48(m，1H)，8.34(s，1H)，7.39(d，J＝7.7Hz，1H)，7.28(d，J＝7.9Hz，1H)，7.10-7.01(m，2H)，6.99-6.93(m，1H)，4.54(br s，1H)，3.80(s，8H)，3.37-3.34(m，1H)，3.20-3.05(m，1H)，3.04-2.87(m，2H)，2.36(br s，1H)，2.28(d，J＝6.2Hz，1H)；ES-LCMS m/z 512.3[M+H]⁺。

Example 24

Synthesis I-25

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N-methoxy-N-methyl-7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (I-25)

To 5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (30mg, 63.06 μmol, 1 eq) in DCM (4mL) was added HATU (35.97mg, 94.59 μmol, 1.5 eq), TEA (12.76mg, 126.12 μmol, 17.55 μ L, 2 eq) and N-methoxymethanamine (12.30mg, 126.12 μmol, 2 eq, HCl). Mixing the mixture in N₂Stirred under an atmosphere at 20 ℃ for 1 hour. The mixture was concentrated under reduced pressure, followed by addition of water (30 mL). The mixture was extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Dried, filtered and concentrated. The mixture was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) followed by lyophilization to give 5- (5-fluoro-3-pyridinyl) -N-methoxy-N-methyl-7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (15.98mg, 26.86. mu. mol, 42)6% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.10(s，1H)，8.82(d，J＝2.8Hz，1H)，8.67(s，1H)，8.47(d，J＝9.3Hz，1H)，7.39(d，J＝7.5Hz，1H)，7.35-7.25(m，2H)，7.05(t，J＝7.0Hz，1H)，7.00-6.91(m，1H)，4.69(br s，1H)，3.87(s，3H)，3.43(s，3H)，3.18-2.95(m，4H)，2.37(dd，J＝5.6，10.2Hz，2H)；ES-LCMS m/z 486.2[M+H]⁺。

Example 25

Synthesis I-26

The synthesis scheme is as follows:

step 1: (3R) -N- (3-isopropyl-5-phenyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-26)

Reacting 7-chloro-3-isopropyl-5-phenyl-pyrazolo [1, 5-a]A mixture of pyrimidine (60mg, 218.15. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (44.69mg, 239.96. mu. mol, 1.1 equivalents), DIEA (84.58mg, 654.44. mu. mol, 113.99. mu.L, 3 equivalents) in i-PrOH (2mL) was degassed and N was used₂Purifying 3 times, and mixing the mixture with N₂Stirred at 80 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10min) and then lyophilized to give (3R) -N- (3-isopropyl-5-phenyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (45.09mg, 91.19 μmol, 41.8% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.12(s，1H)，7.97(d，J＝7.7Hz，2H)，7.68-7.50(m，3H)，7.39(d，J＝7.9Hz，1H)，7.27(d，J＝8.2Hz，1H)，7.09-7.01(m，1H)，7.00-6.92(m，1H)，6.78(s，1H)，4.56(m，1H)，3.39-3.33(m，2H)，3.16-2.90(m，3H)，2.53-2.07(m，2H)，1.39(d，J＝6.8Hz，6H)；ES-LCMS m/z 422.2[M+H]⁺。

Example 26

Synthesis of I-27a

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-benzimidazol-5-yl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-27)

4, 5, 6, 7-tetrahydro-1H-benzimidazol-5-amine (62mg, 451.95. mu. mol, 1 eq.), 7-chloro-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (145.99mg, 451.95. mu. mol, 1 eq.) and DIEA (175.24mg, 1.36mmol, 236.17. mu.L, 3 eq.) in i-PrOH (3mL) was stirred at 90 ℃ for 12 h. The reaction mixture was concentrated to dryness under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAc: 20/0 to 0/1, TLC: PE/EtOAc: 1/1, R_f0.10). The desired fractions were dried to dryness under reduced pressure. The residue was passed through a preparative SFC (column: AD (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 35% to 35%, min) to give peak 1(Rt ═ 5.226) and peak 2(Rt ═ 5.531). Peak 1 was concentrated to dryness under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 10 minutes) to purify. The desired fractions were lyophilized to give 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-benzimidazol-5-yl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (25.12mg, 50.16 μmol, 11.1% yield, 100.0% purity, 3HCl) (Rt ═ 5.226, [ α [)]^25.5 _D-18.573(0.105g/100mL in MeOH with ee% ═ 97.4%).¹H NMR(400MHz，CD₃OD)δppm 9.08(s，1H)，8.83(s，1H)，8.77(s，1H)，8.47(d，J＝8.4Hz，1H)，8.25(s，1H)，7.07(s，1H)，4.72(br s，1H)，3.45-3.31(m，2H)，3.07-2.87(m，3H)，2.44-2.35(m，1H)，2.33-2.22(m，1H)，1.39(d，J＝6.8Hz，6H)；ES-LCMSm/z 392.2[M+H]⁺。

Example 27

Synthesis I-28a

The synthesis scheme is as follows:

step 1: 2- (4-methoxyphenyl) propionitrile

To a stirred solution of 1- (4-methoxyphenyl) ethanol (2g, 13.14mmol, 1 eq) in DCM (10mL) was added a solution of TMSCN (2.61g, 26.28mmol, 3.29mL, 2 eq) and indium tribromide (465.90mg, 1.31mmol, 0.1 eq) in DCM (10mL) dropwise over 30 min. The resulting mixture was then stirred at 30 ℃ for 15 minutes. TLC (PE/EtOAc ═ 10/1, R_f0.55) showed the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 10/1, TLC: PE/EtOAc: 10/1, R_f0.55) to yield 2- (4-methoxyphenyl) propionitrile (1g, 5.58mmol, 42.5% yield, 90.0% purity) as a yellow oil.¹HNMR(400MHz，CDCl₃)δppm 7.27(s，2H)，6.97-6.86(m，2H)，3.91-3.79(m，4H)，1.63(d，J＝7.3Hz，3H).

Step 2: 2- (4-methoxyphenyl) propan-1-amine

To a solution of 2- (4-methoxyphenyl) propionitrile (800mg, 4.47mmol, 1 eq) in MeOH (40mL) was added Raney nickel (Raney-Ni) (0.5 g). The mixture is degassed and treated with H₂Purified three times and the mixture in H₂Stirred at 30 ℃ for 5 hours under an atmosphere. TLC (PE/EtOAc ═ 10/1, R_f0.10) showed that reactant 1 was almost exhausted and a new spot was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (DCM/MeOH ═ 10/1 to 5/1, TLC: DCM/MeOH ═ 10/1, R_f0.60) to yield 2- (4-methoxyphenyl) propan-1-amine (710mg, 3.87mmol, 86.6% yield, 90.0% purity) as a yellow oil.¹H NMR(400MHz，CDCl₃)δppm 7.13(d，J＝8.5Hz，2H)，6.87(d，J＝8.5Hz，2H)，3.80(s，3H)，2.88-2.69(m，3H)，1.23(d，J＝6.8Hz，3H)；ES-LCMS m/z 166.1[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [2- (4-methoxyphenyl) propyl]Pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (250mg, 773.93. mu. mol, 1.0 eq) in i-PrOH (10mL) was added DIEA (300.07mg, 2.32mmol, 404.41. mu.L, 3.0 eq) and 2- (4-methoxyphenyl) propan-1-amine (200mg, 1.09mmol, 1.41 eq). The mixture was stirred at 60 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.75) to yield a yellow solid5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [2- (4-methoxyphenyl) propyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (300mg, 715.15 μmol, 92.4% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.02(d，J＝1.5Hz，1H)，8.53(d，J＝2.9Hz，1H)，8.19-8.12(m，1H)，7.86(s，1H)，7.22(d，J＝8.6Hz，2H)，6.94-6.86(m，2H)，6.38(t，J＝5.7Hz，1H)，6.19(s，1H)，3.79(s，3H)，3.68-3.53(m，2H)，3.39-3.29(m，1H)，3.22-3.13(m，1H)，1.47-1.39(m，9H)；ES-LCMS m/z 420.2[M+H]⁺。

Step 4: 4- [ (1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]-1-methyl-ethyl]Phenol (I-28)

Reacting 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [2- (4-methoxyphenyl) propyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (290.00mg, 691.31. mu. mol, 1 eq.) was added to HBr (25mL, 60% in water). The mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.50). The compound was passed through SFC (conditions: column: OJ (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O ETOH](ii) a B%: 25% -25%, min). The separated solution was concentrated to give the crude product which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 45% -75%, 10min) and then lyophilized to give 4- [ (1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]-1-methyl-ethyl]Phenol (26.29mg, 54.96 μmol, 7.9% yield, 100.0% purity, 2HCl salt (R)_t4.768min, 100.0 ee%, and [ α ]]²⁵ _D＝+81.522(MeOH，c＝0.104g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.81-8.79(m，2H)，8.24(s，1H)，8.11(td，J＝2.2，9.0Hz，1H)，7.12-7.06(m，2H)，6.62-6.56(m，2H)，6.30(s，1H)，3.90-3.79(m，2H)，3.30-3.25(m，1H)，3.19-3.11(m，1H)，1.41(d，J＝7.1Hz，3H)，1.36(dd，J＝2.5，6.9Hz，6H)；ES-LCMS m/z 406.2[M+H]⁺。

Example 28

Synthesis I-29

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid methyl ester (300mg, 929.31 μmol, 1 eq) in i-PrOH (20mL) were added DIEA (360.32mg, 2.79mmol, 485.61 μ L, 3 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (190.39mg, 1.02mmol, 1.1 eq). Mixing the mixture in N₂Stirred at 60 ℃ for 3 hours under an atmosphere. The mixture was concentrated under reduced pressure, followed by addition of water (80 mL). The mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_fPurification ═ 0.6) to give the product 5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (270mg, 561.92. mu. mol, 60.4% yield, 95% purity).¹H NMR(400MHz，CD₃OD)δppm9.09(s，1H)，8.58(d，J＝2.6Hz，1H)，8.47(s，1H)，8.37-8.25(m，1H)，7.95(s，1H)，7.47(d，J＝7.9Hz，1H)，7.35(d，J＝7.9Hz，1H)，7.22-7.06(m，2H)，6.79(d，J＝8.6Hz，1H)，6.66(s，1H)，4.36(br s，1H)，3.97(s，3H)，3.41(dd，J＝4.5，15.3Hz，1H)，3.07-2.88(m，3H)，2.42-2.27(m，2H)；ES-LCMS m/z 457.2[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

To 5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (220mg, 457.86. mu. mol, 1 equivalent) in H₂To a solution of O (4mL), MeOH (2mL) and THF (2mL) was added LiOH. H₂O (275.60mg, 6.57mmol, 14.34 equiv.). Mixing the mixture in N₂Stirring was carried out at 50 ℃ for 12 hours under an atmosphere. The residue was dissolved in water (30mL), adjusted to pH 6 by 1N HCl, and extracted with EtOAc (40 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (150mg, 315.29 μmol, 68.8% yield, 93.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 9.25(s，1H)，8.59-8.50(m，2H)，8.49-8.40(m，1H)，7.38(d，J＝7.8Hz，1H)，7.26(d，J＝8.0Hz，1H)，7.09(s，1H)，7.06-6.87(m，2H)，4.50(s，1H)，3.28(s，1H)，3.15-3.02(m，1H)，3.00-2.83(m，2H)，2.43-2.31(m，1H)，2.30-2.15(m，1H)；ES-LCMS m/z 443.1[M+H]⁺。

Step 3: [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (4-methylpiperazin-1-yl) methanone (I-29)

To 5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (50mg, 105.10 μmol, 1 eq) in DCM (5mL) were added HATU (59.94mg, 157.65 μmol, 1.5 eq) and TEA (21.27mg, 210.20 μmol, 29.26 μ L, 2 eq) and 1-methylpiperazine (15.79mg, 157.65 μmol, 17.49 μ L, 1.5 eq). Mixing the mixture in N₂Stirred under an atmosphere at 20 ℃ for 1 hour. The mixture was concentrated under reduced pressure, followed by addition of water (20 mL). The mixture was extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by preparative HPLC (column: Philomena GeminiC 18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 10% -40%, 10min) followed by lyophilization to give [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (4-methylpiperazin-1-yl) methanone (24.27mg, 36.20 μmol, 34.4% yield, 100% purity, 4 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.41(s，1H)，9.01-8.88(m，2H)，8.43(s，1H)，7.37(d，J＝7.7Hz，1H)，7.27(d，J＝8.2Hz，1H)，7.22(s，1H)，7.04(t，J＝7.5Hz，1H)，6.99-6.93(m，1H)，4.79-4.51(m，3H)，3.60(d，J＝11.9Hz，4H)，3.29(s，3H)，3.20-3.07(m，1H)，3.03-2.90(m，5H)，2.43-2.21(m，2H)；ES-LCMS m/z 525.3[M+H]⁺。

Example 29

Synthesis I-30

The synthesis scheme is as follows:

step 1: (3R) -N- (6-chloro-3-isopropyl-imidazo [1, 2-a)]Pyrazine esters-8-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To 6, 8-dichloro-3-isopropyl-imidazo [1, 2-a ]]To a solution of pyrazine (45mg, 195.57 μmol, 1 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (38.25mg, 205.35 μmol, 1.05 eq) in i-PrOH (5mL) was added DIEA (75.83mg, 586.72 μmol, 102.20 μ L, 3 eq). The mixture was stirred at 60 ℃ for 3 hours. LC-MS showed 55% starting material remaining and 5% desired compound detected. The mixture was stirred at 60 ℃ for 16 hours. LC-MS showed 34% starting material remaining and 30% of the desired compound was detected. The mixture was stirred at 60 ℃ for 16 hours. LC-MS showed 21% starting material remaining and 53% desired compound was detected. The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.45) to yield the product (3R) -N- (6-chloro-3-isopropyl-imidazo [1, 2-a) as a pale yellow oil]Pyrazin-8-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60mg, 157.94 μmol, 80.8% yield, 100.0% purity).¹HNMR(400MHz，CDCl₃)δppm 7.80(s，1H)，7.45(d，J＝7.5Hz，1H)，7.32(s，1H)，7.22(s，1H)，7.17-7.12(m，1H)，7.12-7.06(m，1H)，6.28(d，J＝9.3Hz，1H)，4.81(br s，1H)，3.29(dd，J＝5.4，16.0Hz，1H)，3.15-3.04(m，1H)，2.99-2.89(m，2H)，2.81(dd，J＝6.9，15.1Hz，1H)，2.28-2.25(m，1H)，2.23-2.15(m，1H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 380.2[M+H]⁺。

Step 2: (3R) -N- [6- (5-fluoro-3-pyridinyl) -3-isopropyl-imidazo [1, 2-a [ ]]Pyrazin-8-yl radical]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-30)

To (3R) -N- (6-chloro-3-isopropyl-imidazo [1, 2-a)]Pyrazine esters-8-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60mg, 157.94 μmol, 1 eq) and (5-fluoro-3-pyridinyl) boronic acid (44.51mg, 315.89 μmol, 2.0 eq) in 1, 4-dioxane (2mL) and H₂Pd (dppf) Cl was added to a solution of O (0.5mL)₂(11.56mg, 15.79. mu. mol, 0.1 equiv.) and Cs₂CO₃(154.38mg, 473.83. mu. mol, 3.0 equiv.). Sealing pipe N₂Purify for 3 minutes and heat at 110 ℃ for 0.5 hour under microwave. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC two times (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10 minutes; column: gemini150 × 255 u; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 50% -80%, 10min) and then lyophilized to give the compound (3R) -N- [6- (5-fluoro-3-pyridinyl) -3-isopropyl-imidazo [1, 2-a) as a white solid]Pyrazin-8-yl radical]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (26.85mg, 60.59 μmol, 38.4% yield, 99.4% purity).¹H NMR(400MHz，CD₃OD)δppm 9.07(s，1H)，8.38(d，J＝2.6Hz，1H)，8.25(td，J＝2.2，10.2Hz，1H)，8.19(s，1H)，7.34(d，J＝7.7Hz，1H)，7.28-7.23(m，2H)，7.04-6.97(m，1H)，6.96-6.89(m，1H)，4.82-4.74(m，1H)，4.59(s，1H)，3.39-3.31(m，1H)，3.27-3.21(m，1H)，2.93(t，J＝6.2Hz，2H)，2.83(dd，J＝7.2，15.1Hz，1H)，2.35(dt，J＝2.5，6.4Hz，1H)，2.25-2.13(m，1H)，1.38(dd，J＝2.3，6.7Hz，6H)；ES-LCMS m/z 441.3[M+H]⁺。

Example 30

Synthesis I-31

The synthesis scheme is as follows:

step 1: 7-hydroxy-3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidine-6-carboxylic acid ethyl ester

A mixture of diethyl 2- (ethoxymethylene) malonate (621.89mg, 2.88mmol, 581.21. mu.L, 1 eq), 4-isopropyl-1H-pyrazol-5-amine (400mg, 2.88mmol, 1 eq) in AcOH (3mL) was degassed and N-substituted₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 120 ℃ for 2 hours. The reaction mixture was cooled to 0 ℃ and filtered. The solid was washed with ethanol and petroleum ether and dried under reduced pressure to give 7-hydroxy-3-isopropyl-pyrazolo [1, 5-a as a white solid]Pyrimidine-6-carboxylic acid ethyl ester (700mg, 2.65mmol, 92.3% yield, 94.5% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.55(s，1H)，7.91(s，1H)，4.34(q，J＝7.2Hz，2H)，3.11(m，1H)，1.40-1.31(m，9H)；ES-LCMS m/z 250.2[M+H]⁺。

Step 2: 3-isopropylpyrazolo [1, 5-a ]]Pyrimidin-7-ols

To 7-hydroxy-3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidine-6-carboxylic acid ethyl ester (300mg, 1.20mmol, 1 eq.) in H₂To a solution in O (3mL) was added hydrochloric acid (6.12g, 61.27mmol, 6mL, 36.5%, 50.90 equiv.). The mixture was stirred at 120 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give 3-isopropylpyrazolo [1, 5-a ] as a dark brown solid]Pyrimidin-7-ol (200mg, 902.92 μmol, 75.0% yield, 80.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.12(s，1H)，7.94(d，J＝7.5Hz，1H)，5.98(d，J＝7.3Hz，1H)，2.91-2.78(m，1H)，1.25(d，J＝6.8Hz，6H)；ES-LCMS m/z 178.1[M+H]⁺。

Step 3: 7-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidines

3-isopropyl pyrazolo [1, 5-a)]Pyrimidin-7-ol (100mg, 564.33. mu. mol, 1 eq.) in POCl₃(88.6g, 577.83mmol, 53.70mL, 1023.93 equiv.) the solution was stirred at 120 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with ice followed by NaHCO₃Solids were added to the above solution until pH 8. The reaction mixture was extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 7-chloro-3-isopropyl-pyrazolo [1, 5-a as a brown oil]Pyrimidine (100mg, 511.12 μmol, 90.6% yield), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm8.34(d，J＝4.4Hz，1H)，8.11(s，1H)，6.93(d，J＝4.4Hz，1H)，2.92-2.88(m，1H)，1.29(d，J＝6.8Hz，6H)；ES-LCMS m/z196.1[M+H]⁺

Step 4: n- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-31)

Reacting 7-chloro-3-isopropyl-pyrazolo [1, 5-a ]]A mixture of pyrimidine (75.20mg, 384.36. mu. mol, 1 equivalent), 2- (1H-indol-3-yl) ethylamine (73.90mg, 461.24. mu. mol, 1.2 equivalents), DIEA (496.76mg, 3.84mmol, 669.49. mu.L, 10 equivalents) in i-PrOH (2mL) was degassed and N₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 55 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Syneri Max-RP C12100X 305 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 15% -45%, 12min) and then freeze-drying to give N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (22.81mg, 54.77 μmol, 14.3% yield, 94.2% purity, 2 HCl).¹H NMR(400MHz，CD₃CD)δppm 8.14(s，1H)，7.80(d，J＝7.1Hz，1H)，7.44(d，J＝7.9Hz，1H)，7.26(d，J＝8.2Hz，1H)，7.15-7.06(m，1H)，6.98(t，J＝7.5Hz，1H)，6.78(t，J＝7.2Hz，1H)，5.95(d，J＝7.3Hz，1H)，3.93(t，J＝6.5Hz，2H)，3.21(t，J＝6.5Hz，2H)，3.10(m，1H)，1.32(d，J＝6.8Hz，6H)；ES-LCMS m/z320.0[M+H]⁺。

Example 31

Synthesis I-32a

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- (4, 5, 6, 7-tetrahydro-1H-indazol-6-yl) pyrazolo [1, 5-a]Pyrimidin-7-amines

4, 5, 6, 7-tetrahydro-1H-indazol-6-amine (40mg, 291.58. mu. mol, 1 eq.), 7-chloro-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]A solution of pyrimidine (84.77mg, 291.58. mu. mol, 1 equiv), DIEA (376.85mg, 2.92mmol, 507.89. mu.L, 10 equiv.) in i-PrOH (4mL) was stirred at 120 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAC: 100/1 to 1/1, TLC: PE/EtOAC: 1/1, R_f0.5) to yield 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- (4, 5, 6, 7-tetrahydro-1H-indazol-6-yl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-amine (90mg, 218.42 μmol, 74.9% yield, 95.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.16(t，J＝1.4Hz，1H)，8.52(d，J＝2.6Hz，1H)，8.37(td，J＝2.2，9.9Hz，1H)，7.93(s，1H)，7.37(s，1H)，6.77(s，1H)，4.42(s，1H)，3.48-3.31(m，2H)，2.91-2.84(m，1H)，2.84-2.76(m，2H)，2.31-1.97(m，2H)，1.40(d，J＝6.8Hz，6H)；ES-LCMSm/z 492.2[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (6S) -4, 5, 6, 7-tetrahydro-1H-indazol-6-yl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-32)

5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- (4, 5, 6, 7-tetrahydro-1H-indazol-6-yl) pyrazolo [1, 5-a]Pyrimidin-7-amine (130mg, 327.45. mu. mol, 1 eq.) was passed through SFC (column: OD (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O MeOH](ii) a B%: 45% -45%, min) to obtain peak 1 (t)_R1.465min) and peak 2 (t)_R1.687 min). The reaction mixture (peak 1) was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% to 65%, 10min) followed by lyophilization to give 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (6S) -4, 5, 6, 7-tetrahydro-1H-indazol-6-yl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (39.42mg, 76.66 μmol, 23.4% yield, 97.4% purity, 3HCl) (EE ═ 99.3%, t_R＝1.465min)，[α]²⁶ _D＝-27.146，C＝0.106g/100mL，MeOH)。¹H NMR(400MHz，CD₃OD)δppm 9.10(s，1H)，8.85(d，J＝2.2Hz，1H)，8.50(d，J＝8.8Hz，1H)，8.27(s，1H)，8.09(s，1H)，7.09(s，1H)，4.76(s，1H)，3.50(dd，J＝5.3，16.5Hz，1H)，3.39(m J＝6.8Hz，1H)，3.19-3.11(m，1H)，2.93(dd，J＝4.4，7.9Hz，2H)，2.41-2.30(m，1H)，2.28-2.14(m，1H)，1.40(d，J＝6.8Hz，6H)；ES-LCMS m/z 392.2[M+H]⁺。

Example 32

Synthesis I-33

The synthesis scheme is as follows:

step 1: 3- [2- [ tert-Butoxycarbonyl- [5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

To 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]To a solution of pyrimidin-7-amine (650mg, 1.75mmol, 1 eq) in 1, 4-dioxane (30mL) was added DMAP (639.72mg, 5.24mmol, 3 eq) and (Boc)₂O (1.14g, 5.24mmol, 1.20mL, 3 equiv.). The mixture was stirred at 110 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.75) to yield the compound 3- [2- [ tert-butoxycarbonyl- [5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (575mg, 985.06. mu. mol, 56.4% yield, 98.1% purity).¹H NMR(400MHz，CDCl₃)δppm 8.74(t，J＝1.5Hz，1H)，8.55(d，J＝2.9Hz，1H)，8.19(d，J＝2.2Hz，1H)，8.01(d，J＝7.3Hz，1H)，7.87-7.81(m，1H)，7.47(d，J＝7.7Hz，1H)，7.27-7.23(m，2H)，7.20-7.14(m，1H)，6.77(d，J＝2.4Hz，1H)，6.57(s，1H)，4.25(t，J＝6.8Hz，2H)，3.13(t，J＝6.7Hz，2H)，1.62(s，9H)，1.42(s，9H)；ES-LCMS m/z573.3[M+H]⁺。

Step 2: 3- [2- [ tert-Butoxycarbonyl- [5- (5-fluoro-3-pyridinyl) -3-iodo-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

Reacting 3- [2- [ tert-butyloxycarbonyl- [5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (250mg,428.29 μmol, 1 eq) and NIS (192.72mg, 856.58 μmol, 2 eq) in DCM (10mL) and MeCN (10mL) were stirred at 25 ℃ for 12 h. TLC (PE/EtOAc ═ 4/1, R_f0.40) showed complete consumption of starting material. The reaction mixture is washed with Na₂S₂O₃Aqueous solution (10mL) was quenched and extracted with DCM (10 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration to dryness under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 20/1 to 5/1, TLC: PE/EtOAc: 4/1, R_f0.40). The desired fractions were concentrated to dryness under reduced pressure to give 3- [2- [ tert-butoxycarbonyl- [5- (5-fluoro-3-pyridyl) -3-iodo-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (280mg, 400.84. mu. mol, 93.6% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.76(s，1H)，8.57(d，J＝2.4Hz，1H)，8.18(s，1H)，8.00(brs，1H)，7.96-7.91(m，1H)，7.45(d，J＝7.6Hz，1H)，7.26(br s，2H)，7.20-7.15(m，1H)，6.58(s，1H)，4.23(t，J＝6.8Hz，2H)，3.12(t，J＝6.8Hz，2H)，1.62(s，9H)，1.42(s，9H)；ES-LCMSm/z 699.2[M+H]⁺。

Step 3: 3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

Reacting 3- [2- [ tert-butyloxycarbonyl- [5- (5-fluoro-3-pyridyl) -3-iodo-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (150mg, 214.74. mu. mol, 1 eq.), tributyl (1-ethoxyvinyl) stannane (310.21mg, 858.95. mu. mol, 289.92. mu.L, 4 eq.), and Pd (dppf) Cl₂A mixture of (31.43mg, 42.95. mu. mol, 0.2 eq) in toluene (2mL) was treated with N₂Bubbled for 2 minutes and then sealed. The reaction mixture was irradiated under microwave (1 bar) at 100 ℃ for 2 hours. To the mixture was added aqueous KF solution (10mL, 1g/10 mL). The mixture was stirred at 25 ℃ for 30 min and then extracted with EtOAc (10 mL;)3) And (4) extracting. The organic layer was washed with Na₂SO₄Drying, filtration and concentration to dryness under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 2/1, TLC: PE/EtOAc: 4/1, R_f0.20). The desired fractions were concentrated to dryness under reduced pressure to give 3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (80mg, 124.17. mu. mol, 57.8% yield, 95.4% purity).¹H NMR(400MHz，CDCl₃)δppm 8.78(s，1H)，8.66(d，J＝2.0Hz，1H)，8.61(s，1H)，7.96(br s，1H)，7.80(d，J＝8.8Hz，1H)，7.42(d，J＝8.0Hz，1H)，7.24-7.21(m，2H)，7.14(t，J＝7.2Hz，1H)，6.65(s，1H)，4.33-4.27(m，2H)，3.14(t，J＝6.4Hz，2H)，2.84(s，3H)，1.59(s，9H)，1.43(s，9H)；ES-LCMS m/z 615.3[M+H]⁺。

Step 4: 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanones

3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]A mixture of tert-butyl indole-1-carboxylate (80mg, 124.17. mu. mol, 1 eq.) and TFA (4.62g, 40.52mmol, 3mL, 326.32 eq.) in DCM (9mL) was stirred at 25 ℃ for 30 min. TLC (PE/EtOAc ═ 1/1, R_f0.50) showed complete consumption of starting material. The reaction mixture was concentrated to dryness at 30 ℃ under reduced pressure. The residue was dissolved in water (10mL) and saturated NaHCO was used₃The aqueous solution was basified until pH 8 and extracted with EtOAc (15mL × 3). The organic layer was washed with Na₂SO₄Drying, filtering and concentrating to dryness under reduced pressure to give 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanone (50mg, 101.34 μmol, 81.6% yield, 84.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 10.81(s，1H)，9.16(s，1H)，8.71(d，J＝2.8Hz，1H)，8.62(t，J＝6.4Hz，1H)，8.53(s，1H)，8.26-8.20(m，1H)，7.65(d，J＝7.6Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.20(s，1H)，7.08-7.03(m，1H)，7.01-6.97(m，1H)，6.86(s，1H)，3.94-3.85(m，2H)，3.13(t，J＝6.8Hz，2H)，2.71(s，3H)；ES-LCMS m/z 415.1[M+H]⁺。

Step 5: 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (I-33)

To 1- [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]To a solution of ethanone (50mg, 101.34 μmol, 1 eq) in MeOH (5mL) was added NaBH₄(38.34mg, 1.01mmol, 10 equiv.) and the mixture was then stirred at 25 ℃ for 1 hour. TLC (PE/EtOAc ═ 1/1, R_f0.40) showed complete consumption of starting material. The reaction mixture was quenched with water (10mL) and concentrated under reduced pressure. The residue was extracted with EtOAc (15 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration to dryness under reduced pressure gave a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 36% -66%, 10 minutes). Lyophilizing the desired fractions to obtain 1- [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino ] as a white solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (3.29mg, 7.90 μmol, 7.8% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.79(s，1H)，8.51(d，J＝2.8Hz，1H)，8.04(br s，1H)，7.95(s，1H)，7.84(d，J＝8.4Hz，1H)，7.69(d，J＝7.6Hz，1H)，7.37(d，J＝8.0Hz，1H)，7.22(d，J＝6.8Hz，2H)，7.07(s，1H)，6.56(br s，1H)，6.09(s，1H)，5.35(s，1H)，3.89-3.83(m，2H)，3.27(t，J＝6.4Hz，2H)，3.21(d，J＝3.6Hz，1H)，1.70(d，J＝6.4Hz，3H)；ES-LCMS m/z 417.2[M+H]⁺。

Example 33

Synthesis I-34

The synthesis scheme is as follows:

step 1: (3R) -N- [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-34)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 171.13. mu. mol, 1 eq), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (31.87mg, 171.13. mu. mol, 1 eq) and DIEA (22.12mg, 171.13. mu. mol, 29.81. mu.L, 1 eq) in i-PrOH (2mL) was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure to give a residue which was purified by preparative HPLC (column: Syneri Max-RP C12100X 305 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -70%, 12 min). Lyophilizing the desired fractions to obtain (3R) -N- [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (29.03mg, 55.63 μmol, 32.5% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.76(s，1H)，9.25(s，1H)，8.67(d，J＝2.8Hz，1H)，8.46(td，J＝2.0，10.4Hz，1H)，8.30(br s，1H)，8.04(s，1H)，7.32(d，J＝7.6Hz，1H)，7.24(d，J＝8.0Hz，1H)，7.03(s，1H)，6.97(t，J＝6.8Hz，1H)，6.93-6.87(m，1H)，4.58-4.40(m，1H)，3.14-2.95(m，2H)，2.94-2.78(m，2H)，2.29(s，3H)，2.15(br s，2H)；ES-LCMS m/z 413.2[M+H]⁺。

Example 34

Synthesis I-35

The synthesis scheme is as follows:

step 1: (3R) -N- [5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-35)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]To a solution of pyrimidine (35mg, 102.58 μmol, 1 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (21.02mg, 112.83 μmol, 1.1 eq) in i-PrOH (3mL) was added DIEA (39.77mg, 307.73 μmol, 53.60 μ L, 3.0 eq). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 10min) and then lyophilized to give (3R) -N- [5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (28.79mg, 49.45 μmol, 48.2% yield, 98.9% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.36(s，1H)，8.87-8.79(m，2H)，8.34(s，1H)，7.37(d，J＝7.7Hz，1H)，7.26(d，J＝8.2Hz，1H)，7.17(s，1H)，7.06-6.99(m，1H)，6.98-6.91(m，1H)，4.57-4.46(m，1H)，3.33-3.31(m，1H)，3.17-3.04(m，1H)，3.00-2.88(m，2H)，2.42-2.33(m，1H)，2.31-2.19(m，1H)；ES-LCMS m/z 467.2[M+H]⁺。

Example 35

Synthesis I-36

The synthesis scheme is as follows:

step 1: (3R) -N- [ 6-chloro-2- (5-fluoro-3-pyridinyl) pyrimidin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

A mixture of 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine (100mg, 389.26 μmol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (79.75mg, 428.19 μmol, 1.1 equivalents), DIEA (150.93mg, 1.17mmol, 203.41 μ L, 3 equivalents) in i-PrOH (3mL) was degassed and N-PrOH (3mL) was used₂And purifying for 3 times. Mixing the mixture in N₂Stirring was carried out at 55 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAC: 100/1 to 3/1, TLC: PE/EtOAC: 3/1, R_f0.4) to yield (3R) -N- [ 6-chloro-2- (5-fluoro-3-pyridinyl) pyrimidin-4-yl as a white solid]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (130mg, 320.18 μmol, 82.3% yield, 97.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.38(s，1H)，8.55(d，J＝2.9Hz，1H)，8.34(d，J＝9.0Hz，1H)，7.91(s，1H)，7.47(d，J＝7.7Hz，1H)，7.34(d，J＝7.9Hz，1H)，7.21-7.16(m，1H)，7.14-7.10(m，1H)，6.34(s，1H)，3.25(dd，J＝5.0，15.5Hz，1H)，3.04-2.74(m，4H)，2.23(s，2H)；ES-LCMS m/z 394.1[M+H]⁺。

Step 2: (3R) -N- [2- (5-fluoro-3-pyridinyl) -6-pyrrolidin-1-yl-pyrimidin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-36)

Mixing (3R) -N- [ 6-chloro-2- (5-fluoro-3-pyridine)Yl) pyrimidin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60mg, 147.77 μmol, 1 eq) and pyrrolidine (727.50mg, 10.23mmol, 853.87 μ L, 69.22 eq) in i-PrOH (2mL) were placed in a microwave tube. The sealed tube was heated at 135 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl (Agela) Durashell C18150X 255 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 12min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) -6-pyrrolidin-1-yl-pyrimidin-4-yl as a brown solid]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (42.07mg, 78.06 μmol, 52.8% yield, 99.8% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm10.83(s，1H)，9.30(s，1H)，8.85(s，1H)，8.67-8.48(m，1H)，8.31(s，1H)，7.35(d，J＝7.5Hz，1H)，7.26(d，J＝7.9Hz，1H)，7.03-6.98(m，1H)，6.96-6.89(m，1H)，5.78(s，1H)，4.29(m，1H)，3.75-3.60(m，3H)，3.51(s，1H)，3.10(dd，J＝4.6，15.0Hz，1H)，3.02-2.89(m，2H)，2.76-2.63(m，1H)，2.22-2.02(m，2H)，1.98(s，4H)；ES-LCMS m/z 429.3[M+H]⁺。

Example 36

Synthesis of I-37a

The synthesis scheme is as follows:

step 1: 5- (5-bromo-3-pyridinyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a]Pyrimidin-7-amines

To 5- (5-bromo-3-pyridyl) -7-chloro-3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (100.00mg, 264.48. mu. mol, 1 eq.) in i-PrOH (5mL) was added 5-methoxyIndan-2-amine (52.81mg, 264.48. mu. mol, 1 eq, HCl) and DIEA (341.82mg, 2.64mmol, 460.67. mu.L, 10 eq). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.31) to yield 5- (5-bromo-3-pyridinyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-amine (120mg, 250.84 μmol, 94.8% yield, 100% purity).¹H NMR(400MHz，CDCl₃)δppm 9.18(d，J＝1.8Hz，1H)，8.74(d，J＝2.2Hz，1H)，8.58(t，J＝2.1Hz，1H)，7.87(s，1H)，7.18(d，J＝8.4Hz，1H)，6.83(s，1H)，6.79(dd，J＝2.5，8.3Hz，1H)，6.58(d，J＝7.7Hz，1H)，6.37(s，1H)，4.71-4.60(m，1H)，3.81(s，3H)，3.50(m，2H)，3.37(t，J＝6.9Hz，1H)，3.08(m，2H)，1.42(d，J＝6.8Hz，6H)；ES-LCMS m/z 478.1，480.1[M+H]⁺。

Step 2: 5- [ 3-isopropyl-7- [ (5-methoxyindan-2-yl) amino group]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitriles

In N₂Downward 5- (5-bromo-3-pyridyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a]To a solution of pyrimidin-7-amine (120.0mg, 250.84. mu. mol, 1 eq) in DMF (6mL) was added Zn (CN)₂(117.83mg, 1.00mmol, 4 equiv.) and Pd (PPh)₃)₄(57.97mg, 50.17. mu. mol, 0.2 equiv.). The mixture was stirred at 85 ℃ for 32 hours. The reaction mixture was quenched by the addition of water (30mL) followed by extraction with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.55) to yield 5- [ 3-isopropyl-7- [ (5-methoxyindan-2-yl) amino group as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (80mg, 18)8.46 μmol, 75.1% yield, 100% purity).¹H NMR(400MHz，CDCl₃)δppm 9.47(d，J＝2.2Hz，1H)，8.94(d，J＝2.0Hz，1H)，8.72(t，J＝2.1Hz，1H)，7.89(s，1H)，7.18(d，J＝8.2Hz，1H)，6.88-6.76(m，2H)，6.65(d，J＝7.5Hz，1H)，6.38(s，1H)，4.73-4.58(m，1H)，3.82(s，3H)，3.51(m，2H)，3.36(t，J＝7.0Hz，1H)，3.09(m，2H)，1.42(d，J＝6.8Hz，6H)；ES-LCMS m/z 425.2[M+H]⁺。

Step 3: 5- [7- [ [ (2S) -5-hydroxyindan-2-yl]Amino group]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (I-37)

Reacting 5- [ 3-isopropyl-7- [ (5-methoxyindan-2-yl) amino group]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Mixture of pyridine-3-carbonitrile (35.00mg, 74.21. mu. mol, 1 eq.) and pyridine hydrochloride (428.76mg, 3.71mmol, 50 eq.) in N₂The mixture was stirred at 190 ℃ for 1 hour. The reaction mixture was slowly added with saturated NaHCO₃Aqueous (20mL) was quenched, followed by extraction with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc: 1/1, TLC: PE/EtOAc: 1/1, R_f0.53) to yield 5- [7- [ (5-hydroxyindan-2-yl) amino group as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (15mg, 34.20. mu. mol, 46.0% yield, 93.6% purity) (Note: a total of 80mg of target from both batches was used for SFC isolation). The racemate passes through chiral SFC (AD (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 55% -55%, min; peak 1 (R)_t1.817) and peak 2 (R)_t2.477) to be separated. The separated solution was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 10min) and then freeze-dried to give a yellow solid5- [7- [ [ (2S) -5-hydroxyindan-2-yl]Amino group]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (19.05mg, 39.41 μmol, 22.7% yield, 100% purity, 2HCl) (EE ═ 100%, R_t＝1.817min，[α]²⁶ _D＝3.608(c＝1.03mg/mL，MeOH))。¹H NMR(400MHz，CD₃OD)δppm 9.44(d，J＝2.2Hz，1H)，9.08(d，J＝2.0Hz，1H)，8.84(t，J＝2.1Hz，1H)，8.09(s，1H)，7.07(d，J＝8.2Hz，1H)，6.88(s，1H)，6.71(s，1H)，6.64(dd，J＝2.2，8.2Hz，1H)，4.96-4.90(m，1H)，3.50-3.41(m，2H)，3.38-3.33(m，1H)，3.19-3.03(m，2H)，1.40(d，J＝7.1Hz，6H)；ES-LCMS m/z 411.2[M+H]⁺。

Example 37

Synthesis I-38

The synthesis scheme is as follows:

step 1: (3R) -N- [5- (5-bromo-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

Reacting 5- (5-bromo-3-pyridyl) -7-chloro-3-isopropyl-pyrazolo [1, 5-a)]A mixture of pyrimidine (150mg, 396.73. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (77.59mg, 416.56. mu. mol, 1.05 equivalents) and DIEA (153.82mg, 1.19mmol, 207.31. mu.L, 3 equivalents) in i-PrOH (10mL) was degassed and N-substituted₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.34) to give (3R) -N- [5- (5-Bromo-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (150mg, 296.16 μmol, 74.6% yield, 99.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.17(d，J＝1.8Hz，1H)，8.73(d，J＝2.0Hz，1H)，8.60-8.55(m，1H)，7.90-7.87(m，1H)，7.47(d，J＝7.7Hz，1H)，7.34(d，J＝8.2Hz，1H)，7.19(br t，J＝7.6Hz，1H)，7.15-7.10(m，1H)，6.58(br d，J＝8.8Hz，1H)，6.40(s，1H)，4.32(br s，1H)，3.45-3.32(m，2H)，3.06-2.90(m，3H)，2.44-2.23(m，2H)，1.43(d，J＝6.8Hz，6H)；ES-LCMS m/z 501.1，503.1[M+H]⁺。

Step 2: 5- [ 3-isopropyl-7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (I-38)

Mixing (3R) -N- [5- (5-bromo-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (80mg, 157.95 μmol, 1 eq.), Pd (PPh3)4(73.01mg, 63.18 μmol, 0.4 eq.), and Zn (CN)₂A mixture of (74.19mg, 631.81. mu. mol, 4 equivalents) in DMF (5mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 85 ℃ for 19 hours under an atmosphere. The mixture was concentrated and water (80mL) was added, followed by extraction with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to a residue which is purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 70% -100%, 10min) to obtain the product 5- [ 3-isopropyl-7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] in yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (11.7mg, 26.14. mu. mol, 16.6% yield, 100.0% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.78(s，1H)，9.66(d，J＝2.0Hz，1H)，9.08-9.01(m，2H)，8.03(s，1H)，7.96(d，J＝9.5Hz，1H)，7.36(d，J＝7.7Hz，1H)，7.28(d，J＝7.9Hz，1H)，7.06(s，1H)，7.01(t，J＝7.4Hz，1H)，6.96-6.90(m，1H)，4.53-4.41(m，1H)，3.32-3.22(m，1H)，3.19-3.00(m，2H)，2.97-2.81(m，2H)，2.23-2.13(m，2H)，1.38(d，J＝6.8Hz，6H)；ES-LCMS m/z 448.2[M+H]⁺。

Example 38

Synthesis I-39

The synthesis scheme is as follows:

step 1: 3-bromo-7-chloro-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidines

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]NBS (32.97mg, 185.23. mu. mol, 1.1 equiv.) was added to a solution of pyrimidine (50mg, 168.39. mu. mol, 1 equiv.) in DCM (2mL) and ACN (4 mL). Mixing the mixture in N₂Stirred under an atmosphere at 30 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-bromo-7-chloro-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a as a yellow solid]Pyrimidine (55.16mg, 168.41 μmol, 100.0% yield, 100% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.12(s，1H)，8.65(d，J＝2.6Hz，1H)，8.43-8.19(m，2H)，7.51(s，1H)；ES-LCMS m/z 327.0，329.0[M+H]⁺.

Step 2: 3-bromo-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-39)

To 3-bromo-7-chloro-5- (5-fluoro-3-pyridyl) pyri dineAzolo [1, 5-a ]]To a solution of pyrimidine (55.16mg, 168.41. mu. mol, 1 eq) in i-PrOH (4mL) was added DIEA (65.30mg, 505.22. mu. mol, 88.00. mu.L, 3 eq) and 2- (1H-indol-3-yl) ethylamine (53.96mg, 336.81. mu. mol, 2 eq). Mixing the mixture in N₂Stirred at 60 ℃ for 5 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl Durashell C18150X 25X 5. mu.; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 12min) and then lyophilized to give 3-bromo-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (65mg, 115.93 μmol, 68.8% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm8.71(s，1H)，8.55(s，1H)，8.18(s，1H)，7.70(d，J＝8.8Hz，1H)，7.62(d，J＝8.0Hz，1H)，7.16(d，J＝8.3Hz，1H)，7.05-6.91(m，3H)，5.94(s，1H)，3.98(t，J＝5.9Hz，2H)，3.22(t，J＝6.0Hz，2H)；ES-LCMS m/z 451.1，453.1[M+H]⁺.

Example 39

Synthesis I-40

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-40)

4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine (60.00mg, 205.68 μmol, 1 eq), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (42.14mg, 226.25 μmol, 1.1 eq), DIEA (79.75mg, 617.05 μmol, 107.4)8 μ L, 3 equivalents) of the mixture in i-PrOH (4mL) was degassed and treated with N₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 55 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 70% -100%, 10min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (42.07mg, 75.45 μmol, 36.7% yield, 98.8% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.46(s，1H)，8.81(d，J＝9.3Hz，1H)，8.76(s，1H)，8.12-7.92(m，1H)，7.37(d，J＝7.7Hz，1H)，7.27(d，J＝7.9Hz，1H)，7.08-7.00(m，1H)，6.99-6.90(m，1H)，3.34(s，1H)，3.31-3.25(m，2H)，3.18-2.79(m，3H)，2.44-2.21(m，2H)，1.42(d，J＝7.1Hz，6H)；ES-LCMS m/z 442.2[M+H]⁺。

Example 40

Synthesis I-41

The synthesis scheme is as follows:

step 1: (3R) -N- [5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-41)

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 166.91 μmol, 1.0 equiv) in i-PrOH (3mL) were added DIEA (64.71mg, 500.72 μmol, 87.21 μ L, 3.0 equiv) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (37.30mg, 200.29 μmol, 1.2 equiv). The mixture was stirred at 60 deg.CFor 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 38% -68%, 10 min). Lyophilizing the desired fractions to obtain (3R) -N- [5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (61.30mg, 120.71 μmol, 72.3% yield, 100.0% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.01(s，1H)，8.77(d，J＝2.6Hz，1H)，8.34-8.27(m，2H)，7.39(d，J＝7.7Hz，1H)，7.28(d，J＝7.9Hz，1H)，7.13(s，1H)，7.09-7.01(m，1H)，7.00-6.93(m，1H)，6.66(d，J＝2.2Hz，1H)，4.68(s，1H)，3.37-3.32(m，2H)，3.14-3.01(m，2H)，2.44-2.28(m，2H)；ES-LCMS m/z 339.2[M+H]⁺。

Example 41

Synthesis of I-42a

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-indazol-5-yl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-42)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (60mg, 206.38 μmol, 1 eq) in i-PrOH (5mL) was added DIEA (266.73mg, 2.06mmol, 359.47 μ L, 10 eq) and 4, 5, 6, 7-tetrahydro-1H-indazol-5-amine (43.36mg, 206.38 μmol, 1 eq, 2 HCl). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAc. 1/0 to0/1，TLC：PE/EtOAc＝1/1，R_f0.16) to yield the product. The product was passed through chiral SFC (AD (250 mm. times.30 mm, 5 μm), mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%; 35% -35%, min; peak 1 (R)_t5.512) and peak 2 (R)_t6.038) to be separated. The separated solution was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% to 65%, 10min) followed by lyophilization to give 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-indazol-5-yl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (29.07mg, 58.0 μmol, 24.1% yield, 100% purity, 3HCl) (EE ═ 94.6%, R_t＝5.512min，[α]²⁶ _D＝-18.785(c 1.05mg/mL，MeOH))。¹H NMR(400MHz，CD₃OD)δppm9.07(s，1H)，8.77(d，J＝2.4Hz，1H)，8.39(td，J＝2.2，9.2Hz，1H)，8.20(s，1H)，7.96(s，1H)，6.98(s，1H)，4.57(s，1H)，3.40-3.34(m，1H)，3.26(dd，J＝5.2，15.3Hz，1H)，3.15-3.04(m，2H)，2.92(dd，J＝9.6，15.3Hz，1H)，2.45-2.36(m，1H)，2.31-2.19(m，1H)，1.41(d，J＝7.1Hz，6H)；ES-LCMS m/z 392.2[M+H]⁺。

Example 42

Synthesis I-43

The synthesis scheme is as follows:

step 1: 3- (5-bromo-3-pyridyl) -3-oxo-propionic acid methyl ester and (Z) -3- (5-bromo-3-pyridyl) -3-hydroxy-prop-2-enoic acid methyl ester

At 30 ℃ under N₂To a mixture of 5-bromopyridine-3-carboxylic acid (5g, 24.75mmol, 1 eq) and TEA (2.50g, 24.75mmol, 3.45mL, 1 eq) in THF (100mL) was added CDI (6.02g, 37.13mmol, 1.5 eq) in one portion. The mixture was stirred at 30 ℃ for 1 hour. Add potassium 3-methoxy-3-oxo-propionate (7.73g, 49.50mmol, 2 equiv.) and MgCl₂(4.71g, 49.50mmol, 2 equiv.) and the mixture was stirred at 30 ℃ for 16 h. The mixture was adjusted to pH 5-6 with 3N HCl and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.47) to yield methyl 3- (5-bromo-3-pyridyl) -3-oxo-propionate (1.85g, 6.45mmol, 26.1% yield, 90.0% purity) and (Z) -methyl 3- (5-bromo-3-pyridyl) -3-hydroxy-prop-2-enoate (1.85g, 6.45mmol, 26.1% yield, 90.0% purity) as a white solid.¹H NMR(400MHz，CDCl₃)δppm 12.46(s，1H)，9.05(d，J＝2.0Hz，1H)，8.90-8.87(m，2H)，8.75(d，J＝2.2Hz，1H)，8.39-8.36(m，1H)，8.21(t，J＝2.1Hz，1H)，5.72(s，1H)，4.02(s，2H)，3.84(s，3H)，3.78(s，3H)；ES-LCMS m/z258.0，260.0[M+H]⁺。

Step 2: 5- (5-bromo-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

A mixture of 3- (5-bromo-3-pyridinyl) -3-oxo-propionic acid methyl ester (1.11g, 3.87mmol, 1 eq) and 1H-pyrazol-5-amine (386.37mg, 4.65mmol, 1.2 eq) in AcOH (5mL) was stirred at 120 ℃ for 1H. The reaction mixture was concentrated under reduced pressure to give 5- (5-bromo-3-pyridyl) pyrazolo [1, 5-a as a yellow solid]Pyrimidin-7-ol (1g, 3.44mmol, 88.7% yield, crude purity).¹H NMR(400MHz，CDCl₃)δppm 10.31(s，1H)，9.00(d，J＝2.0Hz，1H)，8.88(d，J＝2.0Hz，1H)，8.52(t，J＝2.1Hz，1H)，7.91(d，J＝2.0Hz，1H)，7.51(s，1H)，6.25-6.21(m，2H)；ES-LCMS m/z 293.0，295.0[M+H]⁺。

Step 3: 5- (5-bromo-3-pyridinyl) -7-chloro-pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-bromo-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (1g, 3.44mmol, 1 eq) in POCl₃The solution in (8mL) was stirred at 100 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (TLC: PE/EtOAc ═ 3/1, R)_f0.65) to yield 5- (5-bromo-3-pyridinyl) -7-chloro-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (0.8997g, 2.91mmol, 84.6% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.18(d，J＝2.0Hz，1H)，8.81(d，J＝2.2Hz，1H)，8.62(t，J＝2.0Hz，1H)，8.30(d，J＝2.4Hz，1H)，7.44(s，1H)，6.91(d，J＝2.4Hz，1H)；ES-LCMS m/z 309.0，311.0[M+H]⁺。

Step 4: 5- (5-bromo-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amines

To 5- (5-bromo-3-pyridyl) -7-chloro-pyrazolo [1, 5-a]A mixture of pyrimidine (500mg, 1.62mmol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (388.18mg, 2.42mmol, 1.5 eq) in i-PrOH (20mL) was added DIEA (626.28mg, 4.85mmol, 844.04. mu.L, 3 eq) in one portion. The mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.35) to yield 5- (5-bromo-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (629mg, 1.45mmol, 89.9% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.87(d，J＝1.8Hz，1H)，8.71(d，J＝2.2Hz，1H)，8.41-8.37(m，1H)，8.08(br s，1H)，8.01(d，J＝2.2Hz，1H)，7.68(d，J＝7.5Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.23-7.17(m，2H)，7.11(s，1H)，6.61(br s，1H)，6.55(d，J＝2.2Hz，1H)，6.12(s，1H)，3.86(q，J＝6.2Hz，2H)，3.28(t，J＝6.6Hz，2H)；ES-LCMS m/z 435.0，437.0[M+H]⁺。

Step 5: 5- [7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (I-43)

Reacting 5- (5-bromo-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (150mg, 346.18. mu. mol, 1 eq.), Zn (CN)₂A mixture of (162.60mg, 1.38mmol, 87.89. mu.L, 4 equiv.) and Pd (PPh3)4(80.01mg, 69.24. mu. mol, 0.2 equiv.) in DMF (5mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 85 ℃ for 19 hours under an atmosphere. The mixture was concentrated and saturated NaHCO was added₃Solution (10 mL). The mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated. MeOH (30mL) was added to the crude product and stirred for 10 min. The suspension was filtered and the solid collected, washed with PE/EtOAc (2/1, 30 mL. times.2) and dried in vacuo to give 5- [7- [2- (1H-indol-3-yl) ethylamino ] as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (67.84mg, 176.30. mu. mol, 50.9% yield, 98.6% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.80(brs，1H)，9.46(d，J＝2.2Hz，1H)，9.08(d，J＝2.0Hz，1H)，8.76(t，J＝2.1Hz，1H)，8.19(br s，1H)，8.14(d，J＝2.4Hz，1H)，7.65(d，J＝7.9Hz，1H)，7.29(d，J＝7.9Hz，1H)，7.21(s，1H)，7.09-6.97(m，2H)，6.70(s，1H)，6.52(d，J＝2.2Hz，1H)，3.85(d，J＝6.0Hz，2H)，3.14(t，J＝7.3Hz，2H)；ES-LCMS m/z 380.2[M+H]⁺。

Example 43

Synthesis I-44

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N-indan-2-yl-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-44)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 168.55. mu. mol, 1 equivalent), indan-2-amine (26.94mg, 202.25. mu. mol, 1.2 equivalents) and DIEA (65.35mg, 505.64. mu. mol, 88.07. mu.L, 3 equivalents) in i-PrOH (5mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 10min) to yield 5- (5-fluoro-3-pyridinyl) -N-indan-2-yl-3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-amine (27.63mg, 59.44 μmol, 35.3% yield, 99.0% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 9.32(t，J＝1.6Hz，1H)，8.66(d，J＝2.8Hz，1H)，8.50-8.46(m，1H)，8.16(d，J＝8.4Hz，1H)，8.01(s，1H)，7.28-7.25(m，2H)，7.20-7.17(m，2H)，7.00(s，1H)，4.95-4.84(m，1H)，3.43-3.38(m，2H)，3.26-3.22(m，1H)，3.20-3.14(m，2H)，1.37(d，J＝7.2Hz，6H)；ES-LCMS m/z 388.2[M+H]⁺。

Example 44

Synthesis I-45

The synthesis scheme is as follows:

step 1: 3-isopropyl-5-phenyl-pyrazolo [1, 5-a ]]Pyrimidin-7-ols

A mixture of 3-oxo-3-phenyl-propionic acid methyl ester (100mg, 561.21 μmol, 1 eq), 4-isopropyl-1H-pyrazol-5-amine (70.25mg, 561.21 μmol, 1 eq) in AcOH (33.70mg, 561.21 μmol, 32.10 μ L, 1 eq) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 120 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-isopropyl-5-phenyl-pyrazolo [1, 5-a as a dark brown oil]Pyrimidin-7-ol (90mg, 355.31 μmol, 63.3% yield), which was used in the next step without further purification. ES-LCMS M/z 254.1[ M + H ]]⁺。

Step 2: 7-chloro-3-isopropyl-5-phenyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 3-isopropyl-5-phenyl-pyrazolo [1, 5-a ]]Pyrimidin-7-ol (90mg, 355.31. mu. mol, 1 eq.) in POCl₃The solution in (2mL) was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM (10mL × 2) and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAC ═ 100/1 to 10/1, TLC: PE/EtOAC ═ 10/1, R_f0.55) to yield 7-chloro-3-isopropyl-5-phenyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (60mg, 207.11 μmol, 58.3% yield, 93.8% purity).¹H NMR(400MHz，CD₃OD)δppm 8.15-8.07(m，3H)，7.57-7.49(m，3H)，7.40(s，1H)，3.37-3.48(m，1H)，1.45(d，J＝6.8Hz，6H)；ES-LCMS m/z 272.1[M+H]⁺。

Step 3: n- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-5-phenyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-45)

Reacting 7-chloro-3-isopropyl-5-phenyl-pyrazolo [1, 5-a]A mixture of pyrimidine (60mg, 207.11. mu. mol, 1 eq), 2- (1H-indol-3-yl) ethylamine (49.77mg, 310.66. mu. mol, 1.5 eq) and DIEA (133.84mg, 1.04mmol, 180.37. mu.L, 5 eq) in i-PrOH (3mL) was degassed and N₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 50 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomo Synergic 18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10min) and then lyophilized to give N- [2- (1H-indol-3-yl) ethyl as a gray solid]-3-isopropyl-5-phenyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (38.50mg, 81.29 μmol, 39.3% yield, 98.9% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.12(s，1H)，7.58-7.52(m，2H)，7.49-7.43(m，2H)，7.23(d，J＝8.2Hz，1H)，7.20-7.15(m，2H)，7.07-7.02(m，2H)，6.90-6.84(m，1H)，5.71(s，1H)，3.96(t，J＝5.8Hz，2H)，3.29-3.23(m，1H)，3.23-3.19(m，2H)，1.33(d，J＝6.8Hz，6H)；ES-LCMS m/z 396.2[M+H]⁺。

Example 45

Synthesis I-46

The synthesis scheme is as follows:

step 1: 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

A mixture of methyl 3-oxo-3- (3-pyridyl) propionate (100mg, 558.12. mu. mol, 1 eq) and 4-isopropyl-1H-pyrazol-5-amine (69.86mg, 558.12. mu. mol, 1 eq) in AcOH (2mL) was stirred at 120 ℃ for 0.5H. The reaction mixture was concentrated under reduced pressure to give a crude product, 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a, as a brown oil]Pyrimidin-7-ol (120mg, 471.91 μmol, 84.6% yield, crude purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 9.47-8.95(m，1H)，8.80-8.70(m，1H)，8.30-8.20(m，1H)，7.87，7.38(m，1H)，7.60-7.50(m，1H)，7.08，1.24(d，J＝6.8Hz，3H)，1.07(dd，J＝3.5，6.8Hz，3H)；ES-LCMS m/z 255.1[M+H]⁺。

Step 2: 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidines

3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (120.00mg, 471.91. mu. mol, 1 equivalent) in POCl₃(4.95g, 32.28mmol, 3mL, 68.41 equiv.) the solution was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM (20mL) and prepared by preparative TLC (PE/EtOAc ═ 3/1, TLC: PE/EtOAc ═ 3/1, R_f0.40) to yield 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a) as a green solid]Pyrimidine (58mg, 212.66 μmol, 45.1% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.32(brs，1H)，8.75(br s，1H)，8.45(d，J＝6.4Hz，1H)，8.12(br s，1H)，7.52-7.44(m，1H)，7.43-7.39(m，1H)，3.45-3.40(m，1H)，1.51-1.41(m，6H)；ES-LCMS m/z 273.1[M+H]⁺。

Step 3: n- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-46)

To 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (40mg, 146.66. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (35.25mg, 220.00. mu. mol, 1.5 eq) in i-PrOH (5mL) was added DIEA (56.87mg, 439.99. mu. mol, 76.64. mu.L, 3 eq). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 10min) to obtain N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (31.67mg, 60.73 μmol, 41.4% yield, 97.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.84(dd，J＝1.2，5.4Hz，1H)，8.74(d，J＝1.8Hz，1H)，8.11(s，1H)，8.04-7.98(m，1H)，7.91(dd，J＝5.2，7.8Hz，1H)，7.57(d，J＝7.9Hz，1H)，7.14(d，J＝7.9Hz，1H)，7.01-6.95(m，2H)，6.91-6.86(m，1H)，5.81(s，1H)，4.00-3.94(m，2H)，3.24-3.16(m，3H)，1.32(d，J＝6.8Hz，6H)；ES-LCMS m/z 397.2[M+H]⁺。

Example 46

Synthesis I-47

A synthetic scheme;

step 1: 5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

To a solution of (z) -3- (5-fluoro-3-pyridyl) -3-hydroxy-prop-2-enoic acid methyl ester (100.00mg, 486.91 μmol, 1 eq) in AcOH (2mL) was added 4- (trifluoromethyl) -1H-pyri-dineAzole-5-amine (91.32mg, 486.91. mu. mol, 1 eq, HCl). The mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a as a yellow solid]Pyrimidin-7-ol (100mg, 335.35 μmol, 68.9% yield, crude), was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.00(d，J＝1.3Hz，1H)，8.87-8.79(m，2H)，8.35(s，1H)，8.23-8.11(m，2H)；ES-LCMS m/z 299.0[M+H]⁺。

Step 2: 7-chloro-5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-fluoro-3-pyridyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (100mg, 335.35. mu. mol, 1 eq.) in POCl₃(18.85g, 122.94mmol, 11.42mL, 366.59 equiv.) the solution was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with DCM (20mL × 2) and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc ═ 1/0 to 3/1, TLC: PE/EtOAc ═ 3/1, R_f0.64) to yield the product compound 7-chloro-5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (34mg, 80.53. mu. mol, 24.0% yield, 75.0% purity).¹H NMR(400MHz，CDCl₃)δppm9.13(s，1H)，8.67(s，1H)，8.48(s，1H)，8.30(d，J＝6.4Hz，1H)，7.65(s，1H)；ES-LCMS m/z317.1，319.0[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-47)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidine (30mg, 71.06. mu.m)ol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (17.08mg, 106.59. mu. mol, 1.5 eq) to a solution of i-PrOH (5mL) was added DIEA (27.55mg, 213.18. mu. mol, 37.13. mu.L, 3.0 eq). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 52% -82%, 10min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (24.84mg, 45.09 μmol, 63.5% yield, 99.8% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.77(br s，1H)，8.67(s，1H)，8.28(s，1H)，7.91(d，J＝8.2Hz，1H)，7.71-7.63(m，1H)，7.12-7.06(m，1H)，7.04-6.96(m，2H)，6.90(s，1H)，6.02(s，1H)，3.90(t，J＝6.1Hz，2H)，3.16(t，J＝6.1Hz，2H)；ES-LCMS m/z 441.2[M+H]⁺。

Example 47

Synthesis I-48

A synthetic scheme;

step 1: 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- (5-methoxyindan-2-yl) purin-6-amine

In N₂Next, to a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 164.55 μmol, 1 eq.) in i-PrOH (5mL) was added DIEA (170.13mg, 1.32mmol, 229.29 μ L, 8 eq.) and 5-methoxyindan-2-amine (33.60mg, 168.27 μmol, 1.02 eq., HCl). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture is brought under reduced pressureConcentration to give crude 2- (5-fluoro-3-pyridyl) -9-isopropyl-N- (5-methoxyindan-2-yl) purin-6-amine (60mg, 102.80 μmol, 62.4% yield, 71.7% purity) as a dark brown oil, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 11.16(s，1H)，9.54(s，1H)，8.51(d，J＝2.9Hz，1H)，8.45(d，J＝9.0Hz，1H)，7.83(s，1H)，7.17(d，J＝7.9Hz，1H)，6.83(s，1H)，6.77(dd，J＝2.5，8.3Hz，1H)，4.92(m，1H)，4.04(td，J＝6.1，12.3Hz，1H)，3.84-3.79(m，3H)，3.48(dt，J＝7.3，16.5Hz，2H)，3.05-2.92(m，2H)，1.22(d，J＝6.2Hz，6H)；ES-LCMS m/z 419.2[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridyl) -9-isopropyl-N- (5-methoxyindan-2-yl) purin-6-amine (I-48)

A solution of 2- (5-fluoro-3-pyridyl) -9-isopropyl-N- (5-methoxyindan-2-yl) purin-6-amine (60mg, 102.80 μmol, 1 eq.) in HBr (5mL, 60% in water) was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) and then lyophilized to give 2- [ [2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-yl) as a yellow solid]Amino group]Indan-5-ol (21.36mg, 44.75. mu. mol, 43.5% yield, 100% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.58(s，1H)，9.22(s，1H)，8.98(d，J＝8.4Hz，1H)，8.90(s，1H)，7.09(d，J＝8.2Hz，1H)，6.73(s，1H)，6.65(dd，J＝2.4，8.2Hz，1H)，5.24(s，1H)，5.16(td，J＝6.8，13.6Hz，1H)，3.46(ddd，J＝7.2，12.7，15.8Hz，2H)，3.02(dt，J＝4.5，14.9Hz，2H)，1.75(d，J＝6.1Hz，6H)；ES-LCMS m/z 405.1[M+H]⁺

Example 48

Synthesis I-49

The synthesis scheme is as follows:

step 1: 4- [2- [ [5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (I-49)

In N₂Down to 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 164.89. mu. mol, 1 eq.) in i-PrOH (5mL) was added DIEA (170.49mg, 1.32mmol, 229.77. mu.L, 8 eq.) and 4- (2-aminoethyl) phenol (33.93mg, 247.34. mu. mol, 1.50 eq.). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 10min) and then lyophilized to give 4- [2- [ [5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (46.38mg, 109.83. mu. mol, 66.6% yield, 100% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.85-8.75(m，2H)，8.27(d，J＝2.2Hz，1H)，8.09(td，J＝2.3，9.2Hz，1H)，7.07(d，J＝8.6Hz，2H)，6.65-6.56(m，3H)，6.46(s，1H)，3.97(t，J＝6.6Hz，2H)，3.00(t，J＝6.5Hz，2H)；ES-LCMS m/z350.2[M+H]⁺。

Example 49

Synthesis I-50

The synthesis scheme is as follows:

step 1: (6E) -6-hydroxyimino-5H-cyclopenta [ f][1，3]Benzodioxol-7-ones

Reacting 5, 6-dihydrocyclopenta [ f ]][1，3]A suspension of benzodioxol-7-one (0.5g, 2.84mmol, 1 equiv.) in MeOH (45mL) was heated to 45 deg.C, followed by the addition of isoamyl nitrite (539.40mg, 4.60mmol, 0.62mL, 1.62 equiv.) and concentrated HCl (12M in water, 0.47mL, 1.99 equiv.). The mixture was stirred at 45 ℃ for 1.5 hours. The mixture was filtered and the filter cake was washed with cold MeOH (5 mL. times.2) and dried in vacuo to give the product (300 mg). The filtrate was concentrated under reduced pressure to give a residue, to which MeOH (5mL) was added, followed by filtration and drying in vacuo to give the product (200 mg). The compound (6E) -6-hydroxyimino-5H-cyclopenta [ f ] is obtained as a yellow solid][1，3]Benzodioxol-7-one (500mg, 2.44mmol, 85.8% yield, 100% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 12.47(s，1H)，7.14(d，J＝10.4Hz，2H)，6.18(s，2H)，3.64(s，2H)；ES-LCMS m/z 206.1[M+H]⁺。

Step 2: 6, 7-dihydro-5H-cyclopenta [ f)][1，3]Benzodioxol-6-amines

To (6E) -6-hydroxyimino-5H-cyclopenta [ f][1，3]Benzodioxol-7-one (500mg, 2.44mmol, 1 equiv.) in AcOH (25mL) and concentrated H₂SO₄To the solution in (0.3mL) was added Pd/C (0.13g, 10%). Mixing the mixture in H₂(30psi) at 25 ℃ for 12 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue, to which water (50mL) was added, the pH was adjusted to 10-11 with 2N aqueous NaOH solution, and extraction was performed with DCM (30 mL. times.3). Combined organic matterThe layer was washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure to give 6, 7-dihydro-5H-cyclopenta [ f ] as a yellow solid][1，3]Benzodioxol-6-amine (250mg, 1.13mmol, 46.3% yield, 80% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃) δ ppm 6.68(s, 2H), 5.90(s, 2H), 3.91-3.76(m, 1H), 3.09(dd, J ═ 6.8, 15.3Hz, 2H), 2.58(dd, J ═ 4.9, 15.4Hz, 2H); ES-LCMSM/z found no correct mass.

Step 3: n- (6, 7-dihydro-5H-cyclopenta [ f)][1，3]Benzodioxol-6-yl) -5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-50)

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (60mg, 197.87. mu. mol, 1 eq.) in i-PrOH (3mL) was added DIEA (127.87mg, 989.37. mu. mol, 172.33. mu.L, 5 eq.) and 6, 7-dihydro-5H-cyclopenta [ f][1，3]Benzodioxol-6-amine (65.74mg, 296.81. mu. mol, 1.5 equivalents). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) followed by lyophilization to give N- (6, 7-dihydro-5H-cyclopenta [ f ] as a yellow solid][1，3]Benzodioxol-6-yl) -5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (21.53mg, 46.43 μmol, 23.4% yield, 99.7% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.02(t，J＝1.3Hz，1H)，8.81(d，J＝2.6Hz，1H)，8.34-8.29(m，1H)，8.28(d，J＝2.2Hz，1H)，7.05(s，1H)，6.76(s，2H)，6.66(d，J＝2.2Hz，1H)，5.94-5.90(m，2H)，5.08(t，J＝6.8Hz，1H)，3.46(dd，J＝7.7，15.4Hz，2H)，3.18(dd，J＝6.3，15.5Hz，2H)；ES-LCMS m/z 390.1[M+H]⁺。

Example 50

Synthesis I-51

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- (5-methoxyindan-2-yl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (35mg, 133.25. mu. mol, 1.0 equiv.) in i-PrOH (4mL) was added DIEA (86.10mg, 666.24. mu. mol, 116.04. mu.L, 5.0 equiv.) and 5-methoxyindan-2-amine (30mg, 150.24. mu. mol, 1.13 equiv., HCl salt). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridinyl) -N- (5-methoxyindan-2-yl) -3-methyl-pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-amine (50mg, 113.24 μmol, 85.0% yield, 88.2% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.07(s，1H)，8.55(d，J＝2.6Hz，1H)，8.21(d，J＝9.9Hz，1H)，7.86(s，1H)，7.18(d，J＝8.8Hz，1H)，6.87-6.75(m，2H)，6.60(m，1H)，6.39(s，1H)，4.66(s，1H)，3.81(s，3H)，3.70-3.64(m，4H)，2.39(s，3H)；ES-LCMS m/z 390.2[M+H]⁺。

Step 2: 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-51)

Reacting 5- (5-fluoro-3-pyridyl) -N- (5-methoxyindan-2-yl) -3-methyl-pyrazolo [1,5-a]pyrimidin-7-amine (50mg, 113.24 μmol, 1 eq.) was added to HBr (5mL, 60% in water) and the mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10 min). Freeze drying the desired fractions to give 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (15.05mg, 33.46. mu. mol, 29.5% yield, 99.6% purity, 2HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.03(s，1H)，8.75(d，J＝2.5Hz，1H)，8.31(td，J＝2.3，9.3Hz，1H)，8.07(s，1H)，7.08(d，J＝8.3Hz，1H)，6.89(s，1H)，6.72(s，1H)，6.68-6.62(m，1H)，4.99-4.95(m，1H)，3.50-3.41(m，2H)，3.21-3.10(m，2H)，2.37(s，3H)；ES-LCMS m/z 376.1[M+H]⁺。

Example 51

Synthesis I-52

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 164.89. mu. mol, 1.0 equiv.) in i-PrOH (6mL) was added DIEA (106.56mg, 824.47. mu. mol, 143.61. mu.L, 5.0 equiv.) and 5-methoxyindan-2-amine (35mg, 175.28. mu. mol, 1.06 equiv., HCl salt). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was not further purifiedUsed in the next step. The compound 5- (5-fluoro-3-pyridyl) -N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a) is obtained as a yellow oil]Pyrimidin-7-amine (60mg, 139.21 μmol, 84.4% yield, 87.1% purity).¹H NMR(400MHz，CDCl₃)δppm 8.97(s，1H)，8.49(d，J＝2.9Hz，1H)，8.09(td，J＝2.3，9.5Hz，1H)，7.94(d，J＝2.2Hz，1H)，7.11(d，J＝8.4Hz，1H)，6.79-6.69(m，2H)，6.51(d，J＝2.2Hz，1H)，6.37(s，1H)，4.63-4.55(m，1H)，3.77-3.68(m，3H)，3.59(dt，J＝3.0，6.6Hz，4H)；ES-LCMS m/z 376.2[M+H]⁺。

Step 2: 2- [ [5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Indan-5-ols

Reacting 5- (5-fluoro-3-pyridyl) -N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 139.21 μmol, 1 eq) was added to HBr (6mL, 60% in water) and the mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10 min). Freeze-drying the desired fractions to give 2- [ [5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (32.33mg, 72.95. mu. mol, 52.4% yield, 98.0% purity, 2HCl salt).¹H NMR(400MHz，CD₃OD)δppm9.01(s，1H)，8.82(s，1H)，8.34-8.26(m，2H)，7.12-7.05(m，2H)，6.73(s，1H)，6.69-6.63(m，2H)，5.06(s，1H)，3.47(td，J＝8.3，15.9Hz，2H)，3.27-3.15(m，2H)；ES-LCMS m/z 362.1[M+H]⁺。

Example 52

Synthesis I-53

The synthesis scheme is as follows:

step 1: 5- [ 4-chloro-6- (cyclopentyloxy) pyrimidin-2-yl]Pyridine-3-carbonitriles

To a solution of cyclopentanol (20.84mg, 241.96 μmol, 21.96 μ L, 1.5 equiv.) in THF (3mL) was added NaH (9.68mg, 241.96 μmol, 60% in mineral oil, 1.5 equiv.). The mixture was stirred at 0 ℃ for 30 minutes. 5- (4, 6-dichloropyrimidin-2-yl) pyridine-3-carbonitrile (50mg, 161.31. mu. mol, 1 eq.) was added to the above solution and the mixture was stirred at 28 ℃ for 12 h. The reaction mixture is reacted by adding NH₄Cl (2mL) and water (1mL) followed by extraction with EtOAc (20 mL. times.3). The combined organic layers were washed with Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc: 13/1, TLC: PE/EtOAc: 13/1, R_f0.54) to yield 5- [ 4-chloro-6- (cyclopentyloxy) pyrimidin-2-yl as a white solid]Pyridine-3-carbonitrile (35mg, 108.23 μmol, 67.1% yield, 93.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.70(d，J＝2.2Hz，1H)，9.04(d，J＝2.0Hz，1H)，9.01(t，J＝2.1Hz，1H)，6.9l(s，1H)，5.72-5.67(m，J＝3.1，6.0Hz，1H)，2.15-2.08(m，2H)，1.95-1.88(m，2H)，1.87-1.83(m，2H)，1.77-1.70(m，2H)；ES-LCMS m/z 301.1[M+H]⁺。

Step 2: 5- [4- (cyclopentyloxy) -6- [2- (1H-indol-3-yl) ethylamino]Pyrimidin-2-yl]Pyridine-3-carbonitrile (I-53)

Reacting 5- [ 4-chloro-6- (cyclopentyloxy) pyrimidin-2-yl]Pyridine-3-carbonitrile (60mg, 185.54. mu. mol, 1 eq.), 2- (1H-indol-3-yl) ethylamine (74.32mg, 463.85. mu. mol, 2.5 eq.) and DIEA (23.98mg185.54 μmol, 32.32 μ L, 1 eq) in i-PrOH (4mL) was placed in a microwave tube. The sealed tube was heated at 135 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 10min) and then lyophilized to give 5- [4- (cyclopentyloxy) -6- [2- (1H-indol-3-yl) ethylamino) as a yellow solid]Pyrimidin-2-yl]Pyridine-3-carbonitrile (21.28mg, 39.58. mu. mol, 21.3% yield, 99.3% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm10.81(br s，1H)，9.61(s，1H)，9.10(d，J＝2.0Hz，1H)，8.87(s，1H)，7.56(d，J＝7.9Hz，1H)，7.46(br s，1H)，7.31(d，J＝8.2Hz，1H)，7.21-7.15(m，1H)，7.07-7.01(m，1H)，7.00-6.94(m，1H)，5.72(s，1H)，5.39(br s，1H)，3.68(br s，2H)，2.96(t，J＝7.4Hz，2H)，1.96(d，J＝6.0Hz，2H)，1.74-1.64(m，4H)，1.62-1.52(m，2H)；ES-LCMS m/z 425.2[M+H]⁺。

Example 53

Synthesis I-54

The synthesis scheme is as follows:

step 1: 5- (4, 6-dichloropyrimidin-2-yl) pyridine-3-carbonitrile

4, 6-dichloro-2-iodo-pyrimidine (813.84mg, 2.91mmol, 1 eq), (5-cyano-3-pyridinyl) boronic acid (409.00mg, 2.76mmol, 0.95 eq), Pd (dppf) Cl₂(212.96mg, 291.04. mu. mol, 0.1 eq.), Na₂CO₃A mixture of (925.42mg, 8.73mmol, 3.0 equiv.) and water (2.4mL) in 1, 4-dioxane (12mL) was degassed and N₂Purifying 3 times, and mixing the mixture with N₂Stirred at 80 ℃ for 1 hour under an atmosphere. The reaction mixture was diluted with EtOAc (50mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAC. 100/1 to 5/1, TLC: PE/EtOAC. 5/1, R_f0.7) to yield 5- (4, 6-dichloropyrimidin-2-yl) pyridine-3-carbonitrile as a yellow solid (180mg, 580.71 μmol, 20.0% yield, 81.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.81(d，J＝2.4Hz，1H)，9.03(d，J＝2.0Hz，1H)，8.99(d，J＝2.0Hz，1H)，7.44(s，1H)；ES-LCMS m/z 250.9，252.9[M+H]⁺。

Step 2: 5- (4-chloro-6-isopropoxy-pyrimidin-2-yl) pyridine-3-carbonitrile

To a solution of i-PrOH (9.69mg, 161.31. mu. mol, 12.35. mu.L, 1 eq.) in THF (3mL) was added NaH (6.45mg, 161.31. mu. mol, 60%, 1 eq.). The mixture was stirred at 0 ℃ for 30 minutes. 5- (4, 6-dichloropyrimidin-2-yl) pyridine-3-carbonitrile (50mg, 161.31. mu. mol, 1 eq.) was added to the above solution. The mixture was stirred at 28 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was taken up in NH₄Cl (30mL) was diluted and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc: 10/1, TLC: PE/EtOAc: 10/1, R_f0.55) to yield 5- (4-chloro-6-isopropoxy-pyrimidin-2-yl) pyridine-3-carbonitrile as a white solid (25mg, 87.37 μmol, 54.2% yield, 96.0% purity).¹HNMR(400MHz，CD₃OD)δppm 9.70(s，1H)，9.05(d，J＝2.0Hz，1H)，9.01(t，J＝2.1Hz，1H)，6.90(s，1H)，5.61(td，J＝6.3，12.4Hz，1H)，1.44(d，J＝6.2Hz，6H)；ES-LCMS m/z 275.1[M+H]⁺。

Step 3: 5- [4- [2- (1H-indol-3-yl) ethylamino]-6-isopropoxy-Pyrimidin-2-yl]Pyridine-3-carbonitrile (I-54)

5- (4-chloro-6-isopropoxy-pyrimidin-2-yl) pyridine-3-carbonitrile (25mg, 91.01. mu. mol, 1 eq.), 2- (1H-indol-3-yl) ethylamine (21.87mg, 136.51. mu. mol, 1.5 eq.) and DIEA (35.29mg, 273.02. mu. mol, 47.56. mu.L, 3 eq.) were placed in a microwave tube in i-PrOH (3 mL). The sealed tube was heated at 135 ℃ for 5 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 10min) and then lyophilized to give 5- [4- [2- (1H-indol-3-yl) ethylamino ] as a yellow solid]-6-isopropoxy-pyrimidin-2-yl]Pyridine-3-carbonitrile (16.5mg, 32.17. mu. mol, 35.3% yield, 99.0% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm10.84(s，1H)，9.62(s，1H)，9.12(d，J＝2.0Hz，1H)，8.90(s，1H)，7.58(d，J＝8.4Hz，1H)，7.33(d，J＝7.9Hz，1H)，7.20(s，1H)，7.09-7.02(m，1H)，7.01-6.95(m，1H)，5.74(s，1H)，5.41-5.30(m，1H)，3.71(m，2H)，2.97(t，J＝7.3Hz，2H)，1.31(d，J＝6.2Hz，6H)；ES-LCMS m/z 399.2[M+H]⁺。

Example 54

Synthesis I-55

The synthesis scheme is as follows:

step 1: [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (1-piperidinyl) methanone (I-55)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (50mg, 120.07. mu. mol, 1 eq) in pyridine (2mL) was added piperidine (15.34mg, 180.11. mu. mol, 17.79. mu.L, 1.5 eq) and T₃P (152.82mg, 240.15. mu. mol, 142.82. mu.L, 50%, 2 equiv.). Mixing the mixture in N₂Stirring was carried out at 25 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (10mL) and extracted with EtOAc (30mL × 3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 42% -72%, 10min) and then lyophilized to give [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a white solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (1-piperidinyl) methanone (12.74mg, 21.49. mu. mol, 17.9% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.72-8.68(m，1H)，8.57(s，1H)，8.34(s，1H)，7.71(td J＝2.4，8.9Hz，1H)，7.60(d，J＝7.9Hz，1H)，7.14(d，J＝7.9Hz，1H)，7.02-6.96(m，2H)，6.94-6.89(m，1H)，6.03(s，1H)，4.00(t，J＝6.0Hz，2H)，3.71(m，4H)，3.23(t，J＝6.1Hz，2H)，1.75(m，2H)，1.68(m，4H)；ES-LCMSm/z 484.2[M+H]⁺。

Example 55

Synthesis I-56

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]-N, N-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acidAmine (I-56)

Reacting 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid (40mg, 96.06. mu. mol, 1 equivalent), N-methyl methylamine (23.50mg, 288.18. mu. mol, 3 equivalents, HCl), and T₃A mixture of P (611.29mg, 960.60. mu. mol, 571.30. mu.L, 50% in EtOAc, 10 equivalents) in pyridine (5mL) was stirred at 30 ℃ for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (20mL) and water (20mL), extracted with EtOAc (20 mL. times.3), over Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 33% -63%, 10min) to yield 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a yellow solid]-N, N-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (16.67mg, 29.67. mu. mol, 30.9% yield, 98.4% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.82(br s，1H)，9.12(s，1H)，8.69(d，J＝3.2Hz，1H)，8.43(t，J＝6.0Hz，1H)，8.31(s，1H)，8.21(d，J＝10.0Hz，1H)，7.63(d，J＝7.6Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.23(d，J＝1.6Hz，1H)，7.07-7.02(m，1H)，7.00-6.97(m，1H)，6.78(s，1H)，3.87(q，J＝6.8Hz，2H)，3.16-3.03(m，8H)；ES-LCMS m/z 444.2[M+H]⁺。

Example 56

Synthesis I-57

The synthesis scheme is as follows:

step 1: 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indole)Indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanone (I-57)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino at 25 deg.C]-N-methoxy-N-methyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (50mg, 96.85. mu. mol, 1 eq.) to a solution in THF (10mL) MeMgBr (3M Et₂Solution O, 4.68mL, 145.10 equivalents). The mixture was then stirred at 25 ℃ for 0.5 h. Saturated NH for the mixture₄Quenched with Cl (20mL), extracted with EtOAc (20 mL. times.3), over Na₂SO₄Dried, filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (SiO)₂，PE/EA＝1/1，R_f0.56), followed by preparative HPLC (column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) to yield 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanone (17.52mg, 32.98 μmol, 34.1% yield, 98.6% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.81(br s，1H)，9.16(s，1H)，8.72(d，J＝2.8Hz，1H)，8.62(t，J＝6.4Hz，1H)，8.53(s，1H)，8.23(d，J＝10.0Hz，1H)，7.65(d，J＝8.0Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.20(d，J＝2.0Hz，1H)，7.06-7.03(m，1H)，7.02-6.99(m，1H)，6.87(s，1H)，3.89(q，J＝6.8Hz，2H)，3.14(t，J＝7.2Hz，2H)，2.72(s，3H)；ES-LCMS m/z 415.2[M+H]⁺。

Example 57

Synthesis I-58

The synthesis scheme is as follows:

step 1: 4- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carbonyl]Piperazine-1-carboxylic acid tert-butyl ester

Reacting 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid (50mg, 120.07. mu. mol, 1 equivalent), piperazine-1-carboxylic acid tert-butyl ester (26.84mg, 144.09. mu. mol, 1.2 equivalents), and T₃A mixture of P (382.06mg, 600.37. mu. mol, 357.06. mu.L, 50%, 5 equivalents) in pyridine (1mL) was stirred at 25 ℃ for 16 h. The reaction mixture was quenched with water (5mL) and extracted with EtOAc (10 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtering and concentrating to dryness under reduced pressure to give 4- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino as brown solid]Pyrazolo [1, 5-a]Pyrimidine-3-carbonyl]Tert-butyl piperazine-1-carboxylate (100mg, crude), which was used in the next step without further purification.

Step 2: [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]-piperazin-1-yl-methanone (I-58)

To 4- [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carbonyl]To a solution of piperazine-1-carboxylic acid tert-butyl ester (100mg, 171.04 μmol, 1 eq) in MeOH (3mL) was added HCl/MeOH (4M, 3mL) and the mixture was then stirred at 25 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 20% -50%, 10 minutes). Lyophilizing the desired fractions to obtain [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino ] as an off-white solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]-piperazin-1-ylMethanone (19.42mg, 39.99 μmol, 23.4% yield, 99.8% purity).¹H NMR(400MHz，DMSO-d₆)δppm10.80(s，1H)，9.12(s，1H)，8.69(d，J＝2.8Hz，1H)，8.41(t，J＝6.0Hz，1H)，8.32(s，1H)，8.23-8.16(m，1H)，7.63(d，J＝8.4Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.22(d，J＝2.4Hz，1H)，7.05(t，J＝7.2Hz，1H)，7.00-6.95(m，1H)，6.77(s，1H)，3.87(q，J＝6.8Hz，2H)，3.54(m，4H)，3.13(t，J＝7.2Hz，2H)，2.77-2.73(m，4H)；ES-LCMS m/z 485.2[M+H]⁺。

Example 58

Synthesis I-59

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amines

In an ice bath and N₂To a suspension of 2- (1H-indol-3-yl) ethylamine (666.18mg, 4.16mmol, 1.05 eq) in anhydrous THF (10mL) under atmosphere was added NaH (223.55mg, 5.59mmol, 60% in mineral oil, 1.41 eq). After stirring for 30 min, the suspension was cooled to-60 ℃ and a solution of 4, 6-dichloro-2-methylsulfonyl-pyrimidine (900mg, 3.96mmol, 1.0 eq) in anhydrous THF (10mL) was added dropwise and the temperature was maintained below-55 ℃. The resulting mixture was stirred at-55 ℃ for 1 hour. The reaction mixture was slowly poured into water (100mL) and extracted with EtOAc (50mL × 3). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.45) to give 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amine (840mg, 2.68mmol, 67.6% yield, 98.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.04(s，1H)，7.68(d，J＝7.9Hz，1H)，7.36(d，J＝7.9Hz，1H)，7.23(dt，J＝1.1，7.6Hz，1H)，7.19-7.14(m，1H)，6.98(d，J＝2.2Hz，1H)，6.59(s，1H)，5.74(s，1H)，3.83-3.73(m，2H)，3.07(t，J＝6.8Hz，2H)；ES-LCMS m/z 307.0，309.0[M+H]⁺。

Step 2: 4-chloro-6- (cyclopentyloxy) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amines

To a solution of NaH (30.63mg, 765.68. mu. mol, 60% in mineral oil, 1.2 equivalents) in THF (3mL) was added cyclopentanol (57.71mg, 669.97. mu. mol, 60.81. mu.L, 1.05 equivalents). The mixture was stirred at 0 ℃ for 30 minutes. 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amine (200mg, 638.07 μmol, 1 eq.) was added to the above solution and the mixture was stirred at 15 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give 4-chloro-6- (cyclopentyloxy) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrimidin-2-amine (170mg, 309.66 μmol, 48.5% yield, 65.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.03(s，1H)，7.66(t，J＝7.5Hz，1H)，7.39(d，J＝8.2Hz，1H)，7.25-7.19(m，1H)，7.18-7.10(m，1H)，7.08-7.02(m，1H)，6.60(s，1H)，5.98(s，1H)，5.31(m，1H)，3.80-3.72(m，2H)，3.11-3.04(m，2H)，2.01-1.54(m，8H)；ES-LCMS m/z 357.1，358.1[M+H]⁺。

Step 3: 4- (cyclopentyloxy) -6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidine-2-amine (I-59)

4-chloro-6- (cyclopentyloxy) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amine (170mg, 304.89 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (128.88mg, 914.67 μmol, 3 eq), Cs₂CO₃(298.02mg, 914.67. mu. mol, 3, 0 equiv.) and Pd (dppf) Cl₂(22.31mg, 30.49. mu. mol, 0.1 equiv.) in 1, 4-dioxane (6mL) and water (1.2mL) was placed in a microwave tube. The sealed tube was heated at 80 ℃ for 30 minutes under microwave. The reaction mixture was diluted with EtOAc (100mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.40) followed by purification by preparative HPLC (HCl conditions, column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% HCl) -ACN](ii) a B%: 48% -78%, 10min) was purified again. The desired fractions were lyophilized to give 4- (cyclopentyloxy) -6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl ] ethyl as a yellow solid]Pyrimidin-2-amine (25.91mg, 48.46 μmol, 15.9% yield, 98.5% purity, 3HCl salt).¹HNMR(400MHz，CDCl₃)δppm 9.13(s，1H)，8.88(s，1H)，8.64(s，1H)，8.40(d，J＝7.3Hz，1H)，8.15(s，1H)，7.63(d，J＝7.8Hz，1H)，7.38(d，J＝8.0Hz，1H)，7.25(s，1H)，7.20(t，J＝7.4Hz，1H)，7.15-7.09(m，1H)，6.32(s，1H)，5.27(s，1H)，3.85(q，J＝6.5Hz，2H)，3.17(t，J＝6.8Hz，2H)，1.94(d，J＝5.8Hz，2H)，1.84-1.74(m，4H)，1.70-1.62(m，2H)；ES-LCMS m/z 418.2[M+H]⁺。

Example 59

Synthesis I-60

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-piperazin-1-yl-pyrimidin-4-amine

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]A mixture of pyrimidin-4-amine (60mg, 161.50. mu. mol, 1 eq), piperazine (139.11mg, 1.61mmol, 10 eq) and DIEA (104.36mg, 807.49. mu. mol, 140.65. mu.L, 5 eq) in i-PrOH (3mL) was sealed and irradiated under microwave (4 bar) at 150 ℃ for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCD-ACN)](ii) a B%: 8% -38%, 10 minutes). The desired fractions were lyophilized to give 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a yellow solid]-6-piperazin-1-yl-pyrimidin-4-amine (60.34mg, 106.30 μmol, 65.8% yield, 99.2% purity, 4 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.05(s，1H)，8.77(d，J＝2.8Hz，1H)，8.33(d，J＝9.2Hz，1H)，7.64(d，J＝8.0Hz，1H)，7.33(d，J＝7.6Hz，1H)，7.14(s，1H)，7.12-7.07(m，1H)，7.06-7.01(m，1H)，5.58(br s，1H)，3.86-3.72(m，6H)，3.27-3.24(m，4H)，3.14(t，J＝6.0Hz，2H)；ES-LCMS m/z418.1[M+H]⁺。

Example 60

Synthesis of I-61

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]-N-methyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (I-61)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylRadical amino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (60mg, 144.09 μmol, 1 eq) in anhydrous DCM (5mL) were added DIEA (55.87mg, 432.27 μmol, 75.29 μ L, 3 eq), HATU (136.97mg, 360.22 μmol, 2.5 eq) and methylamine hydrochloride (19.46mg, 288.18 μmol, 2 eq). The mixture was stirred at 25 ℃ for 12 hours. Addition of H₂O (10mL), and the mixture was extracted with DCM (10 mL. times.3). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give the crude product, which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: feilomo Gemini C18250X 50mm X10 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 35% to 65% per flow rate over 10 minutes: 25mL/min) followed by lyophilization to give 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino as a yellow solid]-N-methyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (19.25mg, 35.73. mu. mol, 24.79% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝12.5Hz，2H)，8.47(s，1H)，7.94(d，J＝9.0Hz，1H)，7.70(dd，J＝3.0，6.0Hz，1H)，7.15(dd，J＝2.9，6.1Hz，1H)，7.07-7.02(m，2H)，6.97(s，1H)，6.07(s，1H)，3.97(t，J＝6.0Hz，2H)，3.23(t，J＝6.1Hz，2H)，3.04-2.99(m，3H)；ES-LCMS m/z 452.1[M+Na]⁺。

Example 61

Synthesis I-62

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6- (1-piperidinyl) pyrimidin-4-amine (I-62)

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amine (60.61mg, 163.13 μmol, 1.0 equiv.), piperidine (862.20mg, 10.13mmol, 1mL, 62.07 equiv.), and DIEA (63.25mg, 489.39 μmol, 85.24 μ L, 3.0 equiv.) were placed in a microwave tube in i-PrOH (3 mL). The sealed tube was heated at 150 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 30% -60%, 10min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6- (1-piperidinyl) pyrimidin-4-amine (33.57mg, 63.84 μmol, 39.1% yield, 100.0% purity, 3HCl salt).¹H NMR(400MHz，CDCl₃)δppm 10.92(s，1H)，9.29(s，1H)，8.83(s，1H)，8.52(d，J＝6.8Hz，1H)，7.98(s，1H)，7.59(d，J＝7.7Hz，1H)，7.40-7.25(m，2H)，7.16-6.91(m，2H)，5.77(s，1H)，4.17(s，4H)，3.63(d，J＝6.6Hz，2H)，3.02(t，J＝6.7Hz，2H)，1.75-1.47(m，6H)；ES-LCMS m/z 417.2[M+H]⁺。

Example 62

Synthesis I-63

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl]-N4, N4-dimethyl-pyrimidine-4, 6-diamine (I-63)

The mixture containing 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amine (80.81mg, 217.51 μmol, 1.0 eq), N-methylmethylamine (M-methyl-N-methyl-methylamine)177.36mg, 2.18mmol, 10 equiv, HCl salt) and DIEA (168.66mg, 1.31mmol, 227.31. mu.L, 6.0 equiv.) in a microwave tube. The sealed tube was heated at 150 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 10min) and lyophilizing the desired fractions to give 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl ] as a yellow solid]-N4, N4-dimethyl-pyrimidine-4, 6-diamine (28.13mg, 56.54 μmol, 26.0% yield, 97.7% purity, 3HCl salt).¹H NMR(400MHz，DMSO-d₆)δppm 10.93(s，1H)，9.31(s，1H)，8.85(d，J＝2.0Hz，1H)，8.55(d，J＝8.8Hz，1H)，8.09(s，1H)，7.60(d，J＝7.7Hz，1H)，7.42-7.25(m，2H)，7.10-7.04(m，1H)，7.02-6.96(m，1H)，5.59(s，1H)，4.04(s，6H)，3.62(t，J＝6.7Hz，2H)，3.03(t，J＝6.7Hz，2H)；ES-LCMS m/z 377.2[M+H]⁺。

Example 63

Synthesis I-64

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-morpholinyl-pyrimidin-4-amine (I-64)

To 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]To a solution of pyrimidin-4-amine (60mg, 161.50. mu. mol, 1 eq) in i-PrOH (1.5mL) was added DIEA (208.72mg, 1.61mmol, 281.29. mu.L, 10 eq), morpholine (281.39mg, 3.23mmol, 284.24. mu.L, 20 eq). Subjecting the mixture to microwave at 150 deg.CStirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 10min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6-morpholinyl-pyrimidin-4-amine (53.33mg, 101.03 μmol, 62.5% yield, 100% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.87(s，1H)，9.30(s，1H)，8.86-8.32(m，2H)，7.59(d，J＝7.9Hz，1H)，7.35(d，J＝7.9Hz，1H)，7.25(s，1H)，7.11-7.04(m，1H)，7.03-6.94(m，1H)，5.70(s，1H)，3.78-3.60(m，11H)，3.01(t，J＝7.1Hz，2H)；ES-LCMS m/z 419.2[M+H]⁺。

Example 64

Synthesis I-65

The synthesis scheme is as follows:

step 1: [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Morpholinyl-methanones (I-65)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (40mg, 96.06. mu. mol, 1 eq) in pyridine (3mL) was added T₃P (122.26mg, 192.12. mu. mol, 114.26. mu.L, 50%, 2 equivalents) and morpholine (16.74mg, 192.12. mu. mol, 16.91. mu.L, 2.0 equivalents). The mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was quenched by the addition of water (50mL) followed by extraction with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying and filteringAnd concentrated under reduced pressure to give a residue which is purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10min) and then lyophilized to give [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Morpholinyl-methanone (19.50mg, 32.66 μmol, 34.0% yield, 99.6% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.71-8.59(m，2H)，8.34(s，1H)，7.73(d，J＝9.3Hz，1H)，7.63(d，J＝7.7Hz，1H)，7.14(d，J＝7.7Hz，1H)，7.05-6.90(m，3H)，6.06(s，1H)，3.97(t，J＝6.1Hz，2H)，3.75(s，8H)，3.22(t，J＝5.8Hz，2H)；ES-LCMS m/z 486.2[M+H]⁺。

Example 65

Synthesis I-66

The synthesis scheme is as follows:

step 1: 7-fluoro-2-methyl-3-methylsulfanyl-1H-indole

2-fluoroaniline (0.9g, 8.10mmol, 782.61. mu.L, 1 equiv.) and 1-methylthiopropan-2-one (371.24mg, 3.56mmol, 0.44 equiv.) were initially introduced into N-butyl acetate (4ml) and washed with N₂Then cooled to-30 ℃. A solution of sulfuryl chloride (437.28mg, 3.24mmol, 323.91. mu.L, 0.4 eq.) in n-butyl acetate (4ml) was added dropwise. The mixture was stirred at-30 ℃ for 2 hours. The reaction mixture was quenched by the addition of water (50mL) at 0 deg.C, followed by extraction with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtering and concentrating under reduced pressure to give a residue, which is chromatographed on flash silica gelMethod (PE/EtOAc: 1/0-10/1, TLC: PE/EtOAc: 20/1, R_f0.34) to yield the product 7-fluoro-2-methyl-3-methylsulfanyl-1H-indole (1g, 4.56mmol, 56.3% yield, 89.0% purity) as a red brown oil.¹H NMR(400MHz，CDCl₃)δppm 8.31(s，1H)，7.45(d，J＝7.7Hz，1H)，7.07(dt，J＝4.7，7.9Hz，1H)，6.89(dd，J＝7.8，10.9Hz，1H)，2.56(s，3H)，2.27(s，3H)；ES-LCMS m/z195.9[M+H]⁺。

Step 2: 7-fluoro-2-methyl-1H-indoles

To a solution of 7-fluoro-2-methyl-3-methylsulfanyl-1H-indole (737.08mg, 3.36mmol, 1 eq) in TFA (8mL) was added 2-thiobenzoic acid (1.30g, 8.40mmol, 2.5 eq). The mixture was stirred at 25 ℃ for 2 hours. TLC (PE/EtOAc ═ 20/1, R_f0.40) showed complete consumption of starting material and formation of new spots. The reaction mixture was quenched by addition of water (100mL), followed by adjustment of the pH to 10 by 1N aqueous NaOH, and extraction with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 20/1, R_f0.40) to yield 7-fluoro-2-methyl-1H-indole (400mg, 2.09mmol, 62.3% yield, 78.0% purity) as a yellow oil.¹H NMR(400MHz，DMSO-d₆) δ ppm 11.33(s, 1H), 7.20(d, J ═ 7.5Hz, 1H), 6.92-6.74(m, 2H), 6.19(s, 1H), 2.38(s, 3H); ES-LCMS m/z found no correct mass.

Step 3: 7-fluoro-2-methyl-1H-indole-3-carbaldehyde

In N₂POCl was added dropwise to a DMF solution (10mL) at-20 deg.C over a period of 10 minutes₃(481.07mg，3.14mmoL, 291.56 μ L, 2.0 equiv). After 1 hour, DMF (2mL) containing 7-fluoro-2-methyl-1H-indole (300mg, 1.57mmol, 1 equiv.) was added to the above solution, during which time the temperature was maintained below-20 ℃. The reaction mixture was stirred at 15 ℃ for 1 hour. The reaction mixture was purified by addition of NaHCO₃Aqueous (50mL) was quenched, followed by extraction with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.40) to yield 7-fluoro-2-methyl-1H-indole-3-carbaldehyde (200mg, 936.93 μmol, 59.7% yield, 83.0% purity) as a yellow solid.¹HNMR(400MHz，DMSO-d₆)δppm 12.44(s，1H)，10.08(s，1H)，7.85(d，J＝7.7Hz，1H)，7.13(dt，J＝5.1，7.8Hz，1H)，7.02(dd，J＝7.9，11.2Hz，1H)，2.70(s，3H)；ES-LCMS m/z 177.9[M+H]⁺。

Step 4: 7-fluoro-2-methyl-3- [ (E) -2-nitrovinyl]-1H-indoles

To a solution of 7-fluoro-2-methyl-1H-indole-3-carbaldehyde (200mg, 936.93. mu. mol, 1 eq.) in nitromethane (8mL) was added NH₄OAc (216.66mg, 2.81mmol, 3 equiv.). The mixture was stirred at 110 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (50mL), washed with water (10mL), brine (10mL), and washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude material which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.61) to give 7-fluoro-2-methyl-3- [ (E) -2-nitrovinyl) as a yellow solid]-1H-indole (150mg, 619.89. mu. mol, 66.2% yield, 91.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.82(br s，1H)，8.32(d，J＝13.5Hz，1H)，7.76(d，J＝13.5Hz，1H)，7.46(d，J＝7.9Hz，1H)，7.25-7.16(m，1H)，7.01(dd，J＝8.2，10.6Hz，1H)，2.67(s，3H)；ES-LCMS m/z 220.9[M+H]⁺。

Step 5: 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine

To 7-fluoro-2-methyl-3- [ (E) -2-nitrovinyl group at 0 deg.C]To a solution of-1H-indole (150mg, 619.89. mu. mol, 1 equiv) in THF (10mL) was added LAH (1M solution in THF, 3.10mL, 5 equiv) dropwise. After the addition, the mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was diluted with THF (50mL) and quenched at 0 deg.C by the sequential addition of water (0.05mL), aqueous NaOH (0.05mL, 10% in water), and water (0.15 mL). After stirring for 30 min, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give crude 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (100mg, 436.97 μmol, 70.5% yield, 84.0% purity) as a yellow oil which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.23(d，J＝7.8Hz，1H)，6.93-6.82(m，1H)，6.72(dd，J＝7.9，11.4Hz，1H)，2.90-2.80(m，4H)，2.39(s，3H)；ES-LCMS m/z 193.2[M+H]⁺。

Step 6: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo (I-66)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (40.82mg, 137.59. mu. mol, 1 eq) in i-PrOH (3mL) was added DIEA (53.35mg, 412.76. mu. mol, 71.89. mu.L, 3.0 eq) and 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (37.78mg, 165.11. mu. mol, 1.2 eq). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150X 25X 5 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 70% -100%, 10 minutes) to purifyFollowed by lyophilization to give N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (20.36mg, 45.36 μmol, 33.0% yield, 99.5% purity).¹H NMR(400MHz，CD₃OD)δppm 8.58(s，1H)，8.45(d，J＝2.6Hz，1H)，7.89(s，1H)，7.64-7.57(m，1H)，7.37(d，J＝7.9Hz，1H)，6.96(dt，J＝4.6，7.8Hz，1H)，6.69(dd，J＝7.8，11.6Hz，1H)，5.76(s，1H)，3.83(t，J＝6.2Hz，2H)，3.29-3.22(m，1H)，3.13(t，J＝6.1Hz，2H)，2.11(s，3H)，1.38(d，J＝7.1Hz，6H)；ES-LCMS m/z 447.2[M+H]⁺。

Example 66

Synthesis I-67

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6- (4-methylpiperazin-1-yl) pyrimidin-4-amine (I-67)

To 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]To a solution of pyrimidin-4-amine (60mg, 161.50 μmol, 1 eq) and 1-methylpiperazine (24.26mg, 242.25 μmol, 26.87 μ L, 1.5 eq) in i-PrOH (5mL) was added DIEA (62.62mg, 484.49 μmol, 84.39 μ L, 3.0 eq). The mixture was stirred at 110 ℃ for 16 hours. LC-MS showed 83% starting material remaining and 17% of the desired compound was detected. The mixture was dissolved in a microwave tube. 1-methylpiperazine (500mg, 5mmol) was added. N for the mixture₂And purifying for 1 minute. The sealed tube was heated at 150 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena)Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 42% -72%, 10min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a white solid]-6- (4-methylpiperazin-1-yl) pyrimidin-4-amine (49.11mg, 113.81 μmol, 70.5% yield, 100.0% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.82(br s，1H)，9.30(s，1H)，8.64(d，J＝2.9Hz，1H)，8.32(d，J＝10.1Hz，1H)，7.59(d，J＝7.7Hz，1H)，7.34(d，J＝7.9Hz，1H)，7.20(d，J＝2.0Hz，1H)，7.07(t，J＝7.2Hz，1H)，6.98(t，J＝7.4Hz，2H)，5.59(br s，1H)，3.60(br s，2H)，3.51(brs，4H)，2.97(t，J＝7.3Hz，2H)，2.37(d，J＝4.2Hz，4H)，2.20(s，3H)；ES-LCMS m/z 432.2[M+H]⁺。

Example 67

Synthesis I-68

The synthesis scheme is as follows:

step 1: [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (4-methylpiperazin-1-yl) methanone (I-68)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (50mg, 120.07 μmol, 1 eq) and 1-methylpiperazine (18.04mg, 180.11 μmol, 19.98 μ L, 1.5 eq) in DCM (5mL) were added HATU (54.79mg, 144.08 μmol, 1.2 eq) and DIEA (46.55mg, 360.21 μmol, 62.74 μ L, 3.0 eq). The mixture was stirred at 25 ℃ for 16 hours. LC-MS showed 42% starting material remaining and 51% desired compound was detected. 1-Methylpiperazine (18.04 mg) was added180.11 μmol, 19.98 μ L, 1.5 equiv), HATU (54.79mg, 144.08 μmol, 1.2 equiv), DIEA (46.55mg, 360.21 μmol, 62.74 μ L, 3.0 equiv) and DMF (2 mL). The mixture was stirred at 25 ℃ for 5 hours. Subjecting the reaction mixture to hydrogenation with H₂O (20mL) was diluted and extracted with DCM (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 36% -66%, 10min) and then lyophilized to give [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a pale yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]- (4-methylpiperazin-1-yl) methanone (15.94mg, 31.97 μmol, 26.6% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 8.63(s，1H)，8.48(d，J＝2.9Hz，1H)，8.26(s，1H)，7.71-7.62(m，2H)，7.19-7.13(m，1H)，7.07-6.95(m，3H)，6.05(s，1H)，3.90(t，J＝6.2Hz，2H)，3.75(br s，4H)，3.19(t，J＝6.1Hz，2H)，2.54(br s，4H)，2.33(s，3H)；ES-LCMS m/z499.2[M+H]⁺。

Example 68

Synthesis I-69

The synthesis scheme is as follows:

step 1: n- [2- (5-fluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (I-69)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (50mg, 164.55 μmol, eq.) in i-PrOH (3mL) was added DIEA (106.33mg, 822.73 μmol, 143.31 μ L, 5 equivalents) and 2- (5-fluoro-2-methyl-1H-indol-3-yl) ethylamine (37.96mg, 197.46 μmol, 1.2 equivalents). The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 10min) and then lyophilized to give N- [2- (5-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (32.52mg, 58.40 μmol, 35.5% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.35(s，1H)，8.93(s，1H)，8.77(s，1H)，8.62(d，J＝9.3Hz，1H)，7.15-6.94(m，2H)，6.63(t，J＝8.0Hz，1H)，5.10-4.99(m，1H)，4.04(m，2H)，3.09(t，J＝6.6Hz，2H)，2.30(s，3H)，1.71(d，J＝6.8Hz，6H)；ES-LCMS m/z 448.0[M+H]⁺。

Example 69

Synthesis I-70

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-70)

To a solution of 2- (1H-indol-3-yl) ethylamine (29.28mg, 182.74 μmol, 1.2 eq) in i-PrOH (3mL) was added DIEA (59.04mg, 456.85 μmol, 79.57 μ L, 3 eq) and 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidine (40mg, 152.28. mu. mol, 1 equivalent). Mixing the mixture in N₂Stirred under an atmosphere at 50 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residueSubstance which is obtained by preparative HPLC (column: Feilomena Synergi C18150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (32.43mg, 65.15 μmol, 42.8% yield, 99.6% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.72(d，J＝2.6Hz，1H)，8.35(s，1H)，8.10(s，1H)，7.56-7.52(m，1H)，7.50-7.45(m，1H)，7.16-7.10(m，1H)，6.98(s，1H)，6.97-6.92(m，1H)，6.85(m，1H)，5.76(s，1H)，4.06-3.99(m，2H)，3.24-3.19(m，2H)，2.30(s，3H)；ES-LCMS m/z 387.0[M+H]⁺。

Example 70

Synthesis I-71

The synthesis scheme is as follows:

step 1: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (I-71)

To a solution of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (41.67mg, 137.12 μmol, 1 eq) in i-PrOH (3mL) was added DIEA (53.16mg, 411.37 μmol, 71.65 μ L, 3.0 eq), 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (37.66mg, 164.55 μmol, 1.2 eq). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 46% -76%, 10min) and then freeze-drying to obtain N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-amine (27.83mg, 49.98 μmol, 36.4% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.30(s，1H)，8.80(s，1H)，8.74(dd，J＝1.1，2.9Hz，1H)，8.61-8.56(m，1H)，7.28(d，J＝7.9Hz，1H)，6.84(dt，J＝4.7，7.9Hz，1H)，6.63(dd，J＝7.9，11.7Hz，1H)，5.03(td，J＝6.9，13.6Hz，1H)，4.04(m，2H)，3.12(t，J＝6.6Hz，2H)，2.30(s，3H)，1.70(d，J＝6.8Hz，6H)；ES-LCMS m/z 447.9[M+H]⁺。

Example 71

Synthesis I-72

The synthesis scheme is as follows:

step 1: 2, 4-dichloro-6-isopropoxy-pyrimidine

To a solution of i-PrOH (344.04mg, 5.72mmol, 438.27. mu.L, 1.05 eq.) in THF (8mL) was added NaH (261.69mg, 6.54mmol, 60% in mineral oil, 1.2 eq.). The mixture was stirred at 0 ℃ for 30 minutes. 2, 4, 6-trichloropyrimidine (1g, 5.45mmol, 625.00. mu.L, 1.0 equiv.) was added to the above solution and the mixture was stirred at 15 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (150mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 100/1 to 50/1, TLC: PE/EtOAc: 100/1, R_f= 0.20) to give 4, 6-dichloro-2-isopropoxy-pyrimidine (347mg, crude) and 2, 4-dichloro-6-isopropoxy-pyrimidine as colorless oilA mixture of pyridines (173mg, crude).¹H NMR(400MHz，CDCl₃)δppm 7.00(s，1H)，5.35-5.23(m，1H)，1.40(d，J＝6.2Hz，6H)；ES-LCMS m/z 207.1，209.1[M+H]⁺。

Step 2: 4-chloro-N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-pyrimidin-2-amine

To a solution of (2- (1H-indol-3-yl) ethylamine (680.92mg, 4.25mmol, 2.2 equivalents) and 2, 4-dichloro-6-isopropoxy-pyrimidine (100mg, 482.96 μmol, 0.25 equivalents) in i-PrOH (5mL) were added DIEA (749.01mg, 5.80mmol, 1.01mL, 3.0 equivalents) and 4, 6-dichloro-2-isopropoxy-pyrimidine (200mg, 965.92 μmol, 0.5 equivalents). the mixture was stirred at 26 ℃ for 12 hours the reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAc 100/1 to 3/1, TLC: PE/EtOAc 3/1, R_f1＝0.55，R_f20.45) to yield 4-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6-isopropoxy-pyrimidin-2-amine (90mg, 220.37 μmol, 11.4% yield, 81.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.05(s，1H)，7.68-7.61(m，1H)，7.39(d，J＝8.2Hz，1H)，7.25-7.19(m，1H)，7.16-7.10(m，1H)，7.05(s，1H)，5.97(s，1H)，3.78-3.69(m，2H)，3.10-3.03(m，2H)，1.33(d，J＝5.3Hz，6H)；ES-LCMS m/z 331.1，332.1[M+H]⁺。

Step 3: 4- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-pyrimidin-2-amine (I-72)

4-chloro-N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-pyrimidin-2-amine (90.00mg, 220.37 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (62.10mg, 440.73 μmol, 2 eq), Cs₂CO₃(215.40mg, 661.10. mu. mol, 3.0 equiv.) and Pd (dppf) Cl₂(16.12mg, 22.04. mu. mol, 0.1 equiv.) in 1, 4-dioxane (3mL) and water (0.6mL) was placed in a microwave tube. The sealed tube was heated at 120 ℃ for 30 minutes under microwave. The reaction mixture was diluted with EtOAc (20mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 37% -67%, 12min) and lyophilizing the desired fractions to obtain 4- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6-isopropoxy-pyrimidin-2-amine (52.48mg, 104.79 μmol, 47.5% yield, 100.0% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 8.75(m，2H)，8.06(s，1H)，7.60(d，J＝7.8Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.14(s，1H)，7.12-7.06(m，1H)，7.04-6.99(m，1H)，6.62(s，1H)，5.18(s，1H)，3.92(t，J＝6.5Hz，2H)，3.15(t，J＝6.5Hz，2H)，1.36(d，J＝6.3Hz，6H)；ES-LCMS m/z 392.2[M+H]⁺。

Example 72

Synthesis I-73

The synthesis scheme is as follows:

step 1: 2-methyl-3-oxo-propionitrile

To a solution of DIPA (1.84g, 18.16mmol, 2.57mL, 1 equiv.) in THF (20mL) was added n-BuLi (2.5M in n-hexane, 7.63mL, 1.05 equiv.). The mixture was stirred at-65 ℃ for 30 minutes. A solution of propionitrile (1g, 18.16mmol, 1.30mL, 1 equiv.) in THF (10mL) was added dropwise to the above mixture. Mixing the mixture in N₂At-65 ℃ under an atmosphereStirred for 30 minutes. A solution of ethyl formate (1.41g, 19.06mmol, 1.53mL, 1.05 equiv.) in THF (10mL) was added dropwise and stirred at-65 ℃ for 3 hours. TLC (PE/EtOAc ═ 1/1, R_f0.45) indicates that one major new blob is detected. The reaction mixture was quenched by addition of 1N HCl solution (50mL) at-65 ℃ and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave 2-methyl-3-oxo-propionitrile (1.1g, crude) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.60(s，1H)，3.54(d，J＝7.5Hz，1H)，1.55(s，3H)。

Step 2: 4-methyl-1H-pyrazol-5-amines

To a solution of 2-methyl-3-oxo-propionitrile (1.1g, 13.24mmol, 1 equiv.) in EtOH (12mL) was added AcOH (1.39g, 23.17mmol, 1.32mL, 1.75 equiv.) and hydrazine (550.00mg, 17.16mmol, 620.77. mu.L, 1.3 equiv.). The mixture was stirred at 90 ℃ for 12 hours. TLC (PE/EtOAc ═ 1/1, R_f0.10) indicates that one major new blob is detected. The reaction mixture was concentrated under reduced pressure to give a residue which was taken up in NaHCO₃The solution (100mL) was diluted and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by flash silica chromatography (DCM/MeOH ═ 100/1 to 10/1, TLC: PE/EtOAc ═ 10/1, R_f0.75) to yield the compound 4-methyl-1H-pyrazol-5-amine (230mg, 2.37mmol, 17.9% yield, crude) as a yellow oil.¹HNMR(400MHz，CDCl₃)δppm 7.13(s，1H)，1.94-1.92(m，3H)。

Step 3: 5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-ols

To a solution of 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (400mg, 1.99mmol, 1 equiv.) in AcOH (6mL) was added 4-methyl-1H-pyrazol-5-amine (230mg, 2.37mmol, 1.19 equiv.). The mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-ol (500mg, crude), which was used in the next step without further purification. ES-LCMS M/z245.2[ M + H ]]⁺。

Step 4: 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-ol (500mg, 655.14. mu. mol, 1 eq.) in POCl₃The solution in (5mL) was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove POCl₃. The residue was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.40) to yield 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (145mg, 552.02 μmol, 84.3% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.10(s，1H)，8.60(d，J＝2.6Hz，1H)，8.24(dd，J＝1.8，9.3Hz，1H)，8.14(s，1H)，7.39(s，1H)，2.47(s，3H)；ES-LCMS m/z 262.9，264.9[M+H]⁺。

Step 5: 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (2, 5, 7-trifluoro-1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-73)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (40mg, 152.28. mu. mol, 1 eq) in i-PrOH (3mL) was added DIEA (157.45mg, 1.22mmol, 212.19. mu.L, 8.0 eq.) and 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (54.87mg, 182.74 μmol, 1.2 equivalents, ethanedioic acid salt). The mixture was stirred at 50 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%; 42% -62%, 10min) and lyophilizing the desired fractions to obtain the compound 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (2, 5, 7-trifluoro-1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (15.56mg, 27.91 μmol, 18.3% yield, 98.6% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 8.75(d，J＝2.4Hz，1H)，8.45(s，1H)，8.11(s，1H)，7.66-7.61(m，1H)，7.00(dd，J＝2.2，9.3Hz，1H)，6.44(ddd，J＝2.2，9.5，11.2Hz，1H)，5.75(s，1H)，4.00(t，J＝5.7Hz，2H)，3.16-3.10(m，2H)，2.31(s，3H)，2.15(s，3H)；ES-LCMS m/z 437.2[M+H]⁺。

Example 73

Synthesis I-74

A synthetic scheme;

step 1: n- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidin-4-amine (I-74)

4-chloro-2- (5-fluoro-3-pyridyl) -6-isopropoxy-pyrimidine (90mg, 322.77 μmol, 1.0 eq), 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (145.37mg, 484.15 μmol, 1.5 eq, oxalate) and DIEA (333.71mg, 2.58mmol, 449.75 μ L, 8 eq) in i-PrOH (5mL) were placed in a microwave tube. The sealed tube is added under microwave at 150 DEG CThe heat was applied for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.50) and then purified by preparative HPLC (HCl conditions; column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 10min) and lyophilizing the desired fractions to obtain N- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidin-4-amine (26.48mg, 48.07 μmol, 14.9% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.10(s，1H)，8.71(d，J＝2.6Hz，1H)，8.27(s，1H)，6.99(d，J＝9.3Hz，1H)，6.54(t，J＝9.9Hz，1H)，5.69(s，1H)，5.05(s，1H)，3.74(m，2H)，2.97(t，J＝6.6Hz，2H)，2.34(s，3H)，1.37(d，J＝6.2Hz，6H)；ES-LCMSm/z 442.2[M+H]⁺。

Example 74

Synthesis of I-75a, I-75b and I-75c

The synthesis scheme is as follows:

step 1: n- (2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) carbamic acid tert-butyl ester

To a solution of tert-butyl N- (4-oxocyclohexyl) carbamate (1g, 4.69mmol, 1.00mL, 1 eq) in DCM (30mL) was added MgSO 2₄(564.38mg, 4.69mmol, 1 equiv.) and phenylhydrazine (507.05mg, 4.69mmol, 460.96. mu.L, 1 equiv.). The mixture was stirred at 28 ℃ for 2 hours. Then filtered off of MgSO₄The filtrate was evaporated under reduced pressure. The resulting brown oil was dissolved in toluene (20mL) and addedZnCl₂(3.20g, 23.44mmol, 5 equiv.) the mixture was heated at 110 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 5/1, R_f0.30) to yield the compound tert-butyl N- (2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) carbamate as a yellow solid (700mg, 1.96mmol, 41.7% yield, 80.0% purity).¹HNMR(400MHz，CD₃OD)δppm 7.33(d，J＝7.5Hz，1H)，7.23(td，J＝0.9，7.9Hz，1H)，7.04-6.97(m，1H)，6.97-6.90(m，1H)，3.92-3.79(m，1H)，2.92-2.78(m，2H)，2.57-2.31(m，2H)，1.93-1.68(m，2H)，1.47(s，9H)；ES-LCMS m/z 231.1[M-t-Bu+H]⁺。

Step 2: 2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To a solution of tert-butyl N- (2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) carbamate (700mg, 1.96mmol, 1 eq) in DCM (10mL) was added TFA (3.08g, 27.01mmol, 2.0mL, 13.81 eq). The mixture was stirred at 28 ℃ for 2 hours. TLC (PE/EtOAc ═ 5/1, R_f0) indicates complete consumption of the starting material and formation of a new spot. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (30mL) and adjusted to pH 10 by 1% NaOH solution. The mixture was extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave 2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (400mg, 1.80mmol, 92.3% yield, 84.0% purity) as a dark brown solid which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.80(s，1H)，7.44(d，J＝7.7Hz，1H)，7.27-7.23(m，1H)，7.13-7.04(m，2H)，3.34-3.24(m，1H)，3.07-2.97(m，1H)，2.81(t，J＝6.4Hz，2H)，2.50-2.43(m，1H)，2.13-2.05(m，1H)，1.84-1.76(m，1H)；ES-LCMSm/z 187.0[M+H]⁺。

Step 3: (3S) -N- [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-75b) and (3R) -N- [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-75a)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (153.06mg, 515.96 μmol, 1.0 eq) in i-PrOH (10mL) was added DIEA (200.05mg, 1.55mmol, 269.60 μ L, 3.0 eq.) and 2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (145.09mg, 654.35 μmol, 1.27 eq.). The mixture was stirred at 50 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.80). The compound was passed through SFC (conditions: column: AD (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O EtOH](ii) a B%: 45% -45%, min). The separated solution was concentrated to give the crude product which was purified by preparative HPLC (HCl conditions; column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN]60% -90%, 12min) followed by lyophilization to afford the enantiomer as a yellow solid (36.18mg, 65.79 μmol, 12.8% yield, 100.0% purity, 3HCl salt) (Rt: 4.768min, ee% 100.0 and [ α%]²⁹ _D＝-3.430(i-ProH，c＝0.107g/100mL))；¹H NMR(400MHz，CD₃OD)δppm 9.00(s，1H)，8.78(s，1H)，8.36-8.29(m，1H)，8.24(d，J＝1.3Hz，1H)，7.38(d，J＝7.7Hz，1H)，7.27(d，J＝7.9Hz，1H)，7.08-6.93(m，3H)，4.63(s，1H)，3.43-3.32(m，2H)，3.18-2.93(m，3H)，2.43-2.26(m，2H)，1.40(d，J＝6.8Hz，6H)；ES-LCMS m/z441.2[M+H]⁺And the other enantiomer as a yellow solid (36.49mg, 66.36 μmol, 12.9% yield, 100.0% purity, 3HCl salt) (Rt ═ 5.778min, ee ═ 96.4 and [ α%]²⁹ _D＝+3.121(i-ProH，c＝0.104g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.03(s，1H)，8.73(d，J＝2.6Hz，1H)，8.36-8.30(m，1H)，8.18(s，1H)，7.38(d，J＝7.7Hz，1H)，7.29-7.25(m，1H)，7.04(dt，J＝1.2，7.6Hz，1H)，7.00-6.93(m，2H)，4.60(s，1H)，3.40-3.32(m，2H)，3.16-2.92(m，3H)，2.43-2.24(m，2H)，1.40(d，J＝6.8Hz，6H)；ES-LCMS m/z 441.3[M+H]⁺。

Example 75

Synthesis I-77

The synthesis scheme is as follows:

step 1: 5-fluoro-2-methyl-1H-indole-3-carbaldehyde

In N₂POCl was added dropwise to DMF (40mL) under an atmosphere at-20 ℃ over a period of 10 minutes₃(4.11g, 26.82mmol, 2.49mL, 2 equiv.). After stirring for 1 hour, 5-fluoro-2-methyl-1H-indole (2g, 13.41mmol, 1 eq) was added to the above solution, during which time the temperature was maintained below-20 ℃. The reaction mixture was warmed to 15 ℃ and stirred for 1 hour. The reaction mixture was passed through saturated NaHCO₃Aqueous solution (100mL) was quenched and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.67) to yield 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (1.3g, 5.73mmol, 42.7% yield, 78.1% purity) as a yellow solid.¹H NMR(400MHz，CDCl₃)δppm 10.17(s，1H)，8.39(br s，1H)，7.93(d，J＝9.0Hz，1H)，7.08-6.89(m，1H)，2.75(s，3H)；ES-LCMSm/z 178.0[M+H]⁺。

Step 2: 5-fluoro-2-methyl-3- [ (E) -2-nitrovinyl]-1H-indoles

To a solution of 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (1.1g, 4.85mmol, 1 eq) in nitromethane (45mL) was added NH₄OAc (1.12g, 14.54mmol, 3 equiv.). The mixture was stirred at 110 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give 5-fluoro-2-methyl-3- [ (E) -2-nitrovinyl) as a brown solid]-1H-indole (0.92g, crude), which was used in the next step without further purification; ES-LCMS M/z 221.0[ M + H ]]⁺。

Step 3: 2- (5-fluoro-2-methyl-1H-indol-3-yl) ethylamine

To 5-fluoro-2-methyl-3- [ (E) -2-nitrovinyl group at 0 deg.C]To a solution of (1.40g, 6.36mmol, 1 equiv.) of (E) -1H-indole in THF (30mL) was added LAH (1M, 31.79mL, 5 equiv.). After the addition, the mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was diluted with THF (10mL) and then quenched at 0 ℃ by the sequential addition of water (1.4mL), 10% NaOH (1.4mL) and water (4.2 mL). After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 2- (5-fluoro-2-methyl-1H-indol-3-yl) ethylamine (1.0g, crude) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.14(dd，J＝8.8Hz，1H)，7.07(dd，J＝10.0Hz，1H)，6.72(td，J＝5.0，9.1Hz，1H)，2.85-2.74(m，4H)，2.33(s，3H)；ES-LCMS m/z 192.1[M+H]⁺。

Step 4: n- [2- (5-fluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-77)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (64.30mg, 216.75. mu. mol, 1 eq) in i-PrOH (5mL) was added DIEA (140.07mg, 1.08mmol, 188.77. mu.L, 5 eq) and 2- (5-fluoro-2-methyl-1H-indol-3-yl) ethylamine (50mg, 260.10. mu. mol, 1.2 eq). The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 7min) and then lyophilized to give N- [2- (5-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (17.49mg, 31.46 μmol, 14.5% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.75(d，J＝2.4Hz，1H)，8.40(s，1H)，8.21(s，1H)，7.54(d，J＝8.6Hz，1H)，7.07(dd，J＝2.3，9.8Hz，1H)，6.95(dd，J＝4.4，8.6Hz，1H)，6.59(J＝2.4，9.0Hz，1H)，5.71(s，1H)，4.03-3.95(m，2H)，3.28-3.20(m，1H)，3.16-3.09(m，2H)，2.16(s，3H)，1.34(d，J＝6.8Hz，6H)；ES-LCMS m/z447.1[M+H]⁺。

Example 76

Synthesis I-78

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxamides (I-78)

Reacting 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid (35mg, 84.05. mu. mol, 1 eq.), HATU (63.92mg, 168.10. mu. mol, 2 eq.), DIEA (32.59mg, 252.16. mu. mol, 43.92. mu.L, 3 eq.), and NH₄A mixture of Cl (13.49mg, 252.16. mu. mol, 3 equivalents) in DMF (5mL) was stirred at 25 ℃ for 3 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 36% -56%, 10min) and freeze-drying to obtain 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino) as yellow solid]Pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (16.47mg, 31.08. mu. mol, 37.0% yield, 99.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.85(s，1H)，8.73(s，1H)，8.51(s，1H)，8.03(d，J＝9.2Hz，1H)，7.72-7.69(m，1H)，7.12(d，J＝8.4Hz，1H)，7.04-7.01(m，2H)，6.95(s，1H)，6.08(s，1H)，3.98(t，J＝5.6Hz，2H)，3.22(t，J＝5.6Hz，2H)；ES-LCMS m/z 416.2[M+H]⁺。

Example 77

Synthesis I-79

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (2-methyl-1H-indol-3-yl) ethyl]Purine-6-amine (I-79)

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (52.08mg, 171.4)A mixture of 0. mu. mol, 1 eq), 2- (2-methyl-1H-indol-3-yl) ethylamine (29.87mg, 171.40. mu. mol, 1 eq) and DIEA (66.46mg, 514.21. mu. mol, 89.57. mu.L, 3 eq) in i-PrOH (3mL) was stirred at 55 ℃ for 19 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 42% -72%, 12min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -9-isopropyl-N- [2- (2-methyl-1H-indol-3-yl) ethyl as a yellow solid]Purin-6-amine (18.99mg, 34.91. mu. mol, 20.4% yield, 99.1% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.27-9.11(m，2H)，8.85(s，1H)，8.68(d，J＝8.78Hz，1H)，7.51-7.43(m，1H)，7.07-7.00(m，1H)，6.92-6.83(m，2H)，5.13-5.00(m，1H)，4.07(s，2H)，3.11(t，J＝6.53Hz，2H)，2.27(s，3H)，1.73(d，J＝6.53Hz，6H)；ES-LCMS m/z 430.2[M+H]⁺。

Example 78

Synthesis I-80

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-2-isopropoxy-pyrimidine

In an ice bath and N₂To a suspension of NaH (248.00mg, 6.20mmol, 60% in mineral oil, 1.41 equiv.) in anhydrous THF (10mL) was added i-PrOH (277.91mg, 4.62mmol, 354.03. mu.L, 1.05 equiv) under atmosphere. After stirring for 30 min, the suspension was cooled to-60 ℃ and 4, 6-dichloro-2-methylsulfonyl-pyrimidine (1g, 4.40mmol, 625.00 μ L, 1.0 eq.) in anhydrous THF (10mL) was added dropwise while maintaining the temperature below-5 ℃5 ℃ is adopted. The resulting mixture was stirred at-55 ℃ for 1 hour. The reaction mixture was slowly poured into water (100mL) and extracted with EtOAc (30mL × 3). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated to give 4, 6-dichloro-2-isopropoxy-pyrimidine (565mg, 2.56mmol, 58.2% yield, 94% purity) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.02-6.96(m，1H)，5.29(m，1H)，1.40(d，J＝6.0Hz，6H)；ES-LCMS m/z 206.9，208.9[M+H]⁺。

Step 2: 6-chloro-N- [2- (1H-indol-3-yl) ethyl]-2-isopropoxy-pyrimidin-4-amine

To a solution of 4, 6-dichloro-2-isopropoxy-pyrimidine (200mg, 907.96 μmol, 0.5 eq) in i-PrOH (6mL) was added DIEA (704.07mg, 5.45mmol, 948.88 μ L, 3.0 eq) and 2- (1H-indol-3-yl) ethylamine (329.00mg, 2.05mmol, 1.13 eq). The mixture was stirred at 26 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.45) to yield 6-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow oil]-2-isopropoxy-pyrimidin-4-amine (290mg, 841.57 μmol, 46.3% yield, 96% purity).¹H NMR(400MHz，CDCl₃)δppm8.10(s，1H)，7.60(d，J＝7.7Hz，1H)，7.43-7.37(m，1H)，7.24(dt，J＝1.0，7.6Hz，1H)，7.18-7.12(m，1H)，7.05(d，J＝2.4Hz，1H)，5.95(s，1H)，5.26-5.17(m，1H)，3.68(s，2H)，3.08(t，J＝6.6Hz，2H)，1.35(d，J＝6.2Hz，6H)；ES-LCMS m/z 330.9，332.0[M+H]⁺。

Step 3: 6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-2-isopropoxy-pyrimidin-4-amine (I-80)

Reacting 6-chloro-N- [2- (1H-indol-3-yl) ethyl]-2-isopropoxy-pyrimidin-4-amine (90mg, 261.18 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (92.00mg, 652.94 μmol, 2.5 eq), Cs₂CO₃(255.29mg, 783.53. mu. mol, 3.0 equiv.) and Pd (dppf) Cl₂(19.11mg, 26.12. mu. mol, 0.1 equiv.) in water (1.2mL) and 1, 4-dioxane (6mL) was placed in a microwave tube. The sealed tube was heated at 120 ℃ for 30 minutes under microwave. The reaction mixture was diluted with EtOAc (15mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 25% -55%, 10min) and lyophilizing the desired fractions to obtain 6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-2-isopropoxy-pyrimidin-4-amine (43.81mg, 87.48 μmol, 33.5% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD+Na₂CO₃)δppm 8.92(s，1H)，8.53(m，1H)，8.12(m，1H)，7.61(m，1H)，7.33(m，1H)，7.09(d，J＝7.0Hz，2H)，7.02(m，1H)，6.57(s，1H)，5.38-5.26(m，1H)，3.77(m，2H)，3.09(t，J＝7.0Hz，2H)，1.40(d，J＝5.8Hz，6H)；ES-LCMS m/z 392.0[M+H]⁺。

Example 79

Synthesis I-81

The synthesis scheme is as follows:

step 1: 3- (5-bromo-3-pyridinyl) -3-oxo-propionic acid methyl ester

Reacting 5-bromopyridine-3-carboxylic acidA mixture of (1g, 4.95mmol, 1 equiv.) and CDI (1.20g, 7.43mmol, 1.5 equiv.) in THF (10mL) was stirred at 20 deg.C for 1h, TEA (500.93mg, 4.95mmol, 689.03. mu.L, 1 equiv.) was added, the mixture was stirred at 20 deg.C for 1h, followed by the addition of potassium (3-methoxy-3-oxo-propionyl) oxy (1+) (1.55g, 9.90mmol, 2 equiv.) and MgCl (1.55g, 9.90mmol, 2 equiv.)₂(942.66mg, 9.90mmol, 406.32. mu.L, 2 equiv.). The mixture was stirred at 20 ℃ for 11 hours. The reaction mixture was adjusted to pH 2 with 2N HCl and extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 10/1 to 5/1, TLC: PE/EtOAc: 5/1, R_f0.58) to yield methyl 3- (5-bromo-3-pyridinyl) -3-oxo-propanoate as a white solid (554mg, 1.50mmol, 30.4% yield, 70% purity).¹H NMR(400MHz，CD₃OD)δppm 9.07-9.06(m，1H)，8.95(d，J＝1.6Hz，1H)，8.89(d，J＝2.0Hz，1H)，8.76(d，J＝2.4Hz，1H)，8.53-8.52(m，1H)，8.42(t，J＝2.0Hz，1H)，5.97(s，1H)，3.82(s，3H)，3.74(s，3H)；ES-LCMS m/z 259.9，261.9[M+H]⁺。

Step 2: 5- (5-bromo-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-ols

A mixture of 3- (5-bromo-3-pyridinyl) -3-oxo-propionic acid methyl ester (300mg, 813.74 μmol, 1 eq) and 4-isopropyl-1H-pyrazol-5-amine (122.23mg, 976.49 μmol, 1.2 eq) in AcOH (10mL) was stirred at 120 ℃ for 0.5H. The mixture was concentrated under reduced pressure to give 5- (5-bromo-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a brown oil]Pyrimidin-7-ol (450mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.99-8.88(m，1H)，8.74-8.73(m，1H)，8.39-8.37(m，2H)，7.79(s，1H)，3.21-3.20(m，1H)，1.39-1.33(m，6H)；ES-LCMS m/z 333.0，335.0[M+H]⁺。

Step 3: 5- (5-bromo-3-pyridinyl) -7-chloro-3-isopropyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-bromo-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-ol (450mg, 1.35mmol, 1 equiv.) in POCl₃(8.2g, 53.48mmol, 4.97mL, 39.60 equiv.) the solution was stirred at 110 ℃ for 1 hour. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 10/1 to 5/1, TLC: PE/EtOAc: 5/1, R_f0.58) to yield 5- (5-bromo-3-pyridinyl) -7-chloro-3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (331mg, 847.20 μmol, 62.7% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 9.20(s，1H)，8.79(d，J＝2.4Hz，1H)，8.59(t，J＝2.4Hz，1H)，8.14(s，1H)，7.37(s，1H)，3.42(s，1H)，1.45(d，J＝6.8Hz，6H)；ES-LCMS m/z 350.9，352.9[M+H]⁺。

Step 4: 5- (5-bromo-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

Reacting 5- (5-bromo-3-pyridyl) -7-chloro-3-isopropyl-pyrazolo [1, 5-a)]A mixture of pyrimidine (60mg, 153.57. mu. mol, 1 eq), 2- (1H-indol-3-yl) ethylamine (36.91mg, 230.36. mu. mol, 1.5 eq) and DIEA (59.54mg, 460.71. mu. mol, 80.25. mu.L, 3 eq) in i-PrOH (10mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (SiO2, PE/EtOAc 1/1, R)_f0.28) to yield 5- (5-bromo-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (70mg, 117.80 μmol, 76.7% yield, 80% purity).¹H NMR(400MHz，DMSO-d₆)δppm 9.21(d，J＝1.6Hz，1H)，8.77(d，J＝2.0Hz，1H)，8.62(s，1H)，7.99-7.95(m，2H)，7.64(d，J＝8.0Hz，1H)，7.31(d，J＝8.4Hz，1H)，7.23(d，J＝2.0Hz，1H)，7.09-6.99(m，2H)，6.66(s，1H)，3.84(q，J＝6.0Hz，2H)，3.27-3.22(m，1H)，3.13-3.10(m，2H)，1.35(d，J＝6.8Hz，6H)；ES-LCMS m/z 474.9，476.9[M+H]⁺。

Step 5: 5- [7- [2- (1H-indol-3-yl) ethylamino]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (I-81)

Reacting 5- (5-bromo-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (70mg, 117.80. mu. mol, 1 eq.), Pd (PPh)₃)₄(13.61mg, 11.78. mu. mol, 0.1 equiv.) and Zn (CN)₂A mixture of (27.67mg, 235.60. mu. mol, 2 equivalents) in DMF (5mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirring was carried out at 85 ℃ for 12 hours under an atmosphere. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150X 255 u; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 60% -90%, 10min) to yield 5- [7- [2- (1H-indol-3-yl) ethylamino ] as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-5-yl]Pyridine-3-carbonitrile (18.46mg, 43.72 μmol, 37.1% yield, 99.819% purity).¹H NMR(400MHz，CD₃OD)δppm 9.07(d，J＝2.0Hz，1H)，8.86(d，J＝1.6Hz，1H)，7.97(t，J＝2.0Hz，1H)，7.90(s，1H)，7.74-7.71(m，1H)，7.18-7.17(m，1H)，7.13-7.10(m，2H)，6.95(s，1H)，5.86(s，1H)，3.87(t，J＝6.0Hz，2H)，3.28-3.19(m，1H)，3.18(t，J＝6.0Hz，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 422.0[M+H]⁺。

Example 80

Synthesis of I-82a, I-82b and I-82c

The synthesis scheme is as follows:

step 1: n-benzyl-6-methoxy-tetralin-2-amine

To a solution of 6-methoxytetralin-2-one (300mg, 1.70mmol, 1 equiv) in anhydrous DCM (5mL) was added phenylmethylamine (182.43mg, 1.70mmol, 185.58. mu.L, 1 equiv), AcOH (102.23mg, 1.70mmol, 97.37. mu.L, 1 equiv) and NaBH (OAc)3(541.24mg, 2.55mmol, 1.5 equiv). The mixture was stirred at 25 ℃ for 12 hours. Aqueous NaOH (1M, 20mL) was added and the mixture was extracted with DCM (20mL × 3). The combined organic layers were washed with brine (20mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 2/1, R_f0.67) to yield N-benzyl-6-methoxy-tetralin-2-amine as a brown oil (255mg, 883.18 μmol, 51.88% yield, 92.6% purity).¹H NMR(400MHz，CD₃OD)δppm 7.38-7.28(m，4H)，7.26-7.21(m，1H)，6.98(d，J＝8.4Hz，1H)，6.67(dd，J＝2.5，8.3Hz，1H)，6.61(d，J＝2.4Hz，1H)，3.89(s，2H)，3.75(s，3H)，3.04-2.93(m，2H)，2.91-2.72(m，2H)，2.64-2.50(m，1H)，2.12-1.99(m，1H)，1.62-1.56(m，2H)；ES-LCMS m/z 268.2[M+H]⁺。

Step 2: 6-methoxy tetralin-2-amine

In N₂To a solution of N-benzyl-6-methoxy-tetralin-2-amine (255mg, 883.18 μmol, 1 eq) in anhydrous EtOH (10mL) and anhydrous THF (10mL) was added Pd/C (10%, 255mg) under an atmosphere. Will be provided withDegassing the suspension and applying H₂And purifying for 3 times. Mixing the mixture in H₂(50psi) at 50 ℃ for 8 hours. The mixture was filtered and concentrated to give the crude 6-methoxytetralin-2-amine (210mg, 874.40 μmol, 99.0% yield, 73.8% purity) as a black oil, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 6.94(d，J＝8.4Hz，1H)，6.68-6.64(m，1H)，6.62(d，J＝2.4Hz，1H)，3.74-3.71(m，3H)，3.10(ddt，J＝3.3，5.1，10.2Hz，1H)，2.93(dd，J＝4.1，15.5Hz，1H)，2.88-2.81(m，2H)，2.49(dd，J＝9.8，15.5Hz，1H)，2.06-1.97(m，1H)，1.64-1.51(m，1H)；ES-LCMS m/z 178.3[M+H]⁺。

Step 3: 2-aminotetralin-6-ol

A solution of 6-methoxytetralin-2-amine (210mg, 874.39. mu. mol, 1 eq.) in HBr solution (5mL) was stirred at 100 ℃ for 8 h. The mixture was concentrated to give the crude product 2-aminotetralin-6-ol (195mg, 350.66 μmol, 40.10% yield, 43.9% purity, HBr) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 6.91(d，J＝8.4Hz，1H)，6.58(dd，J＝2.4，8.4Hz，1H)，6.53(s，1H)，3.54-3.44(m，1H)，3.06(dd，J＝5.1，15.4Hz，1H)，2.86(dd，J＝5.1，8.2Hz，2H)，2.71(dd，J＝10.1，15.4Hz，1H)，2.21-2.12(m，1H)，1.85-1.75(m，1H)；ES-LCMS m/z 164.2[M+H]⁺。

Step 4: 2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Tetralin-6-ol

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (100mg, 337.09. mu. mol, 1 eq.) in i-prOH (5mL) was added DIEA (130.70mg, 101mmol, 176.14 μ L, 3 equivalents) and 2-aminotetralin-6-ol (150.39mg, 404.51 μmol, 1.2 equivalents). Subjecting the mixture to microwave at N₂Stirred at 120 ℃ for 3 hours under an atmosphere. The mixture was concentrated to remove the solvent. Addition of H₂O (10mL), extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 1/1, R_f0.60) to give 2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Tetralin-6-ol (78mg, 184.97 μmol, 54.9% yield, 99.0% purity).¹H NMR(400MHz，CD₃OD)δppm9.15(s，1H)，8.51(d，J＝2.6Hz，1H)，8.36(d，J＝9.3Hz，1H)，7.92(s，1H)，6.93(d，J＝7.5Hz，1H)，6.74(s，1H)，6.61-6.53(m，2H)，4.58(s，2H)，4.35-4.23(m，1H)，2.94-2.81(m，2H)，2.35-2.18(m，1H)，2.09-1.86(m，2H)，1.40(d，J＝7.1Hz，6H)；ES-LCMS m/z 418.0[M+H]⁺。

Step 5: (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Tetralin-6-ol (I-82b) and (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Tetralin-6-ol (I-82a)

2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Naphthin-6-ol (78mg, 184.97. mu. mol, 1 eq.) was passed through SFC (column: AD (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂OIPA](ii) a B%: 40% -40%, min). The separated solution was concentrated to give the crude product, which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: feilomo Synergi C18150X 30mm X4 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 55% to 85% per flow rate over 12 minutes: 25mL/min) followed by lyophilization gave the enantiomer (24.75) as a yellow solidmg, 50.47 μmol, 27.3% yield, 100% purity, 2HCl, SFC: t is_R＝5.168min，ee＝100％，OR：[α]^26.6 _D＝167.660)。¹H NMR(400MHz，CD₃OD)δppm 8.97(s，1H)，8.79(d，J＝2.6Hz，1H)，8.34-8.28(m，1H)，8.25(s，1H)，6.98-6.91(m，2H)，6.61-6.55(m，2H)，4.47(s，1H)，3.40-3.33(m，1H)，3.18(dd，J＝4.6，15.4Hz，1H)，3.09-2.99(m，2H)，2.96-2.87(m，1H)，2.25(s，1H)，2.07(dq，J＝5.5，11.8Hz，1H)，1.38(d，J＝7.1Hz，6H)；ES-LCMS m/z418.0[M+H]⁺(ii) a And the other enantiomer as a yellow solid (26.47mg, 53.98. mu. mol, 29.2% yield, 100% purity, 2HCl, SFC: T_R＝5.742min，ee＝100％，OR：[α]^26.8 _D＝-167.394)。¹H NMR(400MHz，CD₃OD)δppm 8.97(s，1H)，8.78(d，J＝2.9Hz，1H)，8.30(td，J＝2.2，9.0Hz，1H)，8.24(s，1H)，6.98-6.91(m，2H)，6.62-6.54(m，2H)，4.48(s，1H)，3.37-3.31(m，1H)，3.22-3.13(m，1H)，3.09-2.98(m，2H)，2.96-2.87(m，1H)，2.26(d，J＝10.4Hz，1H)，2.07(tdd，J＝5.6，11.6，17.7Hz，1H)，1.38(d，J＝6.8Hz，6H)；ES-LCMS m/z418.0[M+H]⁺。

Example 81

Synthesis I-83

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-83)

Mixing 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-2-methylRadical-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 160.79. mu. mol, 1 eq), 2- (1H-indol-3-yl) ethylamine (25.76mg, 160.79. mu. mol, 1 eq) and DIEA (62.34mg, 482.37. mu. mol, 84.02. mu.L, 3 eq) in i-PrOH (5mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 12min) to yield 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (41.24mg, 76.67 μmol, 47.7% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm8.68(d，J＝2.8Hz，1H)，8.33(s，1H)，7.51(d，J＝7.8Hz，1H)，7.47-7.45(m，1H)，7.15(d，J＝7.6Hz，1H)，7.02(s，1H)，6.97(t，J＝7.6Hz，1H)，6.84-6.82(m，1H)，5.71(s，1H)，4.01-3.97(m，2H)，3.27(t，J＝7.2Hz，1H)，3.23-3.19(m，2H)，2.57(s，3H)，1.36(d，J＝7.2Hz，6H)；ES-LCMS m/z 429.3[M+H]⁺。

Example 82

Synthesis I-84

The synthesis scheme is as follows:

step 1: 2-acetyl-3-methyl-butyronitrile

At-78 ℃ under N₂To a mixture of DIPA (1.22g, 12.03mmol, 1.70mL, 1 equiv.) in THF (10mL) was added n-BuLi (2.5M in THF, 5.05mL, 1.05 equiv.) dropwise. The mixture was stirred at-78 ℃ for 15 minutes, then warmed to 0 ℃ and stirred for 1 hour. The mixture was cooled to-78 ℃ and 3-formazan was added dropwiseButyronitrile (1g, 12.03mmol, 1.27mL, 1 eq.) in THF (10mL) and stirred at-78 deg.C for 15 min. A solution of ethyl acetate (1.11g, 12.63mmol, 1.24mL, 1.05 equiv.) in THF (10mL) was added dropwise. The mixture was stirred at 20 ℃ for 16 hours. TLC (PE/EtOAc ═ 1/1, R_f0.74) indicates that a new blob is formed. The mixture was quenched with 2N HCl (10mL), extracted with EtOAc (50 mL. times.3), washed with brine (20mL), and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 10/1 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.74) to yield 2-acetyl-3-methyl-butyronitrile (661mg, 4.22mmol, 35.1% yield, 80.0% purity) as a yellow oil.¹H NMR(400MHz，CDCl₃) δ ppm 3.32(d, J ═ 5.2Hz, 1H), 2.44-2.38(m, 1H), 2.37(s, 3H), 1.11(d, J ═ 6.8Hz, 3H), 1.09-1.05(m, 3H); ES-LCMS: the correct quality was not found.

Step 2: 4-isopropyl-3-methyl-1H-pyrazol-5-amine

A mixture of 2-acetyl-3-methyl-butyronitrile (750.00mg, 4.79mmol, 1 equiv.), hydrazine hydrate (311.96mg, 6.23mmol, 302.87. mu.L, 1.3 equiv.), and AcOH (503.76mg, 8.39mmol, 479.77. mu.L, 1.75 equiv.) in EtOH (20mL) was stirred in N₂The mixture was stirred at 90 ℃ for 16 hours. The mixture was concentrated under reduced pressure to give a residue which was taken up in saturated NaHCO₃Diluted (20mL) and extracted with DCM (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave 4-isopropyl-3-methyl-1H-pyrazol-5-amine (560mg, 3.62mmol, 75.5% yield, 90.0% purity) as a yellow solid.¹H NMR(400MHz，CDCl₃)δppm2.82-2.69(m，1H)，2.18(s，3H)，1.23(d，J＝6.8Hz，6H)；ES-LCMS m/z 140.2[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidin-7-ols

A mixture of 4-isopropyl-3-methyl-1H-pyrazol-5-amine (502.05mg, 3.25mmol, 0.8 equiv.) and 3- (5-fluoro-3-pyridinyl) -3-oxo-propionic acid methyl ester (816.33mg, 4.06mmol, 1 equiv.) in AcOH (10mL) was stirred at 120 ℃ for 3 hours. The mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a) as a purple solid]Pyrimidin-7-ol (1.2g, crude), which was used in the next step without further purification.¹HNMR(400MHz，CD₃OD)δppm 8.82(s，1H)，8.68-8.66(m，1H)，8.14-8.08(m，2H)，3.30-3.24(m，1H)，2.46-2.41(m，3H)，1.37(d，J＝7.2Hz，6H)；ES-LCMS m/z 287.2[M+H]⁺。

Step 4: 7-chloro-5- (5-fluoro-3-pyridinyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-fluoro-3-pyridyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-ol (1.2g, 4.19mmol, 1 eq) in POCl₃(16.3g, 106.31mmol, 9.88mL, 25.36 equiv.) the solution was stirred at 110 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 10/1 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.75) to yield 7-chloro-5- (5-fluoro-3-pyridinyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (381mg, 1.23mmol, 29.2% yield, 98.0% purity).¹HNMR(400MHz，CD₃OD)δppm 9.08(s，1H)，8.57(d，J＝2.4Hz，1H)，8.20-8.15(m，1H)，7.28(s，1H)，3.36-3.24(m，1H)，2.57(s，3H)，1.48(d，J＝6.8Hz，6H)；ES-LCMS m/z 305.0[M+H]⁺。

Step 5: n- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-84)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a)]A mixture of pyrimidine (50mg, 160.79. mu. mol, 1 eq), 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (33.80mg, 160.79. mu. mol, 1 eq) and DIEA (62.34mg, 482.36. mu. mol, 84.02. mu.L, 3 eq) in i-PrOH (10mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 58% -78%, 10min) to yield N- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl ] as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-2-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (32.01mg, 54.45 μmol, 33.9% yield, 100% purity, 3 HCl).¹HNMR(400MHz，CD₃OD)δppm 8.75(d，J＝2.8Hz，1H)，8.43(s，1H)，7.66-7.63(m，1H)，6.93-6.89(m，1H)，6.46-6.39(m，1H)，5.73(s，1H)，3.97-3.94(m，2H)，3.31-3.23(m，1H)，3.13-3.09(m，2H)，2.57(s，3H)，2.23(s，3H)，1.36(d，J＝7.2Hz，6H)；ES-LCMS m/z479.3[M+H]⁺。

Example 83

Synthesis I-85

The synthesis scheme is as follows:

step 1: n- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -5- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-85)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]A mixture of pyrimidine (40mg, 147.68. mu. mol, 1 eq), 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (60mg, 153.73. mu. mol, 1.04 eq, 2 ethanedioic acid) and DIEA (60.00mg, 464.24. mu. mol, 80.86. mu.L, 3.14 eq) in i-PrOH (3mL) was stirred at 50 ℃ for 19 hours. The mixture was concentrated to dryness under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -52%, 12 min). The desired fractions were lyophilized to give N- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -5- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a as an off-white solid]Pyrimidin-7-amine (22.94mg, 43.14 μmol, 29.2% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.71(d，J＝2.4Hz，1H)，8.47(s，1H)，8.22(d，J＝2.4Hz，1H)，7.59(td，J＝2.4，9.2Hz，1H)，7.01(dd，J＝2.4，9.2Hz，1H)，6.51(d，J＝2.4Hz，1H)，6.44(ddd，J＝2.4，9.6，11.2Hz，1H)，5.85(s，1H)，4.04-3.92(m，2H)，3.17-3.08(m，2H)，2.13(s，3H)；ES-LCMS m/z 423.2[M+H]⁺。

Example 84

Synthesis I-86

The synthesis scheme is as follows:

step 1: 2-cyclopropyl-3-oxo-propionitrile

To a solution of DIPA (3.74g, 36.98mmol, 5.23mL, 1 equiv.) in THF (15mL) was added n-BuLi (2.5M in n-hexane, 15.53mL, 1.05 equiv.). The mixture was stirred at-78 ℃ for 10 minutes. 2-Cyclopropylacetonitrile (3 g)36.98mmol, 3.42mL, 1 eq) in THF (15mL) was added dropwise to the above mixture. Then the mixture is added to N₂Stirred at-78 ℃ for 10 minutes under an atmosphere. A solution of ethyl formate (2.88g, 38.88mmol, 3.13mL, 1.05 equiv.) in THF (15mL) was added dropwise and stirred at-78 deg.C for 40 min. The reaction mixture was then warmed to 25 ℃ for 12 hours. TLC (PE/EtOAc ═ 1/1, R_f0.50) indicates that one major new blob is detected. The reaction mixture was quenched at 0 ℃ by addition of 1N HCl solution (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 100/1 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.50) to yield the compound 2-cyclopropyl-3-oxo-propionitrile (3.4g, crude) as a yellow oil.¹H NMR(400MHz，CDCl₃)δppm 9.61(d，J＝1.1Hz，1H)，4.61-4.55(m，1H)，4.01-3.84(m，1H)，1.92-1.79(m，2H)，1.66-1.52(m，2H).

Step 2: 4-cyclopropyl-1H-pyrazol-5-amines

To a solution of 2-cyclopropyl-3-oxo-propionitrile (3.4g, 31.16mmol, 1 eq) in EtOH (30mL) was added AcOH (3.27g, 54.52mmol, 3.12mL, 1.75 eq) and hydrazine (1.30g, 40.50mmol, 1.46mL, 1.3 eq). The mixture was stirred at 90 ℃ for 12 hours. TLC (PE/EtOAc ═ 1/1, R_f0.10) indicates that one major new blob is detected. The reaction mixture was concentrated under reduced pressure to give a residue which was taken up in NaHCO₃The solution (200mL) was diluted and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica chromatography (DCM/MeOH ═ 100/1 to 10/1, TLC: PE/EtOAc ═ 10/1, R_f0.70) to yield 4-cyclopropyl-1H-pyrazol-5-amine (1.7g, crude) as a brown solid.¹H NMR(400MHz，CDCl₃)δppm 7.04(d，J＝0.7Hz，1H)，1.49-1.39(m, 1H), 0.83-0.75(m, 2H), 0.49-0.41(m, 2H); ES-LCMS m/z did not detect the desired MS.

Step 3: 3-cyclopropyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

To a solution of 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (500mg, 2.49mmol, 1 eq) in AcOH (6mL) was added 4-cyclopropyl-1H-pyrazol-5-amine (370.54mg, 3.01mmol, 1.21 eq). The mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-cyclopropyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a as a yellow solid]Pyrimidin-7-ol (830mg, crude), which was used in the next step without further purification.¹HNMR(400MHz，DMSO-d₆)δppm 8.90(s，1H)，8.80(d，J＝2.6Hz，1H)，8.25(td，J＝2.2，9.7Hz，1H)，7.68(s，1H)，6.09(s，1H)，2.05(m，2H)，0.94-0.87(m，2H)，0.73-0.64(m，2H)；ES-LCMSm/z 271.2[M+H]⁺。

Step 4: 7-chloro-3-cyclopropyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidines

3-cyclopropyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (830mg, 3.07mmol, 1 eq.) in POCl₃The solution in (5mL) was stirred at 110 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.40) to yield the compound 7-chloro-3-cyclopropyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (290mg, 924.12 μmol, 30.1% yield, 92.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.09(s，1H)，8.60(d，J＝2.6Hz，1H)，8.20(td，J＝2.1，9.4Hz，1H)，8.01(s，1H)，7.37(s，1H)，2.17(tt，J＝5.2，8.4Hz，1H)，1.11-1.03(m，2H)，1.02-0.95(m，2H)；ES-LCMS m/z 289.0，291.0[M+H]⁺。

Step 5: 3-cyclopropyl-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-86)

To 7-chloro-3-cyclopropyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (45mg, 143.40. mu. mol, 1.0 equiv.) in i-PrOH (3mL) was added DIEA (55.60mg, 430.19. mu. mol, 74.93. mu.L, 3.0 equiv.) and 2- (1H-indol-3-yl) ethylamine (29.87mg, 186.42. mu. mol, 1.3 equiv.). The mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 43% -73%, 10min) and lyophilizing the desired fractions to obtain 3-cyclopropyl-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (40.50mg, 77.61 μmol, 54.1% yield, 100% purity, 3HCl salt).¹HNMR(400MHz，CD₃OD)δppm 8.73(d，J＝2.5Hz，1H)，8.36(s，1H)，8.00(s，1H)，7.54-7.46(m，2H)，7.15(d，J＝8.0Hz，1H)，7.00(s，1H)，6.97(t，J＝7.5Hz，1H)，6.85-6.80(m，1H)，5.78(s，1H)，4.07-3.99(m，2H)，3.26-3.19(m，2H)，1.96-1.87(m，1H)，1.05-0.97(m，2H)，0.78-0.70(m，2H)；ES-LCMS m/z 412.9[M+H]⁺。

Example 85

Synthesis I-87

The synthesis scheme is as follows:

step 1: 3-cyclopropyl-N- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -5- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-87)

Reacting 7-chloro-3-cyclopropyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]A mixture of pyrimidine (40mg, 127.46. mu. mol, 1 eq), 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (54.72mg, 140.21. mu. mol, 1.1 eq, 2 ethanedioic acid) and DIEA (0.055g, 425.56. mu. mol, 74.12. mu.L, 3.34 eq) in i-PrOH (3mL) was stirred at 50 ℃ for 19 hours. The mixture was concentrated to dryness under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 12 min). Lyophilizing the desired fractions to give 3-cyclopropyl-N- (2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) -5- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a ] as an off-white solid]Pyrimidin-7-amine (22.33mg, 37.39 μmol, 29.3% yield, 95.7% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝1.6Hz，1H)，8.43(s，1H)，7.97(s，1H)，7.62(d，J＝8.8Hz，1H)，6.93(dd，J＝2.0，9.2Hz，1H)，6.49-6.35(m，1H)，5.73(s，1H)，3.96(t，J＝5.2Hz，2H)，3.10(t，J＝5.6Hz，2H)，2.14(s，3H)，1.98-1.86(m，1H)，1.07-0.94(m，2H)，0.79-0.67(m，2H)；ES-LCMS m/z 463.2[M+H]⁺。

Example 86

Synthesis I-88

The synthesis scheme is as follows:

step 1: n- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidine-4-amine (I-88)

4-chloro-2- (5-fluoro-3-pyridyl) -6-isopropoxy-pyrimidine (55mg, 172.59 μmol, 1 eq), 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (50.31mg, 225.64 μmol, 1.31 eq) and DIEA (66.92mg, 517.77 μmol, 90.19 μ L, 3.0 eq) in i-PrOH (3mL) were placed in a microwave tube. The sealed tube was heated at 125 ℃ for 6 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Feilomena Synergi C18150X 30mm X4. mu.m; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 65% -95%, 12 min). The desired fractions were lyophilized to give N- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl ] as a yellow solid]-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidin-4-amine (15.59mg, 28.70 μmol, 16.6% yield, 98.81% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.12(s，1H)，8.76(d，J＝2.5Hz，1H)，8.36(d，J＝8.8Hz，1H)，7.21(s，1H)，7.11(dd，J＝1.6，9.2Hz，1H)，6.66(t，J＝9.9Hz，1H)，5.80(s，1H)，5.07(s，1H)，3.81(s，2H)，3.06(t，J＝6.7Hz，2H)，1.39(d，J＝6.0Hz，6H)；ES-LCMS m/z428.2[M+H]⁺。

Example 87

Synthesis I-89

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [2- (2-methyl-1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-89)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (40mg, 132.08. mu. mol, 1 eq) and 2- (2-methyl-1H-indol-3-yl) ethylamine (34.52mg, 198.13. mu. mol, 1.5 eq) in i-PrOH (10mL) was added DIEA (51.21mg, 396.25. mu. mol, 69.02. mu.L, 3.0 eq). The mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomo Synergic 18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 47% -72%, 12min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [2- (2-methyl-1H-indol-3-yl) ethyl as a red solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (47.07mg, 86.87 μmol, 65.8% yield, 99.3% purity, 3 HCl).¹HNMR(400MHz，CD₃OD)δppm 8.68(d，J＝2.0Hz，1H)，8.20(s，1H)，8.07(s，1H)，7.37(d，J＝8.6Hz，1H)，7.32-7.27(m，1H)，6.86-6.82(m，1H)，6.69(dquin，J＝1.3，7.0Hz，2H)，5.43(s，1H)，3.89-3.83(m，2H)，3.15-3.07(m，1H)，3.03-2.98(m，2H)，1.95(s，3H)，1.19(d，J＝6.8Hz，6H)；ES-LCMS m/z 429.3[M+H]⁺。

Example 88

Synthesis of I-90

The synthesis scheme is as follows:

step 1: 3-tert-butyl-5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-90)

To 3-tert-butyl-7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]The amount of pyrimidine (40mg,128.63 μmol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (30.91mg, 192.95 μmol, 1.5 eq) to a solution of i-PrOH (10mL) was added DIEA (49.87mg, 385.89 μmol, 67.21 μ L, 3.0 eq). The mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue which was purified by preparative HPLC (column: Feilomo Synergic 18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 70% -90%, 12min) and then lyophilized to give 3-tert-butyl-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (42.66mg, 78.86 μmol, 61.3% yield, 99.4% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.82(br s，1H)，9.13(s，1H)，8.67(d，J＝2.2Hz，1H)，8.22(d，J＝8.6Hz，1H)，8.04(br s，1H)，7.94(s，1H)，7.64(d，J＝7.9Hz，1H)，7.31(d，J＝7.9Hz，1H)，7.23(d，J＝2.0Hz，1H)，7.10-6.95(m，2H)，6.64(s，1H)，3.83(q，J＝6.9Hz，2H)，3.11(t，J＝7.1Hz，2H)，1.46(s，9H)；ES-LCMS m/z 429.3[M+H]⁺。

Example 89

Synthesis of I-91

The synthesis scheme is as follows:

step 1: 2-formyl-3, 3-dimethyl-butyronitrile

At-78 ℃ under N₂To a mixture of DIPA (833.20mg, 8.23mmol, 1.16mL, 1 equiv.) in THF (20mL) was added n-BuLi (2.5M, 3.46mL, 1.05 equiv.) dropwise. The mixture was stirred at-78 ℃ for 10 minutes, then heated to 0 ℃ and stirred for 1 hour. The mixture was cooled to-78 c,3, 3-dimethylbutyronitrile (800mg, 8.23mmol, 12.66mL, 1 eq.) dissolved in THF (15mL, anhydrous) was added dropwise and stirred at-78 deg.C for 10 min. A solution of ethyl formate (640.46mg, 8.65mmol, 695.40. mu.L, 1.05 equiv.) in THF (15mL, anhydrous) was added dropwise and stirred at-78 ℃ for 40 minutes, then the mixture was warmed to 5-14 ℃ for 16 hours. TLC (PE/EtOAc ═ 3/1, R_f0.34) indicates that a primary new blob is detected. The reaction mixture was quenched by addition of 1N HCl solution (50mL) at-78 deg.C and extracted with DCM (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.34) to give the product 2-formyl-3, 3-dimethyl-butyronitrile (750mg, 5.39mmol, 65.5% yield, 90.0% purity) as a yellow oil.¹H NMR(400MHz，CDCl₃)δppm 9.66(d，J＝2.2Hz，1H)，3.27(d，J＝2.4Hz，1H)，1.23(s，9H)。

Step 2: 4-tert-butyl-1H-pyrazol-5-amine

A mixture of 2-formyl-3, 3-dimethyl-butyronitrile (750mg, 5.39mmol, 1 equiv.), hydrazine (224.65mg, 7.01mmol, 253.56. mu.L, 1.3 equiv.), and AcOH (566.71mg, 9.44mmol, 539.73. mu.L, 1.75 equiv.) in EtOH (20mL) was degassed and N was used₂And purifying for 3 times. Then the mixture is added to N₂Stirring was carried out at 80-90 deg.C (reflux) under an atmosphere for 16 hours. TLC (PE/EtOAc ═ 1/1, R_f0.55) indicates that most of the starting material was consumed and one major new spot with greater polarity was detected. The reaction mixture was concentrated under reduced pressure. The residue is washed with H₂O (20mL) dilution with NaHCO₃The solid was adjusted to pH 9-10 and extracted with DCM (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude 4-tert-butyl-1H-pyrazol-5-amine (750mg, 5.39mmol, 99.9% yield, crude purity) as a yellow solid, which was not further processedStep purification was used in the next step.¹H NMR(400MHz，CDCl₃)δppm 7.12(s，1H)，1.30(s，9H)。

Step 3: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-ols

To a solution of 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (1.08g, 5.37mmol, 1 eq) in AcOH (20mL) was added 4-tert-butyl-1H-pyrazol-5-amine (747.23mg, 5.37mmol, 1 eq). The mixture was stirred at 120 ℃ for 0.5 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the crude product 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ] pyrimidin-7-ol (1.46g, 5.36mmol, 100.0% yield, crude) as a yellow oil, which was used in the next step without further purification.

Step 4: 3-tert-butyl-7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidines

3-tert-butyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (1.67g, 5.83mmol, 1 eq) in POCl₃(37.81g, 246.59mmol, 22.92mL, 42.28 equivalents) and degassing with N₂And purifying for 3 times. Then the mixture is added to N₂Stirred under an atmosphere at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with DCM (50mL × 2) and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc ═ 1/0 to 10/3, TLC: PE/EtOAc ═ 3/1, R_f0.48) to yield the product 3-tert-butyl-7-chloro-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (950mg, 3.05mmol, 52.4% yield, 98.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.13(t，J＝1.5Hz，1H)，8.61(d，J＝2.8Hz，1H)，8.22-8.16(m，1H)，8.12(s，1H)，7.41(s，1H)，1.56(s，9H)；ES-LCMS m/z 305.1，307.1[M+H]⁺。

Step 5: 3-tert-butyl-N- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-91)

To 3-tert-butyl-7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (40mg, 128.63 μmol, 1 eq) and 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (57.93mg, 192.95 μmol, 1.5 eq, oxalic acid) in i-PrOH (10mL) was added DIEA (49.87mg, 385.89 μmol, 67.21 μ L, 3.0 eq). The mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 70% -90%, 12min) to give 3-tert-butyl-N- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl as an orange solid]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (34.14mg, 57.39 μmol, 44.6% yield, 98.8% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 11.21(s，1H)，9.06-8.98(m，1H)，8.66(d，J＝2.6Hz，1H)，8.13-8.01(m，2H)，7.95(s，1H)，7.22(dd，J＝2.1，9.6Hz，1H)，6.76(ddd，J＝2.2，9.6，11.4Hz，1H)，6.42(s，1H)，3.71(q，J＝6.8Hz，2H)，3.01(t，J＝6.6Hz，2H)，2.20(s，3H)，1.47(s，9H)；ES-LCMS m/z 479.3[M+H]⁺。

Example 90

Synthesis I-92

The synthesis scheme is as follows:

step 1: 5-amino-1H-pyrazoles-4-Carboxylic acid methyl ester

A solution of 5-amino-1H-pyrazole-4-carboxylic acid (1g, 7.87mmol, 1 eq) in HCl/MeOH (4M, 40mL, 20.34 eq.) was stirred at 60 ℃ for 12H. The reaction mixture was concentrated under reduced pressure to give methyl 5-amino-1H-pyrazole-4-carboxylate (1.4g, 7.49mmol, 95.2% yield, 95.0% purity, HCl) as a white solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.31(s，1H)，3.84(s，3H)；ES-LCMS m/z142.2[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -7-hydroxy-pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

To a solution of 3- (5-fluoro-3-pyridyl) -3-oxo-propionic acid methyl ester (160mg, 795.28 μmol, 1 eq) in AcOH (5mL) was added 5-amino-1H-pyrazole-4-carboxylic acid methyl ester (148.67mg, 795.28 μmol, 1 eq, HCl). The mixture was stirred at 120 ℃ for 4 hours. The reaction mixture was concentrated to give 5- (5-fluoro-3-pyridyl) -7-hydroxy-pyrazolo [1, 5-a as a yellow solid]Pyrimidine-3-carboxylic acid methyl ester (230mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.83(s，1H)，8.72(d，J＝2.6Hz，1H)，8.29(s，1H)，8.22(s，1H)，6.34(s，1H)，3.92(s，3H)；ES-LCMS m/z 289.2[M+H]⁺。

Step 3: 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

Reacting 5- (5-fluoro-3-pyridyl) -7-hydroxy-pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (230mg, 797.96. mu. mol, 1 eq.) in POCl₃(5mL) inThe solution of (2) was stirred at 110 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (

12g

Silica flash column, eluent 0-50% ethyl acetate/petroleum ether gradient, 30mL/min) to obtain 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a) as a white solid]Pyrimidine-3-carboxylic acid methyl ester (180mg, 516.50 μmol, 64.7% yield, 88.0% purity).¹HNMR(400MHz，CDCl₃)δppm 9.08(s，1H)，8.65(s，1H)，8.59(d，J＝2.6Hz，1H)，7.69(s，1H)，7.56(s，1H)，3.93(s，3H)；ES-LCMS m/z 307.1，309.1[M+H]⁺。

Step 4: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid methyl ester (180mg, 516.50. mu. mol, 1 eq), 2- (1H-indol-3-yl) ethylamine (82.75mg, 516.50. mu. mol, 1 eq) in i-PrOH (10mL) was added DIEA (200.26mg, 1.55mmol, 269.90. mu.L, 3 eq). The mixture was then stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino as an off-white solid]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (120mg, 242.55 μmol, 47.0% yield, 87.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.59(s，1H)，8.46(d，J＝2.9Hz，1H)，8.41(s，1H)，7.84(br s，1H)，7.15-7.15(m，1H)，7.13-7.08(m，3H)，6.94(s，1H)，6.07(s，1H)，3.86(s，3H)，3.11-3.05(m，4H)；ES-LCMS m/z 431.1[M+H]⁺。

Step 5: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid methyl ester (60mg, 121.27. mu. mol, 1 eq) in MeOH (2mL), THF (2mL), and water (4mL) was added LiOH. H₂O (72.00mg, 1.72mmol, 14.15 equiv.) and the mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (20mL) and extracted with EtOAc (20mL × 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure to give 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino as a brown solid]Pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid (50mg, 84.05 μmol, 69.3% yield, 70.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.58(s，1H)，8.46(d，J＝2.4Hz，1H)，8.40(s，1H)，7.62(s，1H)，7.54(d，J＝7.7Hz，1H)，7.35(d，J＝8.2Hz，1H)，7.10(d，J＝7.9Hz，1H)，6.95(m，2H)，6.07(s，1H)，3.90(t，J＝6.2Hz，2H)，3.13-3.08(m，2H)；ES-LCMS m/z 417.2[M+H]⁺。

Step 6: 5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]-N-methoxy-N-methyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (I-92)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (50mg, 84.05. mu. mol, 1 eq.) and N-methoxymethanamine (12.30mg, 126.08. mu. mol, 1.5 eq., HCl) in DCM (5mL) were added HATU (47.94mg, 126.08. mu. mol, 1.5 eq.) and TEA (17.01mg, 168.10. mu. mol, 23.40. mu.L, 2 eq.). Then the mixture is mixed at 20The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (20mL) and extracted with EtOAc (20mL × 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10 min). Evaporation of the desired fractions gave 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino ] as a pale yellow solid]-N-methoxy-N-methyl-pyrazolo [1, 5-a]Pyrimidine-3-carboxamide (20.19mg, 35.14. mu. mol, 41.8% yield, 99.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.74(d，J＝2.6Hz，1H)，8.61(s，1H)，8.40(s，1H)，7.57-7.51(m，2H)，7.10(d，J＝8.4Hz，1H)，7.01(s，1H)，6.94(t，J＝7.3Hz，1H)，6.87-6.81(m，1H)，6.04(s，1H)，4.07(t，J＝5.8Hz，2H)，3.85(s，3H)，3.37(s，3H)，3.24(t，J＝5.7Hz，2H)；ES-LCMS m/z 460.4[M+H]⁺。

Example 91

Synthesis I-93

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl]-N4-isopropyl-N4-methyl-pyrimidine-4, 6-diamine (I-93)

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amine (60mg, 163.13. mu. mol, 1.0 eq.), N-methylpropan-2-amine (702.00mg, 9.60mmol, 1mL, 58.84 eq.) and DIEA (63.25mg, 489.39. mu. mol, 85.24. mu.L, 3.0 eq.) to i-PrOH (2mL) was placed in a microwave tube. The sealed tube was heated at 125 ℃ for 10 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Feilomena Synergi C18150X 30mm X4. mu.m; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 22% -52%, 12min) and lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridinyl) -N6- [2- (1H-indol-3-yl) ethyl ] in the form of a yellow solid]-N4-isopropyl-N4-methyl-pyrimidine-4, 6-diamine (19.96mg, 49.25 μmol, 30.2% yield, 99.80% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD+Na₂CO₃)δppm 9.26(s，1H)，8.47(d，J＝2.6Hz，1H)，8.39-8.33(m，1H)，7.65-7.59(m，1H)，7.35-7.31(m，1H)，7.12-7.06(m，2H)，7.04-6.98(m，1H)，5.34(s，1H)，4.95(s，1H)，3.66(t，J＝6.9Hz，2H)，3.07(t，J＝6.9Hz，2H)，2.79(s，3H)，1.18(d，J＝6.8Hz，6H)；ES-LCMS m/z 405.3[M+H]⁺。

Example 92

Synthesis I-94a

The synthesis scheme is as follows:

step 1: 3-aminotetralin-6-ol

To a solution of 7-hydroxytetralin-2-one (500mg, 3.08mmol, 1 eq) in anhydrous MeOH (5mL) was added NH₄OAc (7.13g, 92.49mmol, 30 equiv.). After stirring for 5 hours, NaBH was added₄(349.88mg, 9.25mmol, 3 equiv.). The mixture was stirred at 25 ℃ for 3 hours. The mixture was concentrated to remove the solvent. Addition of H₂O (10mL), the mixture was extracted with EtOAc (20 mL. times.2). The aqueous solution was adjusted to pH 6-7 by 3N HCl,extract with EtOAc (10 mL. times.2). The aqueous solution was adjusted to pH 6-7 by 1n naoh. The mixture was then lyophilized to give a solid. The solid was dissolved in i-PrOH (10 mL). The resulting mixture was filtered and concentrated to give 3-aminotetralin-6-ol (550mg, 2.66mmol, 86.4% yield, 79.0% purity) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 6.91(d，J＝8.2Hz，1H)，6.58(dd，J＝2.4，8.4Hz，1H)，6.51(s，1H)，3.53-3.42(m，1H)，3.06(dd，J＝5.4，15.5Hz，1H)，2.89-2.73(m，3H)，2.17(d，J＝10.1Hz，1H)，1.84-1.74(m，1H)；ES-LCMS m/z164.3[M+H]⁺。

Step 2: 3- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Tetralin-6-ol

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (100mg, 330.21. mu. mol, 1 eq) in i-PrOH (10mL) was added DIEA (128.03mg, 990.63. mu. mol, 172.55. mu.L, 3 eq) and 3-aminotetralin-6-ol (204.67mg, 990.63. mu. mol, 3 eq). Subjecting the mixture to microwave at N₂Stirred at 120 ℃ for 3 hours under an atmosphere. The mixture was concentrated to remove the solvent. Addition of H₂O (10mL), the mixture was extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 2/1, R_f0.50) to give 3- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Tetralin-6-ol (63mg, 138.83 μmol, 42.0% yield, 92.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.19(s，1H)，8.56(d，J＝2.5Hz，1H)，8.45-8.37(m，1H)，7.96(s，1H)，6.98(d，J＝8.3Hz，1H)，6.78(s，1H)，6.66-6.56(m，2H)，4.62(s，2H)，4.32(s，1H)，3.01-2.89(m，3H)，2.28(s，1H)，2.03(d，J＝5.5Hz，1H)，1.44(d，J＝7.0Hz，6H)；ES-LCMS m/z 418.2[M+H]⁺。

Step 3: (3R) -3- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Tetralin-6-ol (I-94)

3- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Naphthin-6-ol (100mg, 220.37. mu. mol, 1 eq.) was passed through SFC (column: Chiralcel OD 250X 305 u; mobile phase: [ 0.1% NH ]₃.H₂OEtOH](ii) a B%: 45% -45%, min) to give the product (Rt ═ 3.922min) which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: philomo Gemini 150X 25mm X10 μm/mobile phase: water (0.05% HCl) -ACN/gradient: b from 50% to 80% per flow rate over 10 minutes: 25mL/min) followed by lyophilization to give (3R) -3- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Naphthin-6-ol (19.02mg, 45.10. mu. mol, 20.47% yield, 99.0% purity) ([ α ]]²⁵ _D＝-23.996)。¹H NMR(400MHz，CD₃OD)δppm 8.99(s，1H)，8.81(d，J＝2.4Hz，1H)，8.38-8.31(m，1H)，8.25(s，1H)，7.00-6.91(m，2H)，6.60(dd，J＝2.5，8.3Hz，1H)，6.55(d，J＝2.4Hz，1H)，4.50(s，1H)，3.41-3.32(m，1H)，3.23-3.15(m，1H)，3.11-3.02(m，1H)，3.01-2.94(m，1H)，2.94-2.86(m，1H)，2.32-2.21(m，1H)，2.14-2.02(m，1H)，1.38(d，J＝6.8Hz，6H)；ES-LCMS m/z 418.2[M+H]⁺。

Example 93

Synthesis I-95

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxylic acid methyl ester

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (270mg, 659.39. mu. mol, 1 eq, 71.0%) in DMF (10mL) and MeOH (8mL) was added Et3N (333.62mg, 3.30mmol, 458.90. mu.L, 5.0 eq), Pd (OAc)₂(22.21mg, 98.91. mu. mol, 0.15 equiv.) and DPPF (54.83mg, 98.91. mu. mol, 0.15 equiv.). The mixture was purged three times with CO (50psi) and stirred at 70 ℃ for 24 hours under CO (50 psi). The reaction mixture was concentrated under high vacuum to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.47) to yield the product 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine-7-carboxylic acid methyl ester (180mg, 538.32. mu. mol, 81.6% yield, 94.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.17(d，J＝6.8Hz，1H)，8.62(d，J＝5.3Hz，1H)，8.22(dd，J＝7.9，17.9Hz，2H)，7.81(d，J＝8.2Hz，1H)，4.22-4.00(m，3H)，3.47-3.45(m，1H)，1.47(t，J＝7.4Hz，6H)；ES-LCMS m/z 315.3[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxylic acid

To 5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxylic acid methyl ester (180mg, 538.32. mu. mol, 1 eq.) in MeOH (10mL) and THF (10mL), H₂To a solution in O (5mL) was added LiOH (128.92mg, 5.38mmol, 10 equiv.). The mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue is washed with H₂O (20mL) was diluted, adjusted to pH 3-4 with 1NHCl solution, and extracted with DCM (20mL × 3). The combined organic layers were driedNa₂SO₄Drying, filtration and concentration under reduced pressure gave the crude product 5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine-7-carboxylic acid (100mg, 293.05 μmol, 54.4% yield, 88.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.23(s，1H)，8.65(d，J＝2.6Hz，1H)，8.26(td，J＝2.3，9.3Hz，1H)，8.22(s，1H)，8.14(s，1H)，3.59-3.35(m，1H)，1.49(d，J＝6.8Hz，6H)；ES-LCMS m/z 301.1[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -N- [ (3-hydroxyphenyl) methyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxamide (I-95)

To 5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine-7-carboxylic acid (70mg, 205.14 μmol, 1 eq) and 3- (aminomethyl) phenol (50.53mg, 410.27 μmol, 2.0 eq) in DCM (20mL) were added HATU (117.00mg, 307.71 μmol, 1.5 eq) and DIEA (79.54mg, 615.41 μmol, 107.19 μ L, 3.0 eq). The mixture was stirred at 25 ℃ for 16 hours. The combined reaction mixture is washed with H₂O (20mL) was diluted and extracted with EtOAc (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 47% -77%, 12min) and subsequent lyophilization to give 5- (5-fluoro-3-pyridinyl) -N- [ (3-hydroxyphenyl) methyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxamide (16.16mg, 33.78. mu. mol, 16.5% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm10.41(t，J＝5.8Hz，1H)，9.34-9.27(m，1H)，8.76(d，J＝2.9Hz，1H)，8.62-8.49(m，1H)，8.35(s，1H)，8.20(s，1H)，7.15(t，J＝7.7Hz，1H)，6.88-6.80(m，2H)，6.72-6.61(m，1H)，4.62(d，J＝6.0Hz，2H)，3.42-3.35(m，1H)，1.41(d，J＝7.1Hz，6H)；ES-LCMS m/z 406.2[M+H]⁺。

Example 94

Synthesis I-96

The synthesis scheme is as follows:

step 1: n- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-96)

4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (40mg, 137.12. mu. mol, 1 eq), 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (45.86mg, 205.68. mu. mol, 1.5 eq) and DIEA (17.72mg, 137.12. mu. mol, 23.88. mu.L, 1 eq) in i-PrOH (10mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was washed with MeOH (10mL), filtered and dried under reduced pressure to give N- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl ] as a white solid]-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (18.95mg, 41.98 μmol, 30.6% yield, 100% purity).¹H NMR(400MHz，DMSO-d₆)δppm 11.37(s，1H)，9.29(t，J＝1.6Hz，1H)，9.03-9.01(m，1H)，8.70(d，J＝2.8Hz，1H)，8.26-8.22(m，1H)，8.10(s，1H)，7.34(d，J＝2.0Hz，1H)，7.27(dd，J＝2.0，7.2Hz，1H)，6.91-6.87(m，1H)，3.92(q，J＝6.8Hz，2H)，3.22-3.15(m，1H)，3.09(t，J＝7.2Hz，2H)，1.35(d，J＝6.8Hz，6H)；ES-LCMS m/z 452.2[M+H]⁺。

Example 95

Synthesis I-97a

The synthesis scheme is as follows:

step 1: 1-methoxy-4- [ (E) -2-nitroprop-1-enyl]Benzene and its derivatives

4-methoxybenzaldehyde (5g, 36.72mmol, 4.46mL, 1 eq.), NH₄OAc (566.17mg, 7.34mmol, 0.2 equiv.) in EtNO₂(50mL) of the mixture in N₂Stirred at 110 ℃ for 5 hours under an atmosphere. The mixture was then stirred at 110 ℃ for a further 40 hours. TLC (PE/EtOAc ═ 5/1, R_f0.73) indicates complete consumption of the starting material and formation of a new spot. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 10/1 to 5/1, TLC: PE/EtOAc: 5/1, R_f0.73) to yield 1-methoxy-4- [ (E) -2-nitroprop-1-enyl) as a yellow solid]Benzene (3.7g, 18.19mmol, 49.5% yield, 95% purity).¹H NMR(400MHz，CD₃OD)δppm 8.06(s，1H)，7.52-7.49(m，2H)，7.05-7.02(m，2H)，3.85(s，3H)，2.45(s，3H)；ES-LCMS m/z 194.0[M+H]⁺。

Step 2: 1- (4-methoxyphenyl) propan-2-amine

1-methoxy-4- [ (E) -2-nitroprop-1-enyl group]A mixture of benzene (1g, 4.92mmol, 1 equiv.) and LAH (1M in THF, 14.75mL, 3 equiv.) in THF (10mL) was stirred at 60 ℃ for 14 h. The mixture was quenched with water (0.5mL), 15% NaOH (0.5mL), and water (1.5mL), and the mixture was stirred at 20 ℃ for 3 hours. The mixture was filtered and concentrated under reduced pressure to give a yellow colour1- (4-methoxyphenyl) propan-2-amine (800mg, crude) as a colored oil.¹H NMR(400MHz，CD₃OD)δppm 7.08(d，J＝8.4Hz，2H)，6.86-6.81(m，2H)，3.72(s，3H)，2.96-2.91(m，1H)，2.51-2.42(m，2H)，0.92(d，J＝6.4Hz，3H)；ES-LCMS m/z 166.2[M+H]⁺。

Step 3: 4- (2-aminopropyl) phenol

A solution of 1- (4-methoxyphenyl) propan-2-amine (1.2g, 7.26mmol, 1 eq.) in HBr (8mL) in H₂The mixture in solution in O (3mL) was stirred at 100 ℃ for 3 hours. The mixture was extracted with EtOAc (20mL), pH adjusted to 9 with 15% NaOH, and the aqueous solution was extracted with EtOAc (20 mL. times.3) over Na₂SO₄Drying, filtration and concentration under reduced pressure gave 4- (2-aminopropyl) phenol (445mg, crude) as a brown solid which was used in the next step without further purification.¹HNMR(400MHz，CD₃OD)δppm 7.00(d，J＝8.4Hz，2H)，6.73-6.70(m，2H)，3.07-3.01(m，1H)，2.56-2.51(m，2H)，1.07(d，J＝6.4Hz，3H)；ES-LCMS m/z 152.2[M+H]⁺。

Step 4: 4- [ (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Propyl radical]Phenol (I-97)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (100mg, 330.21. mu. mol, 1 eq), 4- (2-aminopropyl) phenol (99.86mg, 660.42. mu. mol, 2 eq) and DIEA (128.03mg, 990.63. mu. mol, 172.55. mu.L, 3 eq) in i-PrOH (10mL) was degassed and N was used₂Purifying for 3 times, and adding the mixture in N₂Stirred at 80 ℃ for 12 hours under an atmosphere. The mixture was concentrated under reduced pressure to give a residue which was passed through SFC (column: ChiralpakAS-H250X 305 u; mobile phase: [ 0.1% NH ]₃H₂O EtOH](ii) a B%: 20% -20%, min) to obtain 4- [ (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Propyl radical]Phenol (Rt. 4.781min, 50mg) and purified by preparative HPLC (column: Feilomo Synergi C18150X 30mm X4. mu.m; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 52% -62%, 12min) to give 4- [ (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Propyl radical]Phenol (27.45mg, 57.15. mu. mol, 17.3% yield, 99.6% purity, 2HCl) ([ α ]]²⁵ _D＝-90.432)。¹H NMR(400MHz，CD₃OD)δppm8.81-8.76(m，2H)，8.25(s，1H)，8.12-8.07(m，1H)，7.04(d，J＝8.4Hz，2H)，6.54(d，J＝8.4Hz，2H)，6.34(s，1H)，4.42(br s，1H)，3.31-3.29(m，1H)，3.04(dd，J＝4.4，13.6Hz，1H)，2.87-2.83(m，1H)，1.54(d，J＝6.4Hz，3H)，1.36(t，J＝6.8Hz，6H)；ES-LCMS m/z 406.2[M+H]⁺。

Example 96

Synthesis of I-98a

The synthesis scheme is as follows:

step 1: 3- [ (E) -2-Nitroprop-1-enyl]-1H-indoles

1H-indole-3-carbaldehyde (5g, 34.45mmol, 1 eq.), NH₄A mixture of OAc (531.02mg, 6.89mmol, 0.2 equiv.) in nitroethane (50mL) was stirred at 110 ℃ for 24 h. TLC (DCM/MeOH ═ 10/1, R)_f0.8) indicates complete consumption of the starting material and formation of a new spot. The mixture was cooled to 0 ℃. The mixture was filtered and the filter cake was dried under reduced pressure to give 3- [ (E) -2-nitropropane as a brown solid-1-alkenyl]-1H-indole (5.1g, 25.22mmol, 73.2% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 8.53(s，1H)，7.79-7.75(m，2H)，7.46(d，J＝8.0Hz，1H)，7.26-7.20(m，2H)，2.52(s，3H)；ES-LCMS m/z 203.0[M+H]⁺。

Step 2: 1- (1H-indol-3-yl) propan-2-amine

To 3- [ (E) -2-nitroprop-1-enyl group at 0 DEG C]To a solution of (1g, 4.95mmol, 1 equiv.) of (E) -1H-indole in THF (10mL) was added LAH (1M in THF, 14.84mL, 3 equiv.). The mixture was then stirred at 60 ℃ for 2 hours. The mixture was diluted with EtOAc (200mL), quenched with water (0.5mL), 15% NaOH (0.5mL), water (1.5mL), stirred for 3 hours, filtered and concentrated under reduced pressure to give 1- (1H-indol-3-yl) propan-2-amine (1.3g, 3.73mmol, 75.4% yield, 50% purity) as a yellow oil which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.56-7.53(m，1H)，7.35-7.30(m，1H)，7.10-7.06(m，2H)，7.01-6.97(m，1H)，3.21-3.17(m，1H)，2.85-2.79(m，1H)，2.73-2.69(m，1H)，1.15-1.10(m，3H)；ES-LCMS m/z175.2[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -N- [ (1S) -2- (1H-indol-3-yl) -1-methyl-ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-98)

1- (1H-indol-3-yl) propan-2-amine (172.61mg, 495.32. mu. mol, 1.5 equiv.), 7-chloro-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (100mg, 330.21. mu. mol, 1 equivalent) and DIEA (42.68mg, 330.21. mu. mol, 57.52. mu.L, 1 equivalent) in i-PrOH (10mL) was degassed and N was used₂Purifying for 3 times, and adding the mixture in N₂Stirred at 50 ℃ for 3 hours under an atmosphere. The mixture was concentrated under reduced pressure to give a residue which was passed through flash silicaGel chromatography (SiO)₂PE/EtOAc 10/1 to 1/1, TLC: PE/EtOAc-1/1, R_f0.55) and purified by SFC (column: OD (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃/H₂O EtOH](ii) a B%: 30% -30%, min) to obtain 5- (5-fluoro-3-pyridyl) -N- [ (1S) -2- (1H-indol-3-yl) -1-methyl-ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (Rt. 3.870min, 30mg) by preparative HPLC (column: Feilomo Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 50% -80%, 12min) to yield 5- (5-fluoro-3-pyridinyl) -N- [ (1S) -2- (1H-indol-3-yl) -1-methyl-ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (16.33mg, 29.93 μmol, 9.1% yield, 98.6% purity, 3HCl) ([ α)]²⁵ _D＝-261.788)。¹H NMR(400MHz，CD₃OD)δppm 8.67(d，J＝2.4Hz，1H)，8.34(s，1H)，8.18(s，1H)，7.54(d，J＝7.6Hz，1H)，7.45(d，J＝2.0，8.8Hz，1H)，7.14(d，J＝8.4Hz，1H)，6.99(s，1H)，6.95(t，J＝7.5Hz，1H)，6.83-6.81(m，1H)，5.80(s，1H)，4.48-4.43(m，1H)，3.28(d，J＝2.8Hz，1H)，3.23-3.17(m，1H)，3.05-3.01(m，1H)，1.64(d，J＝6.4Hz，3H)，1.34(t，J＝7.2Hz，6H)；ES-LCMS m/z 429.3[M+H]⁺。

Example 97

Synthesis of I-99

The synthesis scheme is as follows:

step 1: n- (2-bromo-4, 6-difluoro-phenyl) carbamic acid tert-butyl ester

2-bromo-4, 6-difluoro-aniline (10g, 48.0)8mmol, 1 equivalent), Boc₂A mixture of O (31.48g, 144.23mmol, 33.13mL, 3 equivalents), DMAP (587.34mg, 4.81mmol, 0.1 equivalent) in THF (100mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂The mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in MeOH (100mL) and K was added₂CO₃(19.93g, 144.23mmol, 3 equiv.) and stirred at 70 ℃ for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water (100mL) was added to the crude mixture and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 10/1, R_f0.36) to yield tert-butyl N- (2-bromo-4, 6-difluoro-phenyl) carbamate as a white solid (12.5g, 40.57mmol, 84.3% yield, 100% purity).¹H NMR(400MHz，CDCl₃)δppm 7.10(td，J＝2.3，7.7Hz，1H)，6.86-6.77(m，1H)，5.84(s，1H)，1.43(s，9H)；ES-LCMS m/z 251.9，253.9[M-t-Bu+H]⁺。

Step 2: n- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl]Carbamic acid tert-butyl ester

N- (2-bromo-4, 6-difluoro-phenyl) carbamic acid tert-butyl ester (4g, 12.98mmol, 1 equiv.), ethynyl (trimethyl) silane (1.91g, 19.47mmol, 2.70mL, 1.5 equiv.), TEA (3.94g, 38.95mmol, 5.42mL, 3.0 equiv.), CuI (247.24mg, 1.30mmol, 0.1 equiv.), and Pd (PPh)₃)₂Cl₂A mixture of (455.60mg, 649.10. mu. mol, 0.05 eq.) in DMF (80mL) was degassed and N was used₂Purification 3 times, followed by N₂The mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was quenched by the addition of water (300mL) followed by extraction with EtOAc (200 mL. times.3). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressureThe residue was obtained by flash chromatography on silica gel (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 20/1, R_f0.31) to yield N- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl group as a dark brown solid]Tert-butyl carbamate (3.0g, 8.20mmol, 63.2% yield, 89.0% purity).¹H NMR(400MHz，CDCl₃)δppm7.00-6.93(m，1H)，6.90-6.81(m，1H)，6.09(s，1H)，1.49(s，9H)，0.26(s，9H)；ES-LCMS m/z 270.1[M-t-Bu+H]⁺。

Step 3: 5, 7-difluoro-1H-indoles

To the EtOH solution (150mL) was added Na (1.51g, 65.64mmol, 8 equiv.) slowly. After stirring at 15 ℃ for 1 hour while completely dissolving Na, N- [2, 4-difluoro-6- (2-trimethylsilylethynyl) phenyl group was added to the mixture]Tert-butyl carbamate (3.0g, 8.20mmol, 1 eq.) and the mixture was stirred at 85 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure to remove EtOH. Water (100mL) was added to the residue, which was extracted with EtOAc (60 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 10/1, R_f0.17) to yield 5, 7-difluoro-1H-indole (600mg, 3.68mmol, 44.8% yield, 94.0% purity) as a yellow oil.¹H NMR(400MHz，CDCl₃) δ ppm8.36(s, 1H), 7.27-7.25(m, 1H), 7.09(dd, J ═ 2.0, 9.0Hz, 1H), 6.74(dt, J ═ 2.1, 10.2Hz, 1H), 6.60-6.47(m, 1H); ES-LCMS m/z found no weight.

Step 4: 5, 7-difluoro-1H-indole-3-carbaldehyde

In N₂Next, to a DMF solution (18mL) was added dropwise over a period of 10 minutes at-20 deg.CAdding POCl₃(1.13g, 7.37mmol, 684.54. mu.L, 2.0 equiv.). After 1 hour, 5, 7-difluoro-1H-indole (600mg, 3.68mmol, 1 eq) in DMF (2mL) was added to the above solution, during which time the temperature was maintained below-20 ℃. The reaction mixture was warmed to 15 ℃ and stirred at 15 ℃ for 1 hour. TLC (PE/EtOAc ═ 1/1, R_f0.40) showed complete consumption of starting material and formation of a new spot. The reaction mixture was purified by addition of NaHCO at 0 deg.C₃Quenched (100mL) and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/2, TLC: PE/EtOAc: 1/1, R_f0.40) to yield 5, 7-difluoro-1H-indole-3-carbaldehyde (500mg, 2.35mmol, 63.7% yield, 85.0% purity) as a yellow solid.¹H NMR (400MHz, acetone) δ ppm 11.72(s, 1H), 10.05(s, 1H), 8.36(s, 1H), 7.73(dd, J ═ 2.4, 9.0Hz, 1H), 7.02(ddd, J ═ 2.2, 9.4, 11.3Hz, 1H); ES-LCMS M/z 182.1[ M + H ]]⁺。

Step 5: 5, 7-difluoro-3- [ ((E) -2-nitrovinyl group]-1H-indoles

To a solution of 5, 7-difluoro-1H-indole-3-carbaldehyde (500mg, 2.35mmol, 1 eq) in nitromethane (15mL) was added NH₄OAc (542.57mg, 7.04mmol, 3.0 equiv.). The mixture was stirred at 110 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was diluted in EtOAc (50mL), washed with water (10mL), brine (10mL), and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 1/1, R_f0.70) to yield 5, 7-difluoro-3- [ (E) -2-nitrovinyl) as a yellow solid]-1H-indole (420mg, 1.82mmol, 77.4% yield, 97.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.23(d，J＝13.5Hz，1H)，7.76-7.57(m，2H)，7.25-7.16(m，1H)，6.91-6.78(m，1H)；ES-LCMS m/z 225.1[M+H]⁺。

Step 6: 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine

To 5, 7-difluoro-3- [ (E) -2-nitrovinyl at 0 deg.C]-1H-indole (420mg, 1.82mmol, 1 equiv.) to a solution in THF (15mL) LAH (1M in THF, 6.36mL, 3.5 equiv.) was added dropwise. After the addition, the mixture was stirred at 80 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.04) showed complete consumption of starting material and formation of new spots. The reaction mixture was diluted with THF (75mL) and quenched at 0 deg.C by the sequential addition of water (0.25mL), aqueous NaOH (0.25mL, 10% in water), and water (0.75 mL). After stirring for 20 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give crude 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (320mg, 1.44mmol, 78.9% yield, 88.0% purity) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.18(s，1H)，7.08(dd，J＝2.1，9.4Hz，1H)，6.70(ddd，J＝2.3，9.5，11.3Hz，1H)，2.94-2.82(m，4H)；ES-LCMS m/z 197.1[M+H]⁺。

Step 7: n- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-99)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (40mg, 132.08 μmol, 1 eq), 2- (5, 7-difluoro-1H-indol-3-yl) ethylamine (44.17mg, 198.13 μmol, 1.5 eq) in i-PrOH (3mL) was added DIEA (85.35mg, 660.42 μmol, 115.03 μ L, 5 eq). The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/M)eOH＝20/1，TLC：DCM/MeOH＝20/1，R_f0.48) to yield N- [2- (5, 7-difluoro-1H-indol-3-yl) ethyl ] as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (30.31mg, 66.35. mu. mol, 50.2% yield, 98.6% purity).¹H NMR(400MHz，CD₃OD)δppm 8.82(t，J＝1.4Hz，1H)，8.49(d，J＝2.6Hz，1H)，7.97-7.85(m，2H)，7.21-7.11(m，2H)，6.72-6.58(m，1H)，6.11(s，1H)，3.85(t，J＝6.5Hz，2H)，3.30-3.24(m，1H)，3.15(t，J＝6.3Hz，2H)，1.38(d，J＝7.1Hz，6H)；ES-LCMSm/z 451.3[M+H]⁺。

Example 98

Synthesis of I-100

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [ (4-hydroxyphenyl) methyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxamide (I-100)

To 5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine-7-carboxylic acid (40mg, 130.54. mu. mol, 1 eq) and 4- (aminomethyl) phenol (19.29mg, 156.65. mu. mol, 1.2 eq) in DCM (20mL) were added HATU (74.45mg, 195.81. mu. mol, 1.5 eq) and DIEA (50.61mg, 391.63. mu. mol, 68.21. mu.L, 3.0 eq). The mixture was stirred at 25 ℃ for 16 hours. The combined reaction mixture is washed with H₂O (20mL) was diluted and extracted with EtOAc (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN]；B％: 47% -77%, 12min) and subsequent lyophilization to give 5- (5-fluoro-3-pyridinyl) -N- [ (4-hydroxyphenyl) methyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-carboxamide (14.42mg, 29.79. mu. mol, 22.8% yield, 98.8% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm9.35(s，1H)，8.77(d，J＝2.9Hz，1H)，8.69(d，J＝9.3Hz，1H)，8.31(s，1H)，8.22(s，1H)，7.26(d，J＝8.6Hz，2H)，6.82-6.72(m，2H)，4.66(s，2H)，3.48-3.42(m，1H)，1.46(d，J＝6.8Hz，6H)；ES-LCMS m/z 406.1[M+H]⁺。

Example 99

Synthesis I-101

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -8-isopropyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-101)

To 4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine (40mg, 137.12. mu. mol, 1 eq.) and 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (33.58mg, 164.55. mu. mol, 1.2 equiv) was added to a solution of i-PrOH (10mL) with DIEA (53.17mg, 411.37. mu. mol, 71.65. mu.L, 3 equiv). The mixture was stirred at 90 ℃ for 3 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Synergi C18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 12min) to obtain 2- (5-fluoro-3-pyridyl) -8-isopropyl-N- [2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (26.15mg, 49.73 μmol, 36.27% yield, 100% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.43-9.38(m，1H)，9.00-8.93(m，2H)，8.49(d，J＝5.6Hz，1H)，8.41(d，J＝8.2Hz，1H)，8.01(s，2H)，7.59-7.54(m，1H)，4.19(t，J＝6.4Hz，2H)，3.41-3.37(m，2H)，3.29-3.22(m，1H)，1.39(d，J＝6.8Hz，6H)；ES-LCMS m/z417.3[M+H]⁺。

Example 100

Synthesis I-102

The synthesis scheme is as follows:

step 1: 2-methyl-4- [ (E) -2-nitrovinyl group]Phenol and its preparation

4-hydroxy-3-methyl-benzaldehyde (1g, 7.34mmol, 1 equiv.) and NaOAc (602.53mg, 7.34mmol, 1 equiv.) in CH₃NO₂The mixture in (10mL) was stirred at 110 ℃ for 48 hours. TLC (PE/EtOAc ═ 5/1, R_f0.23) indicates complete consumption of the starting material and formation of a new spot. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 5/1, R_f0.23) to give 2-methyl-4- [ (E) -2-nitrovinyl) as a yellow solid]Phenol (400mg, 1.12mmol, 15.2% yield, 50% purity).¹HNMR(400MHz，CD₃OD)δppm 7.98(d，J＝13.6Hz，1H)，7.75(d，J＝13.6Hz，1H)，7.65-7.59(m，1H)，7.46-7.37(m，1H)，6.88(d，J＝8.4Hz，1H)，2.24(s，3H)；ES-LCMS m/z 180.1[M+H]⁺

Step 2: 4- (2-aminoethyl) -2-methyl-phenol

To 2-methyl-4- [ (E) -2-nitrovinyl group at 0 deg.C]To a solution of phenol (400mg, 1.12mmol, 1 equiv.) in THF (10mL) was added LAH (1M, 3.35mL, 3 equiv.). The mixture was then stirred at 70 ℃ for 2 hours. The mixture was quenched with water (0.25mL), 15% NaOH (0.25mL), and water (0.75 mL). The mixture was then stirred at 20 ℃ for 3 hours. The mixture was filtered and concentrated under reduced pressure to give 4- (2-aminoethyl) -2-methyl-phenol (350mg, crude) as a brown oil, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.05(s，1H)，6.92(s，1H)，6.85-6.84(m，1H)，3.58-3.55(m，2H)，2.17(s，3H)，1.60-1.57(m，2H)；ES-LCMS m/z152.1[M+H]⁺。

Step 3: 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]-2-methyl-phenol (I-102)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 165.11 μmol, 1.0 eq) and 4- (2-aminoethyl) -2-methyl-phenol (29.96mg, 198.13 μmol, 1.2 eq) in i-PrOH (10mL) was added DIEA (64.02mg, 495.33 μmol, 86.28 μ L, 3 eq). The mixture was stirred at 80 ℃ for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was washed with MeOH (20mL) and filtered. The filter cake was lyophilized to give 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ] as a white solid]Pyrimidin-7-yl]Amino group]Ethyl radical]-2-methyl-phenol (26.08mg, 63.29 μmol, 38.3% yield, 98.4% purity).¹H NMR(400MHz，DMSO-d₆)δppm 9.24(s，1H)，9.03(s，1H)，8.67(s，1H)，8.40-8.36(m，1H)，7.99(s，1H)，7.92(t，J＝6.0Hz，1H)，7.02(s，1H)，6.90(dd，J＝2.0，8.2Hz，1H)，6.73(s，1H)，6.64(d，J＝8.2Hz，1H)，3.74-3.67(m，2H)，3.27-3.19(m，1H)，2.85(t，J＝7.6Hz，2H)，2.07(s，3H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 406.2[M+H]⁺。

Example 101

Synthesis I-103

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-103)

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (30mg, 110.76. mu. mol, 1.0 equiv.) in i-PrOH (3mL) was added DIEA (42.94mg, 332.28. mu. mol, 57.88. mu.L, 3.0 equiv.) and 2- (1H-indol-3-yl) ethylamine (24.00mg, 149.80. mu. mol, 1.35 equiv.). The mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 29% -49%, 10 min). The desired fractions were lyophilized to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (25.41mg, 52.74. mu. mol, 47.62% yield, 100% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝2.5Hz，1H)，8.38(s，1H)，8.26(d，J＝2.3Hz，1H)，7.56(d，J＝7.8Hz，1H)，7.46(td，J＝2.3，9.0Hz，1H)，7.12(d，J＝8.0Hz，1H)，7.00(s，1H)，6.96(t，J＝7.2Hz，1H)，6.89-6.84(m，1H)，6.52(d，J＝2.3Hz，1H)，5.88(s，1H)，4.07(t，J＝5.9Hz，2H)，3.27-3.23(m，2H)；ES-LCMS m/z 373.3[M+H]⁺。

Example 102

Synthesis I-104

The synthesis scheme is as follows:

step 1: 4-chloro-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidine

To a solution of i-PrOH (43.10mg, 717.06. mu. mol, 54.90. mu.L, 1 eq.) in THF (8mL) was added NaH (34.42mg, 860.47. mu. mol, 60% pure, 1.2 eq.). The mixture was stirred at 0 ℃ for 30 minutes. 4, 6-dichloro-2- (5-fluoro-3-pyridinyl) pyrimidine (175mg, 717.06 μmol, 1.0 eq) was added to the above solution and the mixture was stirred at 15 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (50mL) and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 4-chloro-2- (5-fluoro-3-pyridinyl) -6-isopropoxy-pyrimidine (220mg, 690.36 μmol, 96.2% yield, 84.0% purity) as a yellow solid, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.41(s，1H)，8.58(d，J＝2.8Hz，1H)，8.40-8.31(m，1H)，6.67(s，1H)，5.53(m，1H)，1.43(d，J＝6.3Hz，6H)；ES-LCMS m/z 268.1，270.1[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -6-isopropoxy-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrimidine-4-amine (I-104)

Reacting 4-chloro-2- (5-fluoro)-3-pyridinyl) -6-isopropoxy-pyrimidine (60mg, 188.28 μmol, 1.0 equiv.), 2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethylamine (45mg, 220.53. mu. mol, 1.17 equiv.) and DIEA (73.00mg, 564.84. mu. mol, 98.38. mu.L, 3.0 equiv.) were placed in a microwave tube in i-PrOH (3 mL). The sealed tube was heated at 125 ℃ for 6 hours under microwave. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 10 min). Lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridyl) -6-isopropoxy-N- [2- (1H-pyrrolo [3, 2-b ] as a yellow solid]Pyridin-3-yl) ethyl]Pyrimidin-4-amine (20.08mg, 38.97 μmol, 20.7% yield, 97.4% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.20(s，1H)，8.93(dd，J＝1.0，2.5Hz，1H)，8.62(s，1H)，8.53-8.46(m，2H)，8.06(s，1H)，7.65-7.58(m，1H)，6.03(s，1H)，5.22(s，1H)，5.29-5.16(m，1H)，3.96(m，2H)，3.30-3.27(m，2H)，1.42(d，J＝6.0Hz，6H)；ES-LCMS m/z 393.2[M+H]⁺。

Example 103

Synthesis I-105

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-pyrrolidin-1-yl-pyrimidin-4-amine (I-105)

Reacting 6-chloro-2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-4-amine (80mg, 215.33 μmol, 1.0 equiv.), pyrrolidine (1.28g, 17.97mmol, 1.5mL, 83.45 equiv.), and DIEA (139.15mg, 1.08mmol, 187.53 μ L, 5.0 equiv.) in i-PrOH (1.5mL) was placed in a microwave tube. The sealed tube was heated at 130 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 10 min). The desired fractions were lyophilized to give 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a yellow solid]-6-pyrrolidin-1-yl-pyrimidin-4-amine (47.28mg, 91.26 μmol, 42.3% yield, 98.8% purity, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.00(s，1H)，8.77(s，1H)，8.22(s，1H)，7.64(d，J＝7.3Hz，1H)，7.33(d，J＝7.9Hz，1H)，7.16-6.98(m，4H)，3.72(d，J＝6.0Hz，4H)，3.15(t，J＝5.8Hz，4H)，2.00(s，4H)；ES-LCMS m/z 403.3[M+H]⁺。

Example 104

Synthesis I-106

The synthesis scheme is as follows:

step 1: 1-amino-3-methyl-butan-2-ol

2-Isopropyloxirane (600mg, 6.97mmol, 1 eq.) in NH₃·H₂The mixture in O (5mL) was degassed and treated with N₂And purifying for 3 times. Then the mixture is added to N₂Stirring at 10-15 deg.C for 16 hr under atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product 1-amino-3-methyl-butan-2-ol (700mg, 6.79mmol, 97.4% yield, crude) as a colorless oil, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm3.39-3.22(m，1H)，2.91-2.72(m，1H) 2.60-2.49(m, 1H), 1.71-1.62(m, 1H), 0.98-0.91(m, 6H); ES-LCMS m/z found no correct mass.

Step 2: 1- [ (3-Chloropyrazin-2-yl) amino]-3-methyl-butan-2-ol

A mixture of 2, 3-dichloropyrazine (670mg, 4.50mmol, 1 equivalent) and 1-amino-3-methyl-butan-2-ol (695.93mg, 6.75mmol, 1.5 equivalents) in 1, 4-dioxane (3mL) was degassed and treated with N₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 110 ℃ for 16 hours. TLC (PE/EtOAc ═ 5/1, R_f0.54) showed that the starting material was not completely consumed and new spots were found. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 5/1, R_f0.54) to give the product 1- [ (3-chloropyrazin-2-yl) amino group as a colorless oil]-3-methyl-butan-2-ol (500mg, 2.27mmol, 50.5% yield, 98.0% purity).¹H NMR(400MHz，CDCl₃)δppm 7.92(d，J＝2.9Hz，1H)，7.60(d，J＝2.6Hz，1H)，5.61(br s，1H)，3.74(ddd，J＝2.4，6.5，13.8Hz，1H)，3.59-3.58(m，1H)，3.44-3.37(m，1H)，2.83(d，J＝4.4Hz，1H)，1.89-1.72(m，1H)，1.03(dd，J＝6.8，10.6Hz，6H)；ES-LCMS m/z 216.0，218.1[M+H]⁺。

Step 3: 1- [ (3, 5-dichloropyrazin-2-yl) amino]-3-methyl-butan-2-ol

1- [ (3-chloropyrazin-2-yl) amino group]-3-methyl-butan-2-ol (380mg, 1.73mmol, 1 equiv.) and NCS (276.68mg, 2.07mmol, 1.2 equiv.) in CHCl₃(10mL) the mixture was degassed and N was used₂Purification 3 times and in N₂Stirred under an atmosphere at 70 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC:PE/EtOAc＝3/1，R_f0.46) to yield the product 1- [ (3, 5-dichloropyrazin-2-yl) amino) as a yellow oil]-3-methyl-butan-2-ol (345mg, 1.23mmol, 71.1% yield, 89.0% purity).¹HNMR(400MHz，CDCl₃)δppm 7.95(s，1H)，5.59(br s，1H)，3.74(ddd，J＝2.8，6.7，13.7Hz，1H)，3.58-3.56(m，1H)，3.38-3.33(m，1H)，1.83-1.73(m，1H)，1.03(dd，J＝6.8，10.1Hz，6H)；ES-LCMS m/z 250.0，252.0[M+H]⁺。

Step 4: 1- [ (3, 5-dichloropyrazin-2-yl) amino]-3-methyl-butan-2-one

To 1- [ (3, 5-dichloropyrazin-2-yl) amino]To a solution of-3-methyl-butan-2-ol (405mg, 1.44mmol, 1 equiv.) in DCM (30mL) was added Dess-Martin (Dess-Martin) (733.47mg, 1.73mmol, 1.2 equiv.). The mixture was stirred at 20 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.51) showed about 50% starting material remaining. Toiss-martin (300mg, 0.71mmol) was added and the reaction stirred at 20 ℃ for 16 h. TLC (PE/EtOAc ═ 3/1, R_f0.51) showed about 20% starting material remaining. The reaction mixture was purified by addition of saturated Na₂S₂O₃The solution was quenched (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.51) to yield the product 1- [ (3, 5-dichloropyrazin-2-yl) amino) as a yellow oil]-3-methyl-butan-2-one (200mg, 669.06 μmol, 46.4% yield, 83.0% purity).¹H NMR(400MHz，CDCl₃)δppm 7.96(s，1H)，6.03(br s，1H)，4.35(d，J＝4.4Hz，2H)，2.76(m，1H)，1.22(d，J＝6.8Hz，6H)；ES-LCMS m/z 247.9，249.9[M+H]⁺。

Step 5: 6, 8-dichloro-3-isopropyl-imidazo [1, 2-a ]]Pyrazine esters

To 1- [ (3, 5-dichloropyrazin-2-yl) amino]To a solution of-3-methyl-butan-2-one (180mg, 602.16 μmol, 1 eq) in TFA (2mL) was added TFAA (379.41mg, 1.81mmol, 251.27 μ L, 3 eq). The mixture was stirred at 20 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.48) to yield the product 6, 8-dichloro-3-isopropyl-imidazo [1, 2-a) as a light yellow solid]Pyrazine (120mg, 521.53 μmol, 86.6% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 7.94(s，1H)，7.69(s，1H)，3.22-3.16(m，1H)，1.44(d，J＝6.8Hz，6H)；ES-LCMS m/z 230.0，232.0[M+H]⁺。

Step 6: 6-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-imidazo [1, 2-a]Pyrazin-8-amines

To 6, 8-dichloro-3-isopropyl-imidazo [1, 2-a ]]To a solution of pyrazine (50mg, 217.30 μmol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (41.78mg, 260.76 μmol, 1.2 eq) in i-PrOH (3mL) was added DIEA (84.25mg, 651.91 μmol, 113.55 μ L, 3.0 eq). The mixture was stirred at 45 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 1/1, R_f0.44) to yield the product 6-chloro-N- [2- (1H-indol-3-yl) ethyl as a brown oil]-3-isopropyl-imidazo [1, 2-a]Pyrazin-8-amine (60mg, 162.78 μmol, 74.9% yield, 96.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.07(br s，1H)，7.71(d，J＝7.9Hz，1H)，7.38(d，J＝7.9Hz，1H)，7.30(s，1H)，7.24-7.19(m，2H)，7.17-7.12(m，1H)，7.11(d，J＝2.2Hz，1H)，6.21(br s，1H)，4.02-3.89(m，2H)，3.17(t，J＝6.8Hz，2H)，3.12-3.02(m，1H)，1.37(d，J＝7.1Hz，6H)；ES-LCMS m/z354.0，356.1[M+H]⁺。

Step 7: 6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-imidazo [1, 2-a]Pyrazine-8-amine (I-106)

Reacting 6-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-imidazo [1, 2-a]Pyrazin-8-amine (60mg, 162.78. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (45.87mg, 325.56. mu. mol, 2.0 eq), Pd (dppf) Cl₂(11.91mg, 16.28. mu. mol, 0.1 equiv.) and Cs₂CO₃(159.11mg, 488.35. mu. mol, 3.0 equiv.) in 1, 4-dioxane (2mL) and H₂O (0.5mL) was placed in the microwave tube. N for the mixture₂And purifying for 3 minutes. The sealed tube was heated under microwave at 110 ℃ for 30 minutes. The reaction mixture was diluted with ethyl acetate (20mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Feilomo Synergic 18150X 30mm X4 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 12min) and then lyophilized to give 6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-imidazo [1, 2-a]Pyrazin-8-amine (50.13mg, 94.00 μmol, 57.8% yield, 98.2% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.21(br s，1H)，8.86(br s，1H)，8.74(d，J＝9.0Hz，1H)，8.57(s，1H)，7.89(s，1H)，7.51(d，J＝7.8Hz，1H)，7.18(d，J＝8.3Hz，1H)，7.09(s，1H)，6.94(t，J＝7.5Hz，1H)，6.89-6.81(m，1H)，4.06(t，J＝6.1Hz，2H)，3.46(d，J＝6.0Hz，1H)，3.18(t，J＝6.3Hz，2H)，1.42(d，J＝6.3Hz，6H)；ES-LCMS m/z 415.3[M+H]⁺。

Example 105

Synthesis I-107

The synthesis scheme is as follows:

step 1: n- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-107)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (120mg, 404.51 μmol, 1 eq) and 2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethylamine (182.19mg, 606.76 μmol, 1.5 eq, oxalic acid) in i-PrOH (20mL) was added DIEA (261.40mg, 2.02mmol, 352.29 μ L, 5.0 eq). The mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 63% -93%, 10min) and then lyophilized to give N- [2- (5, 7-difluoro-2-methyl-1H-indol-3-yl) ethyl) as a pale yellow solid]-5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (94.41mg, 196.14. mu. mol, 48.5% yield, 96.5% purity, 92.85 mg).¹H NMR(400MHz，DMSO-d₆)δppm 11.16(s，1H)，8.96(s，1H)，8.61(d，J＝2.8Hz，1H)，8.06-7.95(m，3H)，7.20(dd，J＝2.0，9.5Hz，1H)，6.80-6.68(m，1H)，6.34(s，1H)，3.69(q，J＝6.5Hz，2H)，3.19(spt，J＝6.8Hz，1H)，2.99(t，J＝6.7Hz，2H)，2.16(s，3H)，1.33(d，J＝7.0Hz，6H)；ES-LCMS m/z 465.3[M+H]⁺。

Example 106

Synthesis I-108

The synthesis scheme is as follows:

step 1: 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (I-108)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (52.08mg, 171.99. mu. mol, 1 eq) in i-PrOH (3mL) was added 4- (2-aminoethyl) phenol (28.31mg, 206.38. mu. mol, 1.2 eq) and DIEA (66.68mg, 515.96. mu. mol, 89.87. mu.L, 3 eq). The mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated to give the crude product, which was purified by preparative HPLC (MeCN/H)₂O as eluent, acidic conditions, instrument: philomo Gemini 150X 25mm X10 μm/mobile phase: water (0.05% HCl) -CAN/gradient: b from 42% to 72% per flow rate over 10 minutes: 25mL/min) and then lyophilized to give 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (49.37mg, 105.68 μmol, 61.5% yield, 99.4% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.83(d，J＝2.5Hz，2H)，8.27(s，1H)，8.16(dd，J＝1.8，8.8Hz，1H)，7.08(d，J＝8.3Hz，2H)，6.63(d，J＝8.3Hz，2H)，6.38(s，1H)，3.97(t，J＝6.5Hz，2H)，3.38-3.34(m，1H)，3.01(t，J＝6.5Hz，2H)，1.39(d，J＝7.0Hz，6H)；ES-LCMS m/z 392.1[M+H]⁺。

Example 107

Synthesis I-109

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a ]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (80mg, 264.17. mu. mol, 1.0 equiv.) in i-PrOH (3mL) was added DIEA (102.42mg, 792.51. mu. mol, 138.04. mu.L, 3.0 equiv.) and 5-methoxyindan-2-amine (60mg, 367.61. mu. mol, 1.39 equiv.). The mixture was stirred at 50 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.70) to yield 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-amine (120mg, 155.51 μmol, 58.9% yield, 54.1% purity).¹H NMR(400MHz，CDCl₃)δppm 9.08(s，1H)，8.55(d，J＝2.8Hz，1H)，8.21(td，J＝2.3，9.5Hz，1H)，7.87(s，1H)，7.18(d，J＝8.3Hz，1H)，6.83(s，1H)，6.57(d，J＝7.5Hz，1H)，6.41(s，1H)，4.70-4.60(m，1H)，3.81(s，3H)，3.50(ddd，J＝6.8，12.6，15.7Hz，2H)，3.42-3.30(m，1H)，3.08(dt，J＝4.5，16.1Hz，2H)，1.42(d，J＝6.8Hz，6H)；ES-LCMS m/z 418.1[M+H]⁺。

Step 2: 2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-109)

Reacting 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- (5-methoxyindan-2-yl) pyrazolo [1, 5-a]A solution of pyrimidin-7-amine (95mg, 123.11. mu. mol, 1 eq.) in HBr (9mL) was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was prepared byType HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 49% -79%, 10 min). Freeze drying the required fractions to obtain 2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (30.69mg, 61.40. mu. mol, 49.8% yield, 95.3% purity, 2HCl salt).¹H NMR(400MHz，CD₃OD)δppm 9.00(s，1H)，8.83(d，J＝2.5Hz，1H)，8.35(td，J＝2.3，9.0Hz，1H)，8.24(s，1H)，7.08(d，J＝8.3Hz，1H)，6.96(s，1H)，6.71(s，1H)，6.65(dd，J＝2.3，8.0Hz，1H)，5.02(t，J＝6.9Hz，1H)，3.51-3.40(m，2H)，3.40-3.32(m，1H)，3.25-3.12(m，2H)，1.39(d，J＝7.0Hz，6H)；ES-LCMS m/z 404.2[M+H]⁺。

Example 108

Synthesis I-110

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-110)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidine (45mg, 123.83. mu. mol, 1.0 equiv.) in i-PrOH (2mL) was added DIEA (48.01mg, 371.49. mu. mol, 64.70. mu.L, 3.0 equiv.) and 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (25mg, 155.08. mu. mol, 1.25 equiv.). The mixture was stirred at 50 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl))-ACN](ii) a B%: 20% -50%, 10 minutes). Lyophilizing the desired fractions to obtain 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [2- (1H-pyrrolo [3, 2-b ] as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (16.32mg, 30.38 μmol, 24.5% yield, 97.7% pure, 3HCl salt).¹H NMR(400MHz，CD₃OD)δppm 8.97(s，1H)，8.84(d，J＝2.4Hz，1H)，8.57-8.52(m，2H)，8.35(td，J＝2.1，9.0Hz，1H)，8.23(s，1H)，8.10(s，1H)，7.70-7.65(m，1H)，6.90(s，1H)，4.15(t，J＝6.9Hz，2H)，3.45(t，J＝6.9Hz，2H)，3.38-3.33(m，1H)，1.38(d，J＝6.8Hz，6H)；ES-LCMS m/z 416.2[M+H]⁺。

Example 109

Synthesis of I-120

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amines

To a mixture of 2- (1H-indol-3-yl) ethylamine (2.96g, 18.50mmol, 1.05 eq) in THF (50mL) was added NaH (1.06g, 26.42mmol, 1.5 eq). The mixture was heated at 0 ℃ under N₂Stirred under atmosphere for 30 minutes. A solution of 4, 6-dichloro-2-methylsulfonyl-pyrimidine (4g, 17.62mmol, 1 eq) in THF (50mL) was added dropwise to the mixture. The mixture was stirred at-55 ℃ for 12 hours. Addition of 1NNH to the reaction mixture₄Cl solution (5mL) and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc: 3/1, R)_f0.5) to yield 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrimidin-2-amine (2.1g, 5.81mmol, 33.0% yield, 85% purity))。¹H NMR(400MHz，CDCl₃)δppm 8.68(s，1H)，8.00(d，J＝10.8Hz，1H)，7.64(t，J＝6.1Hz，1H)，7.39-7.33(m，1H)，7.26-7.20(m，1H)，7.16-7.09(m，1H)，7.08-6.99(m，1H)，6.61-6.53(m，1H)，3.84-3.70(m，2H)，3.05(d，J＝6.1Hz，2H)；ES-LCMS m/z 307.0，309.1[M+H]⁺。

Step 2: 4-chloro-6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amines

In N₂To 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl under an atmosphere]Pyrimidin-2-amine (300mg, 830.14mol, 1 eq) and (5-fluoro-3-pyridinyl) boronic acid (93.58mg, 664.11mol, 0.8 eq) in 1, 4-dioxane (3mL) and H₂Mixture in O (2mL) with addition of Cs₂CO₃(540.95mg, 1.66mmol, 2 equiv.) and Pd (dppf) Cl₂(60.74mg, 83.01mol, 0.1 equiv.). The mixture was stirred under microwave at 110 ℃ for 20 minutes. The reaction mixture was concentrated. The residue was subjected to silica gel column chromatography (pure PE to PE/EtOAc-3/1, TLC: PE/EtOAc-3/1, R_f0.33) to yield 4-chloro-6- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a pale yellow solid]Pyrimidin-2-amine (70mg, 171.29mol, 20.6% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 8.91(br s，1H)，8.50(br s，1H)，7.97(br s，2H)，7.60(d，J＝7.1Hz，1H)，7.32(d，J＝8.1Hz，1H)，7.15(t，J＝7.6Hz，1H)，7.10-7.04(m，1H)，7.02(br s，1H)，6.92(s，1H)，5.39(br s，1H)，3.79(br s，2H)，3.05(t，J＝6.7Hz，2H)；ES-LCMS m/z 368.1，370.1[M+H]⁺。

Step 3: 4- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidine-2-amine (I-120)

To 4-chloro-6- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amine (70mg, 171.29mol, 1 eq) in MeOH (5mL) and NH₃·H₂To a solution in O (0.2mL) was added Pd/C (30mg, 10% purity). The suspension is degassed under vacuum and treated with H₂The purification is carried out for several times. Mixing the mixture in H₂Stirring was carried out at 10 ℃ for 0.5 hour under an atmosphere of (15 psi). The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 33% -63%, 8min) and then lyophilized to give 4- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl ] as a yellow solid]Pyrimidin-2-amine (20.8mg, 50.20. mu. mol, 29.3% yield, 98.1% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.06(br s，1H)，8.74(br s，1H)，8.32-8.06(m，2H)，7.59-7.55(m，1H)，7.43(d，J＝6.6Hz，1H)，7.24-7.04(m，2H)，7.01-6.93(m，2H)，4.05-3.96(m，2H)，3.15(t，J＝6.4Hz，2H)；ES-LCMS m/z 334.1[M+H]⁺。

Example 110

Synthesis I-121

The synthesis scheme is as follows:

step 1: (3R) -N- (2-methylthiopyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To 4-chloro-2-methylsulfanyl-pyrazolo [1, 5-a ]][1，3，5]To a solution of triazine (500mg, 1.69mmol, 1 equiv, HCl) in MeCN (30mL) were added DIEA (1.31g, 10.12mmol, 1.76mL, 6 equiv) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (314.20mg, 1.69mmol, 1 equiv). The mixture was stirred at 50 ℃ for 2 hours. ConcentratingAnd (3) mixing. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 2/1, TLC: PE/EtOAc: 3/1, R_fPurification No. 0.4) to give (3R) -N- (2-methylthiopyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (300mg, 770.46 μmol, 45.7% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm7.90-7.77(m，2H)，7.44(d，J＝7.8Hz，1H)，7.30(d，J＝8.1Hz，1H)，7.18-7.12(m，1H)，7.11-7.06(m，1H)，6.61(d，J＝8.3Hz，1H)，6.21(s，1H)，3.28(dd，J＝5.0，15.5Hz，1H)，3.00-2.78(m，4H)，2.55(s，3H)，2.31-2.15(m，2H)；ES-LCMS m/z 351.2[M+H]⁺。

Step 2: (3R) -3- [ tert-Butoxycarbonyl- (2-methylthiopyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

To (3R) -N- (2-methylthiopyrazolo [1, 5-a)][1，3，5]To a solution of triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (200mg, 513.64 μmol, 1 eq) in 1, 4-dioxane (30mL) was added DMAP (188.25mg, 1.54mmol, 3 eq) and Boc₂O (672.60mg, 3.08mmol, 708.00. mu.L, 6 equiv.). The mixture was stirred at 110 ℃ for 24 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 5/1, R_f0.5) to give (3R) -3- [ tert-butoxycarbonyl- (2-methylthiopyrazolo [1, 5-a) as an off-white solid][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (300mg, 492.49 μmol, 95.9% yield, 90.4% purity).¹H NMR(400MHz，CDCl₃)δppm 8.11-8.02(m，2H)，7.33(d，J＝7.6Hz，1H)，7.23-7.14(m，2H)，6.41(s，1H)，4.79-4.72(m，1H)，3.31-3.01(m，4H)，2.56(s，3H)，2.41-2.17(m，2H)，1.64(s，9H)，1.32(s，9H)；ES-LCMS m/z 551.3[M+H]⁺。

Step 3: (3R) -3- [ (8-bromo-2-methylsulfanyl-pyrazine)Azolo [1, 5-a ]][1，3，5]Triazin-4-yl) -tert-butoxycarbonyl-amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

To (3R) -3- [ tert-butoxycarbonyl- (2-methylthiopyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]NBS (79.76mg, 448.17. mu. mol, 1.05 equiv.) was added to a solution of tert-butyl (1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (260mg, 426.82. mu. mol, 1 equiv.) in MeCN (20mL) and DCM (20 mL). The mixture was stirred at 10 ℃ for 30 minutes. The mixture was concentrated. The residue was subjected to silica gel column chromatography (PE/EtOAc: 5/1 to 2/1, TLC: PE/EtOAc: 5/1, R_f0.58) to give (3R) -3- [ (8-bromo-2-methylsulfanyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) -tert-butoxycarbonyl-amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (200mg, 299.89 μmol, 70.3% yield, 94.4% purity).¹H NMR(400MHz，CDCl₃)δppm 8.09(d，J＝7.8Hz，1H)，8.05(s，1H)，7.34(d，J＝8.0Hz，1H)，7.25-7.17(m，2H)，4.83-4.73(m，1H)，3.34-3.25(m，1H)，3.23-3.02(m，3H)，2.62(s，3H)，2.36(td，J＝6.2，12.0Hz，1H)，2.23-2.21(m，1H)，1.66(s，9H)，1.36(s，9H)；ES-LCMS m/z 629.2，631.2[M+H]⁺。

Step 4: (3R) -3- [ tert-Butoxycarbonyl- (8-isopropenyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

In N₂To (3R) -3- [ (8-bromo-2-methylthio-pyrazolo [1, 5-a) under an atmosphere][1，3，5]Triazin-4-yl) -tert-butoxycarbonyl-amino]-tert-butyl 1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (200mg, 299.89 μmol, 1 eq), 2-isopropenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane (75.59mg, 449.83 μmol, 1.5 eq) in 1, 4-dioxane (4mL) and H₂Addition of Cs to O (2mL) solution₂CO₃(293.13mg, 899.67. mu. mol, 3 equiv.) and Pd (dppf) Cl₂(21.94mg, 29.99. mu. mol, 0.1 equiv.). The mixture was stirred under microwave at 110 ℃ for 1 hour. After filtration, the filtrate was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 5/1, TLC: PE/EtOAc: 5/1, R_f0.65) to give (3R) -3- [ tert-butoxycarbonyl- (8-isopropenyl-2-methylsulfanyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (180mg, 274.23 μmol, 91.5% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 8.13-8.05(m，2H)，7.32(d，J＝7.6Hz，1H)，7.23-7.15(m，2H)，5.86(s，1H)，5.12(s，1H)，4.79-4.74(m，1H)，3.29-3.01(m，4H)，2.57(s，3H)，2.33-2.18(m，5H)，1.34(s，9H)，1.26(s，9H)；ES-LCMS m/z 591.3[M+H]⁺。

Step 5: (3R) -3- [ tert-Butoxycarbonyl- [2- (3-fluorophenyl) -8-isopropenyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]Amino group]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

In N₂(3R) -3- [ tert-butoxycarbonyl- (8-isopropenyl-2-methylthio-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (140mg, 213.29 μmol, 1 eq), (3-fluorophenyl) boronic acid (89.53mg, 639.88 μmol, 3 eq), Pd (PPh)₃)₄A mixture of (24.65mg, 21.33. mu. mol, 0.1 equiv.) and CuTC (122.02mg, 639.88. mu. mol, 3 equiv.) in THF (2mL) was placed in a microwave tube. The mixture was stirred at 100 ℃ for 3 hours under microwave. After filtration, the filtrate was concentrated. The residue was purified by preparative TLC (PE/EtOAc. RTM. 5/1, R)_f0.68) to yield (3R) -3- [ tert-butoxycarbonyl- [2- (3-fluorophenyl) -8-isopropenyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]Amino group]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (70mg, 64.11. mu. mol, 30.1% yield,58.5% purity).¹H NMR(400MHz，CDCl₃)δppm 8.21-8.13(m，2H)，8.02(d，J＝8.1Hz，2H)，7.31-7.23(m，2H)，7.13-7.06(m，3H)，5.97(s，1H)，5.17(s，1H)，4.85-4.83(m，1H)，3.10-2.97(m，4H)，2.22-2.14(m，5H)，1.29(d，J＝4.4Hz，18H)；ES-LCMS m/z 639.4[M+H]⁺。

Step 6: (3R) -N- [2- (3-fluorophenyl) -8-isopropyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-121)

To (3R) -3- [ tert-butoxycarbonyl- [2- (3-fluorophenyl) -8-isopropenyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]Amino group]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (60mg, 54.95. mu. mol, 1 equivalent) and NH₃·H₂To a solution of O (546.00mg, 4.36mmol, 600.00. mu.L, 28% purity, 79.38 equiv) in MeOH (15mL) was added Pd/C (30mg, 9.16. mu. mol, 10% purity). Mixing the mixture in H₂Stirring was carried out under an atmosphere (15psi) at 25 ℃ for 6 hours. After filtration, the filtrate was concentrated. To the residue were added DCM (3mL) and TFA (1.54g, 13.51mmol, 1mL, 245.78 equiv). The mixture was stirred at 15 ℃ for 1 hour. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 80% -100%, 8min) and then lyophilized to give (3R) -N- [2- (3-fluorophenyl) -8-isopropyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (12.51mg, 26.23. mu. mol, 9.8% yield, 100% purity, HCl, OR: [ α ]]^22.4 _D＝+9.972，(MeOH，c＝0.071g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.24(d，J＝8.1Hz，1H)，8.09(d，J＝10.3Hz，1H)，7.95(s，1H)，7.45(dt，J＝5.9，7.9Hz，1H)，7.37(d，J＝7.8Hz，1H)，7.26(d，J＝7.8Hz，1H)，7.20(dt，J＝2.1，8.3Hz，1H)，7.02(t，J＝7.2Hz，1H)，6.97-6.91(m，1H)，4.89-4.85(m，1H)，3.28-3.23(m，1H)，3.08-2.87(m，3H)，2.43-2.33(m，1H)，2.30-2.19(m，1H)，1.39(d，J＝6.8Hz，6H)；ES-LCMS m/z 441.3[M+H]⁺。

Example 111

Synthesis I-122

The synthesis scheme is as follows:

step 1: n- (1H-pyrazol-5-ylthiocarbamoyl) carbamic acid ethyl ester

To a suspension of 3H-pyrazol-3-amine (15.84g, 190.62mmol, 1 eq) in DCM (160mL) was added ethoxycarbonyl isothiocyanate (25g, 190.62mmol, 22.52mL, 1 eq) at 0 ℃. The mixture was stirred at 25 ℃ for 12 hours under an atmosphere of N2. The mixture was filtered. The filter cake was washed with DCM (20 mL. times.2) and dried to give ethyl N- (1H-pyrazol-5-ylthiocarbamoyl) carbamate (26g, 109.22mmol, 57.3% yield, 90% purity) as a white solid.¹HNMR(400MHz，CD₃OD)δppm 7.59(d，J＝2.2Hz，1H)，7.12(s，1H)，4.27(q，J＝7.2Hz，2H)，1.34(t，J＝7.1Hz，3H)；ES-LCMS m/z 215.1[M+H]⁺。

Step 2: 2-thione-1H-pyrazolo [1, 5-a ]][1，3，5]Triazin-4-ones

To a mixture of ethyl N- (1H-pyrazol-5-ylthiocarbamoyl) carbamate (25.5g, 107.12mmol, 1 eq) in MeCN (300mL) was added K₂CO₃(44.42g, 321.36mmol, 3 equiv.). The mixture was stirred at 85 ℃ for 4 hours. Mixing the raw materialsThe material was diluted with water (100mL) and the pH adjusted to 5-6 with 2N HCl. The solvent was evaporated and the residue was suspended in water (600 mL). The solid was filtered off, washed with water (60 mL. times.2), and dried to give 2-thione-1H-pyrazolo [1, 5-a ] as a white solid][1，3，5]Triazin-4-one (16g, 90.38mmol, 84.4% yield, 95% purity).¹H NMR(400MHz，CD₃OD)δppm 7.83(s，1H)，5.93(d，J＝1.7Hz，1H)；ES-LCMS m/z 169.1[M+H]⁺。

Step 3: 2-methylthio-3H-pyrazolo [1, 5-a ]][1，3，5]Triazin-4-ones

To 2-thione-1H-pyrazolo [1, 5-a ]][1，3，5]To a suspension of triazin-4-one (16g, 90.38mmol, 1 equiv.) in EtOH (120mL) was added H containing NaOH (7.23g, 180.76mmol, 2 equiv.)₂O (9.6mL), MeI (15.96g, 112.44mmol, 7.0mL, 1.24 equiv) was added dropwise. The mixture was stirred at 15 ℃ for 1 hour. The mixture was acidified with 1N aqueous HCl (80mL) and EtOH was evaporated. The mixture was filtered and washed with H₂O (50 mL. times.2) wash. Drying the filter cake to obtain 2-methylsulfanyl-3H-pyrazolo [1, 5-a ] as a white solid][1，3，5]Triazin-4-one (16g, 83.42mmol, 92.3% yield, 95% purity).¹H NMR(400MHz，CD₃OD)δppm 7.74(d，J＝2.0Hz，1H)，5.99(d，J＝2.2Hz，1H)，2.48(s，3H)；ES-LCMS m/z 183.2[M+H]⁺。

Step 4: 8-bromo-2-methylsulfanyl-3H-pyrazolo [1, 5-a ]][1，3，5]Triazin-4-ones

To 2-methylsulfanyl-3H-pyrazolo [1, 5-a ]][1，3，5]To a solution of triazin-4-one (3.0g, 15.64mmol, 1 eq) in DMF (30mL) was added NBS (2.51g, 14.08mmol, 0.9 eq). The mixture was stirred at 15 ℃ for 0.5 h. The mixture was concentrated to give 8-bromo-2-methylsulfanyl-3H-pyrazolo [1, 5-a ] as a green oil][1，3，5]Triazin-4-one (4g, 12.26mmol, 78.4% yield, 80% purity).¹H NMR(400MHz，CD₃OD)δppm 7.72(s，1H)，2.49(s，3H)；ES-LCMS m/z 261.0，263.0[M+H]⁺。

Step 5: 8-bromo-4-chloro-2-methylsulfanyl-pyrazolo [1, 5-a][1，3，5]Triazine

Reacting 8-bromo-2-methylsulfanyl-3H-pyrazolo [1, 5-a ]][1，3，5]Triazin-4-one (2.0g, 6.13mmol, 1 equiv.) and N, N-dimethylaniline (742.58mg, 6.13mmol, 776.76. mu.L, 1 equiv.) in POCl₃(16.50g, 107.61mmol, 10mL, 17.56 equiv.) the suspension was stirred at 130 ℃ for 4 hours. The mixture was added to water (100mL) at 0 ℃ and extracted with EtOAc (200 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 3/1, R_f0.8) to give 8-bromo-4-chloro-2-methylsulfanyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazine (600mg, 2.08mmol, 33.9% yield, 97% purity).¹H NMR(400MHz，CDCl₃)δppm 8.12(s，1H)，2.66(s，3H)；ES-LCMS m/z 278.9，280.9[M+H]⁺。

Step 6: (3R) -N- (8-bromo-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To 8-bromo-4-chloro-2-methylsulfanyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazine (600mg, 2.08mmol, 1 equiv.) in i-PrOH (12mL) was added DIEA (807.22mg, 6.25mmol, 1.09mL, 3 equiv.) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (426.55mg, 2.29mmol, 1.10 equiv.). The mixture was stirred at 50 ℃ for 2 hours. The mixture was concentrated and extracted with EtOAc (60 mL. times.3). The combined organic layers were washed with brine(50mL) washed over Na₂SO₄Drying, filtering and concentrating to give (3R) -N- (8-bromo-2-methylsulfanyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (800mg, 1.68mmol, 80.6% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 7.86-7.80(m，2H)，7.45(d，J＝7.6Hz，1H)，7.32(d，J＝8.1Hz，1H)，7.17(t，J＝6.8Hz，1H)，7.13-7.07(m，1H)，6.59(d，J＝8.3Hz，1H)，4.82-4.78(m，1H)，3.31-3.26(m，1H)，2.99-2.84(m，3H)，2.61(s，3H)，2.30-2.20(m，2H)；ES-LCMS m/z 429.1，431.1[M+H]⁺。

Step 7: (3R) -N- (8-isopropenyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

In N₂To (3R) -N- (8-bromo-2-methylsulfanyl-pyrazolo [1, 5-a) under an atmosphere][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (400mg, 838.50. mu. mol, 1 eq.), Pd (dppf) Cl₂(61.35mg, 83.85. mu. mol, 0.1 equiv.), Cs₂CO₃(683.00mg, 2.10mmol, 2.5 equiv.) in 1, 4-dioxane (10mL) and H₂2-isopropenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane (704.51mg, 4.19mmol, 5 equiv.) was added to the mixture in O (2.5 mL). Mixing the mixture in N₂Stirring was carried out under an atmosphere of microwaves at 110 ℃ for 1.5 hours. The combined reaction mixture was concentrated and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 3/1, R_f0.46) to give (3R) -N- (8-isopropenyl-2-methylsulfanyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (250mg, 550.57 μmol, 65.6% yield, 86% purity).¹H NMR(400MHz，CDCl₃)δppm 7.87(s，1H)，7.81(s，1H)，7.45(d，J＝7.8Hz，1H)，7.32(d，J＝7.8Hz，1H)，7.17(t，J＝7.5Hz，1H)，7.13-7.08(m，1H)，6.57(d，J＝8.6Hz，1H)，5.86(s，1H)，5.06(s，1H)，4.82-4.77(m，1H)，3.29(dd，J＝4.8，15.5Hz，1H)，2.99-2.82(m，3H)，2.58(s，3H)，2.32-2.23(m，2H)，2.21(s，3H)；ES-LCMS m/z 391.2[M+H]⁺。

Step 8: (3R) -N- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-122)

In N₂To (3R) -N- (8-isopropenyl-2-methylsulfanyl-pyrazolo [1, 5-a) under an atmosphere][1，3，5]Mixture of triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (100mg, 220.23. mu. mol, 1 eq) in EtOAc (12mL) was added PtO₂(250mg, 1.10mmol, 5.00 equiv.). Mixing the mixture in H₂Stirring was carried out under an atmosphere (15psi) at 15 ℃ for 20 minutes. The mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 70% -100%, 8min) and then lyophilized to give (3R) -N- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (50mg, 116.56 μmol, 52.9% yield, 100% purity, HCl).¹H NMR(400MHz，CD₃OD)δppm7.90(s，1H)，7.37(d，J＝7.6Hz，1H)，7.26(d，J＝7.6Hz，1H)，7.08-7.00(m，1H)，6.96(t，J＝7.3Hz，1H)，4.73-4.68(m，1H)，3.23(dd，J＝4.9，14.7Hz，1H)，3.14-3.11(m，1H)，2.95(s，2H)，2.91-2.82(m，1H)，2.58(s，3H)，2.30(s，1H)，2.21(d，J＝6.4Hz，1H)，1.33(d，J＝6.8Hz，6H)；ES-LCMS m/z 393.2[M+H]⁺。

Example 112

Synthesis I-123

The synthesis scheme is as follows:

step 1: (3R) -N- [8- (cyclohexen-1-yl) -2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

Reacting (3R) -N- [ 8-bromo-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (200mg, 408.10. mu. mol, 1 eq.), 2- (cyclohexen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (84.94mg, 408.10. mu. mol, 87.75. mu.L, 1 eq.), Pd (dppf) Cl₂(29.87mg, 40.81. mu. mol, 0.1 equiv.), Cs₂CO₃(332.47mg, 1.02mmol, 2.5 equiv.) in H₂Mixture in O (2mL) and 1, 4-dioxane (6mL) was degassed and treated with N₂Purifying for 3 times, and adding the mixture in N₂Stirred under an atmosphere at 90 ℃ for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EA: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.7) to yield (3R) -N- [8- (cyclohexen-1-yl) -2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (110mg, 193.83 μmol, 47.5% yield, 84.5% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.79(s，1H)，9.38(s，1H)，9.08(d，J＝8.6Hz，1H)，8.79-8.66(m，1H)，8.48-8.37(m，1H)，8.28(s，1H)，7.35(d，J＝7.8Hz，1H)，7.27(d，J＝8.1Hz，1H)，7.05-6.97(m，1H)，6.96-6.88(m，1H)，6.73(br s，1H)，4.84-4.82(m，1H)，3.64(s，2H)，3.12(dd，J＝5.1，14.9Hz，1H)，3.07-2.83(m，3H)，2.24-2.15(m，4H)，1.77-1.75(m，2H)，1.67-1.65(m，2H)；ES-LCMS m/z 480.3[M+H]⁺。

Step 2: (3R) -N- [ 8-cyclohexyl-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-123)

In N₂(3R) -N- [8- (cyclohexen-1-yl) -2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]To a solution of-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (90mg, 158.59 μmol, 1 eq) in EtOAc (5mL) was added Pd/C (50mg, 10% purity). The suspension is degassed and treated with H₂The purification is carried out for several times. Mixing the mixture in H₂(15psi) at 10 ℃ for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 85% -100%, 8min) and then lyophilized to give (3R) -N- [ 8-cyclohexyl-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (16.46mg, 28.78. mu. mol, 18.2% yield, 96.9% purity, 2HCl, OR: [ α ]]^24.6 _D9.235(7.5mg/10mL in MeOH)) (optical rotation: [ a ] A]²⁵ _D9.235(7.5mg/10mL in MeOH)).¹H NMR(400MHz，DMSO-d₆)δppm 10.79(s，1H)，9.37(s，1H)，9.02(d，J＝8.6Hz，1H)，8.70(d，J＝2.7Hz，1H)，8.44(dd，J＝1.6，9.9Hz，1H)，8.13(s，1H)，7.34(d，J＝7.6Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.07-6.97(m，1H)，6.96-6.88(m，1H)，4.90-4.75(m，1H)，3.15-3.07(m，1H)，3.05-2.80(m，4H)，2.20-2.19(m，2H)，1.82-1.79(m，2H)，1.87-1.69(m，3H)，1.62-1.59(m，2H)，1.44-1.41(m，2H)，1.31-1.22(m，1H)；ES-LCMS m/z482.3[M+H]⁺。

Example 113

Synthesis I-124

The synthesis scheme is as follows:

step 1: 3-methylpyrazolo [1, 5-a ]]Pyrimidine-5, 7-diols

In N₂A solution of Na (946.88mg, 41.19mmol, 976.16. mu.L, 2.0 equiv.) in MeOH (20mL) was added to a solution of 4-methyl-1H-pyrazol-5-amine (2g, 20.59mmol, 1 equiv.) and dimethyl malonate (2.86g, 21.62mmol, 2.48mL, 1.05 equiv.) in MeOH (20mL) at 20 ℃. The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was cooled to 20 ℃, filtered and a white solid was collected. The solid was diluted with 1n hcl (20mL) and stirred for 10min, filtered and the solid was dried under reduced pressure to give the product 3-methylpyrazolo [1, 5-a ] as a white solid]Pyrimidine-5, 7-diol (2g, 12.11mmol, 58.8% yield, crude purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 10.54(br s，1H)，7.31(s，1H)，4.21(br s，1H)，1.96(s，3H)。

Step 2: 5, 7-dichloro-3-methyl-pyrazolo [1, 5-a)]Pyrimidines

Reacting 3-methylpyrazolo [1, 5-a ]]Pyrimidine-5, 7-diol (500mg, 3.03mmol, 1 equiv.) in POCl₃The solution in (5mL) was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (20mL × 2) and concentrated under reduced pressure. The residue was diluted in DCM (20mL), adjusted to pH 9-10 with DIEA and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 10/1, R_f0.68) to yield product 5 as a white solid,7-dichloro-3-methyl-pyrazolo [1, 5-a)]Pyrimidine (400mg, 1.98mmol, 65.3% yield, 99.8% purity).¹H NMR(400MHz，CDCl₃)δppm 8.09(s，1H)，6.93(s，1H)，2.37(s，3H)；ES-LCMS m/z 202.0，204.0[M+H]⁺。

Step 3: 5-chloro-7- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 5, 7-dichloro-3-methyl-pyrazolo [1, 5-a ]]Pyrimidine (190mg, 938.52. mu. mol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (138.86mg, 985.45. mu. mol, 1.05 eq), Pd (dppf) Cl₂(68.67mg, 93.85. mu. mol, 0.1 equiv.) and Cs₂CO₃(611.58mg, 1.88mmol, 2 equiv.) in 1, 4-dioxane (3mL) and H₂O (1mL) was placed in a microwave tube. The sealed tube was heated at 110 ℃ for 1 hour under microwave. The mixture was concentrated and water (10mL) was added. The mixture was extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.50) to yield 5-chloro-7- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (130mg, 494.92 μmol, 52.7% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.97(s，1H)，8.69(d，J＝2.7Hz，1H)，8.38-8.31(m，1H)，8.04(s，1H)，6.92(s，1H)，2.40(s，3H)；ES-LCMS m/z 263.0，265.0[M+H]⁺。

Step 4: 7- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidine-5-amine (I-124)

Reacting 5-chloro-7- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidine (70mg, 266.49 μmol, 1 eq), 2- (1H-indol-3-yl) ethylamine (64.04mg,399.74 μmol, 1.5 equivalents) and DIEA (103.33mg, 799.48 μmol, 139.26 μ L, 3 equivalents) in i-PrOH (2mL) were placed in a microwave tube. The sealed tube was heated at 150 ℃ for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl DurashellC 18150X 255 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 32% -55%, 9min) and subsequent lyophilization to give 7- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-5-amine (28.21mg, 59.77 μmol, 22.4% yield, 97.3% purity, 2 HCl).¹H NMR(400MHz，CD₃OD+Na₂CO₃)δppm 8.80(br s，1H)，8.62(d，J＝2.7Hz，1H)，8.18(br s，1H)，7.74-7.65(m，2H)，7.31(d，J＝8.1Hz，1H)，7.12-7.04(m，2H)，7.03-6.97(m，1H)，6.27(br s，1H)，3.78(t，J＝7.2Hz，2H)，3.11(t，J＝7.3Hz，2H)，2.24(s，3H)；ES-LCMS m/z 387.][M+H]⁺。

Example 114

Synthesis I-125

The synthesis scheme is as follows:

step 1: 5-fluoro-N' - (1H-imidazol-2-yl) pyridine-3-carboxamidine

To a mixture of ethyl 5-fluoropyridin-3-methide (1g, 5.65mmol, 1 eq.) and 1H-imidazol-2-amine (563.27mg, 6.78mmol, 1.2 eq.) in ACN (15mL) was added AcONa (926.84mg, 11.30mmol, 2 eq). Mixing the mixture in N₂Stirred at 80 ℃ for 25 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc. 1/0 to 2/1, TLC)：PE/EtOAc＝2/1，R_f0.35) to yield 5-fluoro-N' - (1H-imidazol-2-yl) pyridine-3-carboxamidine as a yellow solid (400mg, 1.75mmol, 31.1% yield, 90.0% purity).¹H NMR(400MHz，DMSO-d₆)δppm 11.67(br s，1H)，9.97(br s，1H)，9.05(s，1H)，8.70(d，J＝2.4Hz，1H)，8.29-8.12(m，2H)，6.92(s，1H)，6.85(s，1H)；ES-LCMS m/z 206.1[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridyl) imidazo [1, 2-a][1，3，5]Triazine-4-ols

To a solution of 5-fluoro-N' - (1H-imidazol-2-yl) pyridine-3-carboxamidine (400mg, 1.75mmol, 1 eq) in THF (5mL) and 1, 4-dioxane (5mL) was added diphosgene (694.18mg, 3.51mmol, 423.28 μ L, 2 eq). Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was washed with DMF (5mL), filtered and concentrated to give 2- (5-fluoro-3-pyridinyl) imidazo [1, 2-a) as a white solid][1，3，5]Triazin-4-ol (250mg, 973.24 μmol, 55.5% yield, 90.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 13.64(br s，1H)，9.29(s，1H)，8.78(d，J＝2.7Hz，1H)，8.35(J＝10.0Hz，1H)，7.73-7.65(m，2H)；ES-LCMS m/z 232.0[M+H]⁺。

Step 3: 4-chloro-2- (5-fluoro-3-pyridyl) imidazo [1, 2-a][1，3，5]Triazine

To 2- (5-fluoro-3-pyridyl) imidazo [1, 2-a][1，3，5]Triazin-4-ol (100mg, 389.30. mu. mol, 1 equivalent) in POCl₃To the solution (12mL) was added DIEA (1.48g, 11.48mmol, 2mL, 29.49 equiv.). Mixing the mixture in N₂Stirred at 120 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressureCondensing to obtain the 4-chloro-2- (5-fluoro-3-pyridyl) imidazo [1, 2-a) in a black solid][1，3，5]Triazine (90mg, 360.53 μmol, 92.6% yield, crude), which was used in the next step without further purification. ES-LCMS M/z 350.1[ M + H ]]⁺。

Step 4: (3R) -N- [2- (5-fluoro-3-pyridyl) imidazo [1, 2-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-125)

To 4-chloro-2- (5-fluoro-3-pyridyl) imidazo [1, 2-a][1，3，5]A mixture of triazine (90mg, 360.53 μmol, 1 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (80.58mg, 432.64 μmol, 1.2 eq) in ACN (10mL) was added DIEA (5.34g, 41.34mmol, 7.20mL, 114.65 eq). Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 2 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl DuraShell150 mm-25 mm-5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 23% -53%, 8.5min) followed by lyophilization gave the product which was purified by preparative HPLC (column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 40% -70%, 8min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) imidazo [1, 2-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (15.11mg, 37.83. mu. mol, 10.5% yield, 100.0% purity, [ α ]]²⁴ _D＝98.97(MeOH，c＝0.050g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.39(s，1H)，8.55-8.47(m，2H)，7.93(d，J＝1.7Hz，1H)，7.56(s，1H)，7.36(d，J＝7.6Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.05-6.98(m，1H)，6.97-6.90(m，1H)，4.85-4.79(m，1H)，3.36(J＝5.1Hz，1H)，3.08-2.83(m，3H)，2.44(J＝9.8Hz，1H)，2.26-2.14(m，1H)；ES-LCMS m/z 400.2[M+H]⁺。

Example 115

Synthesis I-126

The synthesis scheme is as follows:

step 1: (3R) -N- (2-chloropyrido [3, 2-d)]Pyrimidin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To 2, 4-dichloropyrido [3, 2-d ]]To a solution of pyrimidine (100mg, 499.94 μmol, 1 eq) in THF (3mL) was added DIEA (193.84mg, 1.50mmol, 261.24 μ L, 3 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (93.11mg, 499.94 μmol, 1 eq). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAC: 100/1 to 1/1, TLC: PE/EtOAC: 1/1, R_f0.5) to give (3R) -N- (2-chloropyrido [3, 2-d) as a yellow solid]Pyrimidin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (150mg, 428.80 μmol, 85.8% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 8.72(dd，J＝1.5，4.4Hz，1H)，7.95(dd，J＝1.5，8.3Hz，1H)，7.75(dd，J＝4.2，8.6Hz，1H)，7.37(d，J＝7.6Hz，1H)，7.26(d，J＝8.1Hz，1H)，7.07-7.00(m，1H)，6.98-6.92(m，1H)，4.80-4.68(m，1H)，3.21(dd，J＝5.1，15.2Hz，1H)，3.06-2.80(m，3H)，2.37-2.12(m，2H)；ES-LCMS m/z 350.1[M+H]⁺。

Step 2: (3R) -N- [2- (5-fluoro-3-pyridinyl) pyrido [3, 2-d]Pyrimidin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-126)

Mixing (3R) -N- (2-chloropyridine)Pyrido [3, 2-d]Pyrimidin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60mg, 171.52. mu. mol, 1 eq.), (5-fluoro-3-pyridinyl) boronic acid (29.00mg, 205.82. mu. mol, 1.2 eq.), Pd (dppf) Cl₂(12.55mg, 17.15. mu. mol, 0.1 equiv.) and Cs₂CO₃(167.65mg, 514.56. mu. mol, 3 equiv.) in 1, 4-dioxane (2mL) and H₂O (0.5mL) was placed in the microwave tube. The sealed tube was heated at 110 ℃ for 0.5 hour under microwave. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 8min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) pyrido [3, 2-d) as a yellow solid]Pyrimidin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (39.09mg, 95.24. mu. mol, 55.5% yield, 100.0% purity, OR: [ α ]]^23.6D＝0.471(MeOH，c＝0.110g/100mL)。¹HNMR(400MHz，CD₃OD)δppm 9.32(s，1H)，9.01(dd，J＝1.2，4.4Hz，1H)，8.83(d，J＝2.4Hz，1H)，8.61-8.49(m，1H)，8.32(dd，J＝1.2，8.6Hz，1H)，8.04(dd，J＝4.4，8.6Hz，1H)，7.33(d，J＝7.6Hz，1H)，7.25(d，J＝8.1Hz，1H)，6.98(t，J＝7.5Hz，1H)，6.91-6.81(m，1H)，5.22-5.04(m，1H)，3.28(s，1H)，3.12-2.86(m，3H)，2.43-2.27(m，2H)；ES-LCMS m/z 411.2[M+H]⁺。

Example 116

Synthesis I-128a

The synthesis scheme is as follows:

step 1: (6S) -N6- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-4, 5, 6, 7-tetrahydro-1, 3-benzothiaAzole-2, 6-diamine (I-128a)

4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (70mg, 236.12. mu. mol, 1 equivalent), (6S) -4, 5, 6, 7-tetrahydro-1, 3-benzothiazole-2, 6-diamine (43.96mg, 259.74. mu. mol, 1.1 equivalents) and DIEA (91.55mg, 708.37. mu. mol, 123.39. mu.L, 3 equivalents) in i-PrOH (10mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was washed with MeOH (20mL × 2) to give (6S) -N6- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a ] as a white solid][1，3，5]Triazin-4-yl]-4, 5, 6, 7-tetrahydro-1, 3-benzothiazole-2, 6-diamine (22.62mg, 53.29 μmol, 22.6% yield, 100.0% purity, SFC: Rt ═ 5.691min, ee ═ 99.8%, OR: [ α% ], ee ═ 99.8% ]]^21.9 _D＝-34.176(CHCl₃，c＝0.104g/100mL))。¹HNMR(400MHz，DMSO-d₆)δppm 9.37(s，1H)，8.97(br s，1H)，8.71(d，J＝2.8Hz，1H)，8.44(d，J＝10.0Hz，1H)，8.13(s，1H)，6.72(s，2H)，4.75-4.72(m，1H)，3.49-3.19(m，1H)，2.90-2.83(m，2H)，2.65-2.58(m，1H)，2.54-2.50(m，1H)，2.09-2.05(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 425.2[M+H]⁺

Example 117

Synthesis I-128b

The synthesis scheme is as follows:

step 1: (6R) -N6- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-4, 5, 6, 7-tetrahydro-1, 3-benzothiazole-2, 6-diamine (I-128b)

4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (70mg, 236.12. mu. mol, 1 equivalent), (6R) -4, 5, 6, 7-tetrahydro-1, 3-benzothiazole-2, 6-diamine (43.96mg, 259.74. mu. mol, 1.1 equivalents) and DIEA (91.55mg, 708.37. mu. mol, 123.38. mu.L, 3 equivalents) in i-PrOH (10mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was washed with MeOH (20mL × 2) to give (6R) -N6- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazin-4-yl]4, 5, 6, 7-tetrahydro-1, 3-benzothiazole-2, 6-diamine (20.56mg, 48.43. mu. mol, 20.5% yield, 100.0% purity, SFC: R_t＝7.228min，ee＝98.44％，OR：[α]^22.1 _D＝29.753(CHCl₃，c＝0.100g/100mL))。¹HNMR(400MHz，DMSO-d₆)δppm 9.37(s，1H)，8.97(d，J＝8.4Hz，1H)，8.71(d，J＝2.8Hz，1H)，8.46-8.42(m，1H)，8.13(s，1H)，6.72(s，2H)，4.77-4.72(m，1H)，3.23-3.17(m，1H)，2.90-2.83(m，2H)，2.67-2.64(m，1H)，2.58-2.53(m，1H)，2.07-2.05(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 425.2[M+H]⁺。

Example 118

Synthesis I-129

The synthesis scheme is as follows:

step 1: n' - [4- (dimethylamino) -1H-pyrazol-5-yl]-5-fluoro-pyridine-3-carboxamidine

To a solution of N4, N4-dimethyl-1H-pyrazole-4, 5-diamine (1.2g, 6.27mmol, 1 eq, HCl) in ACN (20mL) was added ethyl 5-fluoropyridine-3-methide (1.11g, 6.27mmol, 1 eq). Mixing the mixture in N₂Stirring was carried out at 60 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM/MeOH ═ 1/0 to 5/1, TLC: DCM/MeOH ═ 10/1, R_f0.3) to yield N' - [4- (dimethylamino) -1H-pyrazol-5-yl) as a yellow solid]-5-fluoro-pyridine-3-carboxamidine (700mg, 2.52mmol, 40.2% yield, 89.5% purity).¹HNMR(400MHz，DMSO-d₆)δppm 11.96(br s，1H)，9.07(s，1H)，8.66(d，J＝2.0Hz，1H)，8.17(d，J＝10.0Hz，1H)，7.18(s，1H)，2.72(br s，6H)；ES-LCMS m/z248.9[M+H]⁺。

Step 2: 2-8- (dimethylamino) -2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazine-4-ols

In N₂To N' - [4- (dimethylamino) -1H-pyrazol-5-yl at 15 DEG C]-5-fluoro-pyridine-3-carboxamidine (160mg, 576.82. mu. mol, 1 eq) in THF (1mL) and toluene (8mL) was added diphosgene (342.34mg, 1.73mmol, 208.74. mu.L, 3 eq) and the mixture was stirred at 15 ℃ for 0.5 h. Then the mixture is added to N₂Stirring was carried out at 130 ℃ for 2 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give 8- (dimethylamino) -2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a as a yellow solid][1，3，5]Triazin-4-ol (150mg, crude), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 9.15(s，1H)，9.07(s，1H)，8.92(d，J＝2.3Hz，1H)，8.79(d，J＝2.8Hz，1H)，8.03(s，1H)，3.03(s，6H)；ES-LCMS m/z 275.1[M+H]⁺。

Step 3: 4-chloro-2- (5-fluoro-3-pyridinyl) -N, N-dimethyl-pyrazolo [1, 5-a][1，3，5]Triazine-8-amines

Reacting 8- (dimethylamino) -2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-ol (150mg, 546.94. mu. mol, 1 equivalent) in POCl₃(9g, 58.70mmol, 5.45mL, 107.32 equiv.) the mixture was degassed and treated with N₂Purification 3 times at N₂Stirred under an atmosphere at 120 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was quenched by addition of water (50mL), by NaHCO₃The pH was adjusted to 8 with aqueous solution and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.31) to yield 4-chloro-2- (5-fluoro-3-pyridinyl) -N, N-dimethyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-8-amine (25mg, 76.87. mu. mol, 14.0% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 9.35(s，1H)，8.51(br s，1H)，8.27(d，J＝8.8Hz，1H)，7.85(s，1H)，3.05(s，6H)；ES-LCMS m/z 293.1，295.0[M+H]⁺。

Step 4: 2- (5-fluoro-3-pyridinyl) -N8, N8-dimethyl-N4- [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Pyrazolo [1, 5-a][1，3，5]Triazine-4, 8-diamine (I-129)

To 4-chloro-2- (5-fluoro-3-pyridyl) -N, N-dimethyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazin-8-amine (25mg, 76.87. mu. mol, 1 eq.) in i-PrOH (3mL) was added (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (17.18mg, 92.24. mu. mol, 1.2 eq.). The mixture was stirred at 40 ℃ for 2 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)]: b%: 38% -68%, 8min) and then freeze-dried to give a crude oil2- (5-fluoro-3-pyridinyl) -N8, N8-dimethyl-N4- [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as yellow solid]Pyrazolo [1, 5-a][1，3，5]Triazine-4, 8-diamine (34.45mg, 62.30. mu. mol, 81.0% yield, 99.8% purity, 3HCl, [ α ]]^20.6 _D＝+36.080(MeOH，c＝0.1g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.51(br s，1H)，8.74(m，2H)，8.42(br s，1H)，7.37(d，J＝7.8Hz，1H)，7.28(d，J＝8.3Hz，1H)，7.04(t，J＝7.5Hz，1H)，6.99-6.92(m，1H)，5.00-4.92(m，1H)，3.53(br s，6H)，3.28-2.89(m，4H)，2.44-2.23(m，2H)；ES-LCMS m/z443.2[M+H]⁺。

Example 119

Synthesis I-130

The synthesis scheme is as follows:

step 1: (3R) -3- [ [ 8-bromo-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Reacting (3R) -N- [ 8-bromo-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (560mg, 1.09mmol, 1 equiv.), Boc₂A mixture of O (1.43g, 6.57mmol, 1.51mL, 6 equivalents) and DMAP (534.93mg, 4.38mmol, 4 equivalents) in 1, 4-dioxane (50mL) was stirred at 110 ℃ for 12 hours. TLC (PE/EtOAc ═ 5/1, R_f0.65) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 5/1, R_f0.65) to yield a white solid(3R) -3- [ [ 8-bromo-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ] as][1，3，5]Triazin-4-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (660mg, 972.66 μmol, 88.9% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.49(s，1H)，8.60(d，J＝2.8Hz，1H)，8.44(d，J＝8.4Hz，1H)，8.23(s，1H)，8.10(d，J＝8.4Hz，1H)，7.33(d，J＝7.8Hz，1H)，7.22-7.16(m，2H)，4.92(br s，1H)，3.34(d，J＝16.8Hz，1H)，3.25-3.11(m，3H)，2.50(m，1H)，2.33(m，1H)，1.67(s，9H)，1.39(s，9H)；ES-LCMS m/z 678.2，680.2[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carbonitrile (I-130)

Reacting (3R) -3- [ [ 8-bromo-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (50mg, 72.36. mu. mol, 1 eq.), Zn (CN)₂(33.99mg, 289.44. mu. mol, 18.37. mu.L, 4 equiv.) and Pd (PPh)₃)₄A mixture of (16.72mg, 14.47. mu. mol, 0.2 equiv) in DMF (3mL) was placed in a microwave tube and then N was used₂And purifying for 1 minute. The sealed tube was stirred under microwave (1 bar) at 170 ℃ for 20 minutes. The reaction mixture was extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to give a residue which is purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 55% -85%, 8min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as a yellow solid]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carbonitrile (15.36mg, 29.98. mu. mol, 41.4% yield, 97.1% purity, 2HCl, [ α ]]^18.1 _D＝45.287，(MeOH，c＝0.078g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.48(s，1H)，8.80-8.71(m，2H)，8.43(s，1H)，7.32(d，J＝7.6Hz，1H)，7.24(d，J＝8.1Hz，1H)，7.00(t，J＝7.5Hz，1H)，6.94-6.88(m，1H)，4.83(m，1H)，3.26(m，1H)，3.08-2.88(m，3H)，2.37-2.35(m，1H)，2.31-2.18(m，1H)；ES-LCMS m/z425.2[M+H]⁺。

Example 120

Synthesis of I-131

The synthesis scheme is as follows:

step 1: n- (2- (1H-indol-3-yl) ethyl) -8- (tert-butyl) -2- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-131)

To 8-tert-butyl-4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazine (60mg, 176.62. mu. mol, 1 equiv.) to a solution of i-PrOH (3mL) was added 2- (1H-indol-3-yl) ethylamine (29.43mg, 183.68. mu. mol, 1.04 equiv.) and DIPEA (114.13mg, 883.10. mu. mol, 153.82. mu.L, 5 equiv.). The reaction mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl Durashell C18150X 255 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 75% -95%, 8min) and then lyophilized to give 8-tert-butyl-2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (27.49mg, 54.18 μmol, 30.7% yield, 99.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.13(s，1H)，8.80(s，1H)，8.55(d，J＝8.6Hz，1H)，7.95(s，1H)，7.69-7.62(m，1H)，7.19-7.12(m，1H)，7.01-6.93(m，3H)，4.02(J＝6.7Hz，2H)，3.16(t，J＝6.7Hz，2H)，1.48(s，9H)；ES-LCMS m/z 430.3[M+H]⁺。

Example 121

Synthesis I-132

The synthesis scheme is as follows:

step 1: (Z) -N' - (4- (tert-butyl) -1H-pyrazol-5-yl) -5-fluoronicotinamidine

To a solution of ethyl 5-fluoropyridine-3-methide (400mg, 2.26mmol, 1 eq) in toluene (15mL) was added 4-tert-butyl-1H-pyrazol-5-amine (314.54mg, 2.26mmol, 1 eq). Mixing the mixture in N₂The mixture was stirred at 130 ℃ for 24 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 1/1, R_fPurification ═ 0.23) afforded N' - (4-tert-butyl-1H-pyrazol-5-yl) -5-fluoro-pyridine-3-carboxamidine (400mg, 1.45mmol, 64.4% yield, 95.0% purity) as a white solid.¹H NMR(400MHz，CDCl₃)δppm 9.59(s，1H)，8.94(s，1H)，8.57-8.48(m，1H)，8.02(d，J＝9.5Hz，1H)，7.23(s，1H)，1.41(s，9H)；ES-LCMS m/z 262.1[M+H]⁺。

Step 2: 8- (tert-butyl) -2- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a][1，3，5]Triazine-4-ols

To a solution of N' - (4-tert-butyl-1H-pyrazol-5-yl) -5-fluoro-pyridine-3-carboxamidine (400mg, 1.45mmol, 1 eq) in 1, 4-dioxane (5mL) and THF (5mL) was added diphosgeneGas (575.40mg, 2.91mmol, 350.85. mu.L, 2 equiv.). Mixing the mixture in N₂The mixture was stirred at 80 ℃ for 7 hours. The reaction mixture was concentrated under reduced pressure to give 8-tert-butyl-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a as a yellow solid][1，3，5]Triazin-4-ol (400mg, 1.32mmol, 91.0% yield, 95.0% purity) was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm9.22(s，1H)，8.89(s，1H)，8.55(d，J＝9.0Hz，1H)，8.03(s，1H)，1.49(s，9H)；ES-LCMS m/z287.8[M+H]⁺。

Step 3: 8- (tert-butyl) -4-chloro-2- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a][1，3，5]Triazine

8-tert-butyl-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-ol (400mg, 1.32mmol, 1 eq.) in POCl₃(2g, 13.04mmol, 1.21mL, 9.86 equiv.) of the solution in N₂Stirred under an atmosphere at 110 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ice water (10mL) and extracted with DCM (10 mL. times.3). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 3/1, R_f0.7) to give 8-tert-butyl-4-chloro-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazine (130mg, 382.68 μmol, 28.9% yield, 90.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.44(s，1H)，8.56(s，1H)，8.35(d，J＝9.0Hz，1H)，8.11(s，1H)，1.47(s，9H)；ES-LCMS m/z 305.7[M+H]⁺。

Step 4: (R) -N- (8- (tert-butyl) -2- (5-fluoropyridin-3-yl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-132)

To 8-tert-butyl-4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazine (60mg, 176.62 μmol, 1 equiv) to a solution of i-PrOH (3mL) was added (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (34.21mg, 183.69 μmol, 1.04 equiv) and DIPEA (114.14mg, 883.11 μmol, 153.82 μ L, 5 equiv). The reaction mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl Durashell C18150X 255 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 75% -95%, 8min) and then lyophilized to give (3R) -N- [ 8-tert-butyl-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (28.87mg, 53.29 μmol, 30.2% yield, 97.6% purity, 2HCl, [ α ]]²¹ _D＝18.883(MeOH，c＝0.100g/100mL))。¹H NMR(400MHz，CD₃OD)δppm9.41(s，1H)，8.69-8.61(m，2H)，7.94(s，1H)，7.35(d，J＝7.8Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.01(t，J＝7.5Hz，1H)，6.97-6.87(m，1H)，4.81(m，1H)，3.25(d，J＝4.9Hz，1H)，3.10-2.84(m，3H)，2.35(m，1H)，2.29-2.18(m，1H)，1.50(s，9H)；ES-LCMS m/z 456.3[M+H]⁺。

Example 122

Synthesis I-133

The synthesis scheme is as follows:

step 1: 3- (2-aminoethyl) -1H-indol-7-ol

To 2- (7-benzyloxy-1H-indol-3-yl) ethylamine (150mg, 563.19. mu. mol, 1 eq) in MeOH (10mL)To the solution was added Pd/C (50mg, 10%). The mixture is degassed and treated with H₂Purify 3 times and stir at 50 ℃ for 1 hour. The mixture was filtered and concentrated to give 3- (2-aminoethyl) -1H-indol-7-ol (90mg, 510.74 μmol, 90.7% yield) as a yellow solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.06-7.00(m，2H)，6.85-6.77(m，1H)，6.50(d，J＝7.6Hz，1H)，2.96-2.83(m，4H)。

Step 2: 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-7-ol (I-133)

Reacting [ 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]A mixture of methanol (55mg, 171.12. mu. mol, 1 equivalent), 3- (2-aminoethyl) -1H-indol-7-ol (39.20mg, 222.45. mu. mol, 1.3 equivalents) and DIEA (66.35mg, 513.35. mu. mol, 89.42. mu.L, 3 equivalents) in i-PrOH (10mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 80 ℃ for 5 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water-ACN ]](ii) a B%: 17% -47%, 8.5min) and then lyophilized to give 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a ] as a gray solid]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-7-ol (16.9mg, 38.27. mu. mol, 22.4% yield, 94.8% purity).¹H NMR(400MHz，CD₃OD)δppm 8.67(s，1H)，8.47(d，J＝2.4Hz，1H)，8.06(s，1H)，7.73-7.67(m，1H)，7.21(d，J＝8.1Hz，1H)，6.94-6.87(m，2H)，6.51(d，J＝7.3Hz，1H)，5.96(s，1H)，4.80(s，2H)，3.88(t，J＝6.1Hz，2H)，3.21-3.11(m，2H)；ES-LCMS m/z 419.1[M+H]⁺。

Example 123

Synthesis I-135

The synthesis scheme is as follows:

step 1: (3R) -N- (4-chloro-6-isopropoxy-1, 3, 5-triazin-2-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To a solution of 2, 4-dichloro-6-isopropoxy-1, 3, 5-triazine (150mg, 648.90 μmol, 1 eq) in THF (5mL) at 0 ℃ was added dropwise DIPEA (119.93mg, 927.92 μmol, 161.63 μ L, 1.43 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (125.69mg, 674.85 μmol, 1.04 eq) in THF (5 mL). The mixture was stirred at 0 ℃ for 1 hour and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 1/1, R_f0.47) to yield (3R) -N- (4-chloro-6-isopropoxy-1, 3, 5-triazin-2-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (220mg, 553.33 μmol, 85.3% yield, 90.0% purity) as a yellow solid.¹H NMR(400MHz，CDCl₃)δppm 7.80(d，J＝6.4Hz，1H)，7.45-7.38(m，1H)，7.29(dd，J＝3.1，7.7Hz，1H)，7.18-7.05(m，2H)，6.06-5.59(m，1H)，5.41-4.98(m，1H)，4.65-4.51(m，1H)，3.16(d，J＝15.4Hz，1H)，2.96-2.66(m，3H)，2.18-2.06(m，2H)，1.31(d，J＝5.1Hz，6H)；ES-LCMS m/z 358.1[M+H]⁺。

Step 2: (3R) -N- [4- (5-fluoro-3-pyridinyl) -6-isopropoxy-1, 3, 5-triazin-2-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-135)

In N₂(3R) -N- (4-chloro-6-isopropoxy-1, 3, 5-triazin-2-yl) -2, 3, 49-tetrahydro-1H-carbazol-3-amine (200mg, 503.02. mu. mol, 1 eq.) in 1, 4-dioxane (3mL) and H₂To a solution in O (1mL) was added (5-fluoro-3-pyridinyl) boronic acid (70.88mg, 503.02. mu. mol, 1 eq.), Pd (dppf) Cl₂(36.81mg, 50.30. mu. mol, 0.1 equiv.) and Cs₂CO₃(491.68mg, 1.51mmol, 3 equiv.). Mixing the mixture in N₂The mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 8min) to obtain (3R) -N- [4- (5-fluoro-3-pyridyl) -6-isopropoxy-1, 3, 5-triazin-2-yl) as a yellow solid]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (55.56mg, 113.07 μmol, 22.5% yield, 100.0% purity, 2HCl, [ α ]]^21.2 _D＝56.652(MeOH，c＝0.100g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.26(s，1H)，8.75(s，1H)，8.50(d，J＝7.6Hz，1H)，7.30(d，J＝7.6Hz，1H)，7.20(d，J＝7.8Hz，1H)，7.03-6.86(m，2H)，5.44(s，1H)，4.65-4.37(m，1H)，3.16(d，J＝14.7Hz，1H)，2.89(s，2H)，2.70(dd，J＝8.8，14.2Hz，1H)，2.24(s，1H)，2.03(s，1H)，1.41(d，J＝5.1Hz，6H)；ES-LCMS m/z 419.0[M+H]⁺。

Example 124

Synthesis I-136

The synthesis scheme is as follows:

step 1: 2, 4-dichloro-6-isopropoxy-1, 3, 5-triazine

At 0 ℃ under N₂To the reaction mixture of i-PrOH (322.62mg, 5.37mmol,410.98 μ L, 1.1 equiv.) in THF (12mL) was added NaH (253.76mg, 6.34mmol, 60% purity, 1.3 equiv). The mixture was stirred at 0 ℃ for 0.5 h. Then 2, 4, 6-trichloro-1, 3, 5-triazine (1g, 4.88mmol, 1 eq) in THF (8mL) was added dropwise to the mixture at 0 deg.C. Mixing the mixture in N₂The mixture was stirred at 10 ℃ for 11.5 hours. TLC (PE/EtOAc ═ 6: 1, R_f0.6) shows the reaction is complete. The reaction mixture was slowly dissolved in water (50mL) at 0 ℃. The mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 20/1, TLC: PE/EtOAc: 6/1, R_f0.6) to yield 2, 4-dichloro-6-isopropoxy-1, 3, 5-triazine (430mg, 1.86mmol, 38.1% yield, 90.0% purity) as a white solid.¹H NMR(400MHz，CDCl₃)δppm 5.40-5.25(m，1H)，1.37(d，J＝6.1Hz，6H)。

Step 2: 4-chloro-N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-1, 3, 5-triazin-2-amine

To a solution of 2, 4-dichloro-6-isopropoxy-1, 3, 5-triazine (100mg, 432.60 μmol, 1 eq) in THF (10mL) at 0 ℃ was added dropwise DIPEA (79.95mg, 618.62 μmol, 107.75 μ L, 1.43 eq) and 2- (1H-indol-3-yl) ethylamine (72.08mg, 449.90 μmol, 1.04 eq) in THF (5 mL). The mixture was stirred at 0 ℃ for 1 hour and concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 1/1, R_f0.47) to yield 4-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-6-isopropoxy-1, 3, 5-triazin-2-amine (90mg, 244.12 μmol, 56.4% yield, 90.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.13-7.96(m，1H)，7.59-7.47(m，1H)，7.33-7.24(m，1H)，7.16-7.10(m，1H)，7.09-7.04(m，1H)，6.96(t，J＝10.9Hz，1H)，5.39-4.97(m，1H)，3.84-3.59(m，2H)，3.48(d，J＝4.9Hz，1H)，3.09-2.86(m，2H)，1.25-1.19(m，6H)；ES-LCMS m/z 332.1，334.1[M+H]⁺。

Step 3: 4- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-1, 3, 5-triazin-2-amine (I-136)

In N₂4-chloro-N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-1, 3, 5-triazin-2-amine (90mg, 244.12 μmol, 1 eq) in 1, 4-dioxane (3mL) and H₂To a solution in O (1mL) was added (5-fluoro-3-pyridyl) boronic acid (34.40mg, 244.12. mu. mol, 1 eq.), Cs₂CO₃(238.62mg, 732.37. mu. mol, 3 equiv.) and Pd (dppf) Cl₂(17.86mg, 24.41. mu. mol, 0.1 equiv.). Mixing the mixture in N₂The mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 8min) to obtain 4- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl group as a yellow solid]-6-isopropoxy-1, 3, 5-triazin-2-amine (25.60mg, 55.01 μmol, 22.5% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.80(s，1H)，9.24(d，J＝16.1Hz，1H)，8.75(s，1H)，8.38-8.18(m，2H)，7.56(dd，J＝8.2，13.8Hz，1H)，7.29(t，J＝8.4Hz，1H)，7.16(s，1H)，7.06-6.99(m，1H)，6.98-6.90(m，1H)，5.36-5.16(m，1H)，3.75-3.51(m，2H)，2.95(s，2H)，1.34-1.26(m，6H)；ES-LCMS m/z 393.1[M+H]⁺。

Example 125

Synthesis of I-137a, I-137b and I-137c

The synthesis scheme is as follows:

step 1: 1, 4, 6, 7-tetrahydroindol-5-ketoxime

Mixing 1, 4, 6, 7-tetrahydroindol-5-one (150mg, 1.11mmol, 1 equivalent) and NH₂A mixture of OH HCl (92.54mg, 1.33mmol, 1.2 equiv.) and NaOAc (136.56mg, 1.66mmol, 1.5 equiv.) in THF (10mL) was stirred at 60 ℃ for 3 h. TLC (PE/EtOAc ═ 1/1, R_f0.20) showed complete consumption of starting material. Subjecting the reaction mixture to hydrogenation with H₂O (20mL) was diluted and extracted with EtOAc (20 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 1, 4, 6, 7-tetrahydroindol-5-one oxime (160mg, crude) as a brown gum which was used in the next step without further purification.¹HNMR(400MHz，CDCl₃)δ7.81(br s，1H)，6.69-6.64(m，1H)，6.06-5.98(m，1H)，3.63-3.35(m，2H)，2.81-2.74(m，2H)，2.68-2.53(m，2H)；ES-LCMS m/z 151.1[M+H]⁺。

Step 2: 4, 5, 6, 7-tetrahydro-1H-indol-5-amines

A mixture of 1, 4, 6, 7-tetrahydroindol-5-one oxime (160mg, 1.07mmol, 1 equiv.) and Raney's nickel (200mg) in MeOH (10mL) in H₂(15psi) at 10 ℃ for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 4, 5, 6, 7-tetrahydro-1H-indol-5-amine (140mg, crude) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 6.55(d，J＝2.4Hz，1H)，5.80(d，J＝2.4Hz，1H)，3.17-3.05(m，1H)，2.79(dd，J＝4.8，14.8Hz，1H)，2.71-2.63(m，2H)，2.33(dd，J＝8.8，14.8Hz，1H)，2.06-1.96(m，1H)，1.77-1.64(m，1H)；ES-LCMS m/z 137.2[M+H]⁺。

Step 3: 2- (5-fluoro-3-pyridinyl) -8-isopropyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (I-137a) and 2- (5-fluoro-3-pyridyl) -8-isopropyl-N- [ (5R) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-137b)

To 4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazine (120.48mg, 330.41. mu. mol, 1 eq) and 4, 5, 6, 7-tetrahydro-1H-indol-5-amine (45mg, 330.41. mu. mol, 1 eq) in i-PrOH (10mL) was added DIEA (341.63mg, 2.64mmol, 460.41. mu.L, 8 eq). The mixture was stirred at 50 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.5) indicates complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.50) to give the product, which was purified by chiral SFC (column: xylonite (DAICEL) CHIRALCELOJ-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O MeOH](ii) a B%: 35% -35%) to give peak 1 (SFC: rt 3.442) and peak 2 (SFC: rt 3.780). Peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)]75% -100% B), followed by lyophilization to give the enantiomer as a gray solid (17.61mg, 35.16 μmol, 10.6% yield, 100.0% purity, 3HCl, SFC: Rt 3.442, ee 100%, OR: [ α% ] (8 min) ]]^20.2 _D＝-0.069(MeOH c＝0.086g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.37(br s，1H)，9.36(s，1H)，8.87(d，J＝8.8Hz，1H)，8.71(d，J＝2.7Hz，1H)，8.46-8.39(m，1H)，8.13(s，1H)，6.56(t，J＝2.4Hz，1H)，5.77(t，J＝2.4Hz，1H)，4.66(br s，1H)，3.27-3.17(m，1H)，2.86-2.74(m，3H)，2.68(d，J＝7.8Hz，1H)，2.12-1.97(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 392.2[M+H]⁺. Peak 2 (SFC: Rt ═ 3.780) was concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN]75% -100% for 8min) and then lyophilized to give the other enantiomer as a gray solid (16.18mg, 32.31 μmol, 9.8% yield, 100.0% purity, 3HCl, SFC: Rt ═ 3.780, ee ═ 99.12%, OR: [ α% ] (r): [ 8.0% ])]^20.3 _D＝0.066(MeOH c＝0.084g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.38(br s，1H)，9.36(s，1H)，8.88(d，J＝8.6Hz，1H)，8.71(d，J＝2.4Hz，1H)，8.46-8.38(m，1H)，8.13(s，1H)，6.56(br s，1H)，5.77(br s，1H)，4.66(br s，1H)，3.21(td，J＝6.8，13.7Hz，1H)，2.84-2.72(m，3H)，2.71-2.66(m，1H)，2.12-1.99(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMSm/z 392.2[M+H]⁺。

Example 126

Synthesis of I-139a, I-139b and I-139c

The synthesis scheme is as follows:

step 1: (3S) -6, 8-difluoro-N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-139a) and (3R) -6, 8-difluoro-N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a [ ]][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-139b)

To 6, 8-difluoro-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (180mg, 509.83. mu. mol, 1 eq, TFA) and 4-chloro-2- (5-fluoro-3-pyridinyl) -8-isopropylPyrazolo [1, 5-a ]][1，3，5]To a solution of triazine (221.40mg, 607.18. mu. mol, 1.19 equiv.) in i-PrOH (10mL) was added DIEA (527.13mg, 4.08mmol, 710.42. mu.L, 8 equiv.). The mixture was stirred at 50 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.5) indicates complete consumption of the starting material. The reaction mixture was concentrated to dryness under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.50). The desired fractions were concentrated under reduced pressure to give the product which was passed through chiral SFC (column: xylonite CHIRALPAK AD (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 45% -45%, min) to obtain peak 1 (SFC: rt 1.851) and peak 2 (SFC: rt 2.254). Peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)]75% -100% for B), freeze drying the desired fractions to give the enantiomer as a yellow solid (64.24mg, 114.88 μmol, 22.5% yield, 98.4% purity, 2HCl, SFC: Rt 1.851, ee 100%, OR: [ α% ])]^20.2 _D＝0.206(MeOH c＝0.110g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 11.38(s，1H)，9.38(s，1H)，9.06(d，J＝8.6Hz，1H)，8.69(d，J＝2.2Hz，1H)，8.44(d，J＝10.0Hz，1H)，8.15(s，1H)，7.02(d，J＝9.0Hz，1H)，6.86(m，J＝10.6Hz，1H)，4.84(br s，1H)，3.22(d，J＝7.1，14.0Hz，1H)，3.12-2.98(m，2H)，2.88(d，J＝15.4Hz，2H)，2.20(br s，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z478.3[M+H]⁺. Peak 2 was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 75% -100%, 8 min). The desired fractions were lyophilized to give the other enantiomer as a yellow solid (70.3mg, 125.02 μmol, 24.5% yield, 97.9% purity, 2HCl, SFC: Rt ═ 2.254, ee ═ 99.79%, OR: [ a ], []^20.2 _D＝-0.239(MeOH c＝0.117g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 11.38(s，1H)，9.38(s，1H)，9.05(d，J＝8.6Hz，1H)，8.69(d，J＝2.9Hz，1H)，8.49-8.38(m，1H)，8.15(s，1H)，7.02(dd，J＝1.8，9.4Hz，1H)，6.91-6.80(m，1H)，4.94-4.75(m，1H)，3.22(d，J＝6.9，13.8Hz，1H)，3.13-2.98(m，2H)，2.96-2.83(m，2H)，2.28-2.13(m，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 478.2[M+H]⁺。

Example 127

Synthesis I-141

I-141

The synthesis scheme is as follows:

step 1: 8-bromo-2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-141)

To 8-bromo-4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazine (50mg, 152.19. mu. mol, 1 eq) to a solution of i-PrOH (3mL) was added DIEA (59.01mg, 456.58. mu. mol, 79.53. mu.L, 3 eq) and 2- (1H-indol-3-yl) ethylamine (29.26mg, 182.63. mu. mol, 1.2 eq). The mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 8min) and then lyophilized to give 8-bromo-2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (19.80mg, 37.70. mu. mol, 24.8% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.81(s，1H)，9.34(s，2H)，8.76(s，1H)，8.38(s，1H)，8.29(d，J＝9.8Hz，1H)，7.66(d，J＝7.6Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.20(s，1H)，7.04(t，J＝7.6Hz，1H)，7.00-6.91(m，1H)，3.95(t，J＝7.2Hz，2H)，3.13(t，J＝7.2Hz，2H)；ES-LCMS m/z 452.1，454.1[M+H]⁺。

Example 128

Synthesis I-143

The synthesis scheme is as follows:

step 1: 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-5-ol (I-143)

To [ 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]To a solution of methanol (80mg, 287.08. mu. mol, 1 eq) in i-PrOH (4mL) was added 3- (2-aminoethyl) -1H-indol-5-ol (50.59mg, 287.08. mu. mol, 1 eq) and DIEA (111.31mg, 861.24. mu. mol, 150.01. mu.L, 3 eq). Mixing the mixture in N₂Stirred at 90 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 20% -50%, 8min) and then lyophilized to give 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a ] as a white solid]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-5-ol (3.76mg, 8.99. mu. mol, 3.1% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 8.73(s，1H)，8.48(s，1H)，8.06(s，1H)，7.78(d，J＝9.5Hz，1H)，7.09-7.02(m，2H)，6.93(s，1H)，6.67(d，J＝8.8Hz，1H)，6.05(s，1H)，4.80(s，2H)，3.86(t，J＝6.1Hz，2H)，3.13(t，J＝5.9Hz，2H)；ES-LCMS m/z 440.8[M+Na]⁺。

Example 129

Synthesis I-144a

The synthesis scheme is as follows:

step 1: 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidine-3-carbaldehyde

In N₂POCl was added dropwise to a DMF solution (10mL) under an atmosphere at-20 ℃ over a period of 12 minutes₃(5g) In that respect After 1 hour, the compound containing 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidine (1g, 3.76mmol, 1 eq) in DMF (5mL) was added to the above solution, during which time the temperature was maintained below-20 ℃. The mixture was warmed to 20 ℃ and under N₂Stirred under atmosphere for 12 hours. Will contain POCl₃DMF (10mL) (12.85g) was added to the above solution. Mixing the mixture in N₂Stirring was carried out at 20 ℃ for 12 hours under an atmosphere. The mixture was concentrated and water (200mL) was added. The mixture was extracted with DCM (50 mL. times.3). The combined organic layers were washed with 5% LiCl (50mL) and Na₂SO₄Drying, filtering and concentrating to obtain 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidine-3-carbaldehyde (800mg, 2.77mmol, 73.5% yield, 95.7% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 10.29(s，1H)，9.42(s，1H)，8.9-8.79(m，2H)，8.63(d，J＝10.0Hz，1H)，8.52(s，1H)；ES-LCMS m/z 277.0[M+H]⁺。

Step 2: [ 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]Methanol

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a ] at 0 DEG C]A mixture of pyrimidine-3-carbaldehyde (400mg, 1.38mmol, 1 eq) in THF (10mL) was added NaBH₄(78.52mg, 2.08mmol, 1.5 equiv.) and the mixture was stirred under N₂Stirring was carried out at 20 ℃ for 12 hours under an atmosphere. To the reaction mixture was added 0.5N aqueous HCl (0.05 mL). The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.27) to give [ 7-chloro-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-3-yl]Methanol (130mg, 421.25 μmol, 30.4% yield, 90.3% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.28(s，1H)，9.70(d，J＝2.2Hz，1H)，9.48(d，J＝10.3Hz，1H)，9.33(s，1H)，9.15(s，1H)，6.10(br s，1H)，5.71(br s，2H)；ES-LCMS m/z 279.0[M+H]⁺。

Step 3: (1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (I-144a)

To [ 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]To a solution of methanol (55mg, 178.22 μmol, 1 eq) in i-PrOH (3mL) was added (1S) -2-amino-1- (1H-indol-3-yl) ethanol (36.95mg, 178.22 μmol, 1 eq) and DIEA (69.10mg, 534.66 μmol, 93.13 μ L, 3 eq). Mixing the mixture in N₂Stirred at 90 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 25% -55%, 8min) and then lyophilized to give (1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a) as a white solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (40mg, 94.55. mu. mol, 53.0% yield, 98.9% purity, SFC: R_t＝4.476，ee＝99.1％，[α]^19.6 _D＝-11.254(MeOH，c＝0.106g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.73(s，1H)，8.48(d，J＝2.2Hz，1H)，8.07(s，1H)，7.88-7.81(m，2H)，7.29-7.21(m，1H)，7.18(s，1H)，7.13-7.05(m，2H)，6.16(s，1H)，5.30(t，J＝5.6Hz，1H)，4.81(s，2H)，4.07-3.95(m，2H)；ES-LCMS m/z 419.1[M+H]⁺。

Example 130

Synthesis I-144b

The synthesis scheme is as follows:

step 1: (1R) -2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (I-144b)

To [ 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]To a solution of methanol (66.45mg, 215.31 μmol, 1 eq) in i-PrOH (3mL) was added DIEA (83.48mg, 645.93 μmol, 112.51 μ L, 3 eq) and (1R) -2-amino-1- (1H-indol-3-yl) ethanol (53.32mg, 279.90 μmol, 1.3 eq). The reaction mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (basic conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 25% -55%, 8min) was added. The desired fractions were lyophilized to give (1R) -2- [ [5- (5-fluoro-3-pyridinyl) -3- (hydroxymethyl) pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (18.50mg, 44.21. mu. mol, 20.5% yield, 100.0% purity, SFC: R_t＝3.628min，ee＝99.4％，[α]^19.5 _D＝+12.650(MeOH，c＝0.106g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.74(s，1H)，8.48(d，J＝2.4Hz，1H)，8.08(s，1H)，7.90-7.80(m，2H)，7.25(d，J＝8.3Hz，1H)，7.18(s，1H)，7.13-7.05(m，2H)，6.17(s，1H)，5.31(t，J＝5.7Hz，1H)，4.81(s，2H)，4.09-3.95(m，2H)；ES-LCMSm/z 419.1[M+H]⁺。

Example 131

Synthesis I-150a

The synthesis scheme is as follows:

step 1: (1R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (I-150a)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 185.97. mu. mol, 1 eq) in i-PrOH (3mL) was added DIEA (120.18mg, 929.87. mu. mol, 161.96. mu.L, 5 eq) and (1R) -2-amino-1- (1H-indol-3-yl) ethanol (46.06mg, 241.77. mu. mol, 1.3 eq). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 1/2, TLC: PE/EtOAc: 1/1, R_f0.12) to give (1R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (15.35mg, 38.14. mu. mol, 20.5% yield, 100% purity, SFC: R_t＝1.560，ee＝99.008％，[α]^22.1 _D＝+6.048(MeOH，c＝0.133g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.73(s，1H)，8.48(d，J＝2.8Hz，1H)，7.89(s，1H)，7.85-7.79(m，2H)，7.25(d，J＝7.0Hz，1H)，7.19(s，1H)，7.12-7.05(m，2H)，6.11(s，1H)，5.30(t，J＝5.6Hz，1H)，4.06-3.96(m，2H)，2.31(s，3H)；ES-LCMS m/z 403.1[M+H]⁺。

Example 132

Synthesis of I-150b

The synthesis scheme is as follows:

step 1: 2- (1H-indol-3-yl) -2-oxo-acetyl chloride

At 0-5 ℃ under N₂To a solution of indole (10g, 85.36mmol, 1 eq) in THF (100mL) was added dropwise (COCl)₂(11.05g, 87.07mmol, 7.62mL, 1.02 equiv.). The mixture was stirred at 0-5 ℃ for 3 hours. The yellow slurry was filtered and the filter cake was washed with PE (10mL × 2) and dried under reduced pressure to give crude 2- (1H-indol-3-yl) -2-oxo-acetyl chloride (15g, 72.25mmol, 84.6% yield, 100% purity) as a yellow solid which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 13.31(br s，1H)，8.64-8.57(m，1H)，8.34-8.25(m，1H)，7.45-7.38(m，1H)，7.26-7.15(m，2H)。

Step 2: 2- (1H-indol-3-yl) -2-oxo-acetamide

To NH₃·H₂To a solution of O (42.20g, 337.17mmol, 46.37mL, 28%, 10 equiv.) in EtOH (100mL) was added 2-, (1H-indol-3-yl) -2-oxo-acetyl chloride (7g, 33.72mmol, 1 eq). The mixture was stirred at 0 ℃ for 1.5 hours. The slurry was filtered and the filter cake was washed with water (20mL × 2) and dried under reduced pressure to give 2- (1H-indol-3-yl) -2-oxo-acetamide (5.5g, 28.00mmol, 83.0% yield, 95.8% purity) as a white solid which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 12.18(br s，1H)，8.69(s，1H)，8.27-8.17(m，1H)，8.08(br s，1H)，7.71(br s，1H)，7.58-7.48(m，1H)，7.30-7.19(m，2H)；ES-LCMS m/z 189.1[M+H]⁺。

Step 3: 1H-indole-3-carbonyl cyanide

At 10 ℃ under N₂To a solution of 2- (1H-indol-3-yl) -2-oxo-acetamide (5.5g, 28.00mmol, 1 eq) and pyridine (6.64g, 84.00mmol, 6.78mL, 3 eq) in EtOAc (100mL) was added TFAA (8.82g, 42.00mmol, 5.84mL, 1.5 eq). The mixture was stirred at 10 ℃ for 4 hours. The reaction mixture was purified by addition of NaHCO₃Quenched (100mL) and extracted with EtOAc (80 mL. times.3). The combined organic layers were washed with 0.5N aqueous HCl (20mL), brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave crude 1H-indole-3-carbonyl cyanide (3.2g, 12.73mmol, 45.5% yield, 67.7% purity) as a white solid which was used in the next step without further purification.¹HNMR(400MHz，DMSO-d₆)δppm 12.88(br s，1H)，8.63(s，1H)，8.07-8.01(m，1H)，7.58(dd，J＝1.3，7.0Hz，1H)，7.34(dq，J＝1.3，7.2Hz，2H)；ES-LCMS m/z 171.1[M+H]⁺。

Step 4: (1S) -2-amino-1- (1H-indol-3-yl) ethanol

At 0 ℃ under N₂Down to 1H-indole-3-carbonyl cyanide (1g, 3.9)8mmol, 1 equiv.) in THF (40mL) was added LAH (302.00mg, 7.96mmol, 2 equiv.). The mixture was stirred at 15 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.18) showed complete consumption of starting material. The mixture was diluted with THF (50mL), cooled to 0 deg.C and quenched by the sequential addition of water (0.3mL), 10% aqueous NaOH (0.3mL), water (0.9 mL). After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (EtOAc/MeOH 1/0 to 1/1, TLC: EtOAc/MeOH 10/1, R_f0.18) to give the product, which was isolated twice by SFC (first: xylonite CHIRALPAK IC (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 35 to 35 percent. And (3) for the second time: column: xylonite CHIRALPAK IC (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 45% -45%) to yield (1R) -2-amino-1- (1H-indol-3-yl) ethanol (120mg, 629.91 μmol, 15.8% yield, 92.5% purity, ee ═ 92.5%) as a yellow oil.¹H NMR(400MHz，CD₃OD)δppm 7.66(d，J＝7.8Hz，1H)，7.35(d，J＝8.3Hz，1H)，7.22(s，1H)，7.10(t，J＝7.2Hz，1H)，7.05-6.95(m，1H)，4.96(t，J＝6.3Hz，1H)，3.02(d，J＝6.3Hz，2H)；ES-LCMS m/z 159.2[M-H₂O+H]⁺. And (1S) -2-amino-1- (1H-indol-3-yl) ethanol (125mg, 602.96 μmol, 15.2% yield, 85.0% purity, ee ═ 98.698%) as a yellow oil.¹H NMR(400MHz，CD₃OD)δppm 7.67(d，J＝8.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.23(s，1H)，7.11(t，J＝7.2Hz，1H)，7.05-6.99(m，1H)，4.99(t，J＝6.3Hz，1H)，3.08-3.02(m，2H)；ES-LCMS m/z 159.2[M-H₂O+H]⁺。

Step 5(1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (I-150b)

To 7-chloro-5- (5-fluoro)-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 185.97. mu. mol, 1 eq.) in/-PrOH (3mL) was added DIEA (72.11mg, 557.92. mu. mol, 97.18. mu.L, 3 eq.) and (1S) -2-amino-1- (1H-indol-3-yl) ethanol (57.47mg, 277.22. mu. mol, 1.49 eq.). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 1/2, TLC: PE/EtOAc: 1/1, R_f0.18) to give (1S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (29.26mg, 71.26. mu. mol, 38.3% yield, 98.0% purity, SFC: R_t＝2.204，ee＝98.378，[α]^21.4 _D＝-8.227(MeOH，c＝0.10g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.72(s，1H)，8.48(d，J＝2.2Hz，1H)，7.89(s，1H)，7.82(d，J＝5.9Hz，2H)，7.25(d，J＝8.3Hz，1H)，7.19(s，1H)，7.14-7.02(m，2H)，6.10(s，1H)，5.30(t，J＝5.7Hz，1H)，4.08-3.95(m，2H)，2.31(s，3H)；ES-LCMS m/z 403.2[M+H]⁺。

Example 133

Synthesis of I-152a, I-152b, I-152c

The synthesis scheme is as follows:

step 1: (3R) -6, 8-difluoro-N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-152b) and

(3S) -6, 8-difluoro-N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a ] [1, 3, 5] triazin-4-yl ] -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-152a)

To 6, 8-difluoro-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (180mg, 509.83. mu. mol, 1 eq, TFA) and 4-chloro-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazine (221.40mg, 607.18. mu. mol, 1.19 equiv.) in i-PrOH (10mL) was added DIEA (527.13mg, 4.08mmol, 710.42. mu.L, 8 equiv.). The mixture was stirred at 50 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.5) indicates complete consumption of the starting material. The reaction mixture was concentrated to dryness under reduced pressure to give a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.50). The desired fractions were concentrated under reduced pressure to give the product which was passed through chiral SFC (column: xylonite CHIRALPAK AD (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 45% -45%, min) to obtain peak 1 (SFC: rt 1.851) and peak 2 (SFC: rt 2.254). Peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)]75% -100% for B), freeze drying the desired fractions to give the enantiomer as a yellow solid (64.24mg, 114.88 μmol, 22.5% yield, 98.4% purity, 2HCl, SFC: Rt 1.851, ee 100%, OR: [ α% ])]^20.2 _D＝0.206(MeOH c＝0.110g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 11.38(s，1H)，9.38(s，1H)，9.06(d，J＝8.6Hz，1H)，8.69(d，J＝2.2Hz，1H)，8.44(d，J＝10.0Hz，1H)，8.15(s，1H)，7.02(d，J＝9.0Hz，1H)，6.86(m，J＝10.6Hz，1H)，4.84(br s，1H)，3.22(d，J＝7.1，14.0Hz，1H)，3.12-2.98(m，2H)，2.88(d，J＝15.4Hz，2H)，2.20(br s，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z478.3[M+H]⁺. Peak 2 was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 75% -100%, 8 min). The desired fractions were lyophilized to give the other enantiomer as a yellow solid (70.3mg, 125.02 μmol, 24.5% yield, 97.9% purity, 2HCl,SFC：Rt＝2.254，ee＝99.79％，OR：[a]^20.2 _D＝-0.239(MeOH c＝0.117g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 11.38(s，1H)，9.38(s，1H)，9.05(d，J＝8.6Hz，1H)，8.69(d，J＝2.9Hz，1H)，8.49-8.38(m，1H)，8.15(s，1H)，7.02(dd，J＝1.8，9.4Hz，1H)，6.91-6.80(m，1H)，4.94-4.75(m，1H)，3.22(d，J＝6.9，13.8Hz，1H)，3.13-2.98(m，2H)，2.96-2.83(m，2H)，2.28-2.13(m，2H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 478.2[M+H]⁺。

example 134

Synthesis I-154

The synthesis scheme is as follows:

step 1: 8-bromo-4-chloro-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazine

To 4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]NBS (82.82mg, 465.33. mu. mol, 1.1 equiv.) was added to a solution of triazine (110mg, 423.02. mu. mol, 1 equiv.) in MeCN (2mL) and DCM (1 mL). The mixture was stirred at 30 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give 8-bromo-4-chloro-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a as a yellow solid][1，3，5]Triazine (120mg, 365.27 μmol, 86.4% yield), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.56(s，1H)，8.68(d，J＝2.4Hz，1H)，8.51(d，J＝9.3Hz，1H)，8.32(s，1H)；ES-LCMS m/z 327.9，329.9[M+H]⁺。

Step 2: (3R) -N- [ 8-bromo-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-154)

Reacting 8-bromo-4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]A mixture of triazine (70mg, 204.55. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (41.91mg, 225.00. mu. mol, 1.1 equivalents) and DIEA (79.31mg, 613.65. mu. mol, 106.89. mu.L, 3 equivalents) in i-PrOH (3mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 60 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 63% -93%, 8min) and then lyophilized to give (3R) -N- [ 8-bromo-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (32.48mg, 58.92. mu. mol, 28.8% yield, 100.0% purity, 2HCl, OR: [ α ]]^22.1 _D＝0.234(MeOH，c＝0.105g/100mL)。¹H NMR(400MHz，CD₃OD)δppm 9.45(s，1H)，8.85-8.72(m，2H)，8.12(s，1H)，7.34(d，J＝7.8Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.02(t，J＝7.6Hz，1H)，6.97-6.89(m，1H)，4.89-4.83(m，1H)，3.27(m，1H)，3.08-2.86(m，3H)，2.43-2.17(m，2H)；ES-LCMS m/z 480.1，482.1[M+H]⁺。

Example 135

Synthesis I-155

The synthesis scheme is as follows:

step 1: 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl]Pyrimidin-2-amines

In ice bath under N₂To a mixture of 2- (1H-indol-3-yl) ethylamine (666.77mg, 4.16mmol, 1.05 eq) in anhydrous THF (10mL) under atmosphere was added NaH (237.58mg, 5.94mmol, 1.5 eq). After stirring for 30 min, the mixture was cooled to-60 ℃ and anhydrous THF (10mL) containing 4, 6-dichloro-2-methylsulfonyl-pyrimidine (900mg, 3.96mmol, 1 eq) was added dropwise and the temperature was maintained below-55 ℃. The resulting mixture was stirred at-55 ℃ for 1 hour. The reaction mixture is purified by addition of H₂O (15mL) quench with H₂O (15mL) was diluted and extracted with EtOAc (20 mL. times.3). Combined organic layers with H₂O (15 mL. times.2) over Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 1/3, R_f0.43) to yield 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrimidin-2-amine (570mg, 1.48mmol, 37.5% yield, 80% purity).¹H NMR(400MHz，CDCl₃)δppm 7.96(br s，1H)，7.59(d，J＝7.8Hz，1H)，7.31(d，J＝8.1Hz，1H)，7.15(t，J＝7.6Hz，1H)，7.11-7.05(m，1H)，6.99(d，J＝2.0Hz，1H)，6.52(s，1H)，5.37(br s，1H)，3.73-3.68(m，2H)，3.00(t，J＝6.7Hz，2H)；ES-LCMS m/z 307.0，309.0[M+H]⁺。

Step 2: 4-chloro-N- [2- (1H-indol-3-yl) ethyl]-6-isopropoxy-pyrimidin-2-amine

To a solution of i-PrOH (75.12mg, 1.25mmol, 95.70. mu.L, 1.2 equiv.) in THF (3mL) was added NaH (62.50mg, 1.56mmol, 1.5 equiv.) and the mixture was stirred at 0 ℃ for 30 min. Adding 4, 6-dichloro-N- [2- (1H-indol-3-yl) ethyl to the mixture]A solution of pyrimidin-2-amine (400mg, 1.04mmol, 1 eq.) in THF (3mL) was stirred at 60 ℃ for 12 h. Adding H to the mixture₂O(3mL) and concentrated to give a residue which was purified by preparative TLC (PE/EtOAc ═ 3/1, R)_f0.5) to yield 4-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow oil]-6-isopropoxy-pyrimidin-2-amine (470mg, 710.37 μmol, 68.2% yield, 50% purity).¹H NMR(400MHz，CDCl₃)δppm 8.03(br s，1H)，7.66-7.60(m，1H)，7.36(d，J＝8.1Hz，1H)，7.20(t，J＝7.6Hz，1H)，7.15-7.09(m，1H)，7.03(s，1H)，6.57(s，1H)，5.26(d，J＝19.3Hz，1H)，3.78-3.69(m，2H)，3.05(t，J＝6.4Hz，2H)，1.62-1.18(m，6H)；ES-LCMS m/z 331.1[M+H]⁺。

Step 3: n- (2- (1H-indol-3-yl) ethyl) -4-isopropoxy-6-phenylpyrimidin-2-amine (I-155)

In N₂To 4-chloro-N- [2- (1H-indol-3-yl) ethyl group under an atmosphere]-6-isopropoxy-pyrimidin-2-amine (450mg, 680.15 μmol, 1 eq) and phenylboronic acid (124.39mg, 1.02mmol, 1.5 eq) in 1, 4-dioxane (10mL) and H₂Mixture in O (2mL) Pd (dppf) Cl was added₂(49.77mg, 68.01. mu. mol, 0.1 equiv.) and Cs₂CO₃(664.81mg, 2.04mmol, 3 equiv.). The mixture was placed in a microwave tube and heated at 110 ℃ for 30 minutes. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 40% -70%, 8min) and then freeze-drying to give N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-4-isopropoxy-6-phenyl-pyrimidin-2-amine (19.18mg, 44.68 μmol, 6.6% yield, 95.3% purity, HCl).¹H NMR(400MHz，CD₃OD)δppm 7.76(d，J＝7.3Hz，2H)，7.69-7.62(m，1H)，7.58(t，J＝6.6Hz，3H)，7.31(d，J＝8.1Hz，1H)，7.12(s，1H)，7.07(t，J＝7.3Hz，1H)，7.01-6.96(m，1H)，6.50(s，1H)，5.13(td，J＝6.1，12.2Hz，1H)，3.89(t，J＝6.6Hz，2H)，3.13(t，J＝6.6Hz，2H)，1.32(d，J＝6.1Hz，6H)；ES-LCMS m/z 373.3[M+H]⁺。

Example 136

Synthesis of I-160a, I-160b and I-160c

The synthesis scheme is as follows:

step 1: 2- [1- (phenylsulfonyl) indol-3-yl]Acetonitrile

At 0 ℃ under N₂A solution of 1- (benzenesulfonyl) -3- (bromomethyl) indole (7g, 19.99mmol, 1 eq) in THF (50mL) was added dropwise under an atmosphere to a well-stirred suspension of KCN (2.07g, 31.79mmol, 1.59 eq) in DMSO (50mL) and THF (20 mL). The mixture was warmed to 25 ℃ and under N₂Stirred under atmosphere for 15.5 hours. TLC (PE/EtOAc ═ 3/1, R_f0.30) indicates that one major new spot was detected and starting material remained. KCN (1.76g, 27.03mmol, 1.35 equiv.) was added to the mixture. Mixing the mixture in N₂Stirred under atmosphere for 16 hours. Ice water (200mL) was added to the mixture. The mixture was extracted with EtOAc (200 mL. times.3). The combined organic layers were washed with brine (150mL) and Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.30) to yield 2- [1- (phenylsulfonyl) indol-3-yl as a yellow solid]Acetonitrile (2.0g, 5.47mmol, 27.6% yield, 81.0% purity).¹H NMR(400MHz，CD₃OD)δppm 8.02(d，J＝8.3Hz，1H)，7.97-7.93(m，2H)，7.71(s，1H)，7.64-7.59(m，2H)，7.55-7.49(m，2H)，7.42-7.37(m，1H)，7.33-7.28(m，1H)，3.97(d，J＝1.0Hz，2H)；ES-LCMS m/z 297.1[M+H]⁺。

Step 2: 2- [1- (phenylsulfonyl) indol-3-yl]Propionitrile

At-78 ℃ under N₂To 2- [1- (phenylsulfonyl) indol-3-yl under an atmosphere]To a solution of acetonitrile (1g, 2.73mmol, 1 eq) in THF (50mL) was added n-BuLi (2.5M, 1.09mL, 1 eq) dropwise. The mixture was heated at-78 ℃ under N₂Stirred under atmosphere for 1 hour. A solution of MeI (387.96mg, 2.73mmol, 170.16. mu.L, 1 equiv.) in THF (5mL) was added dropwise to the mixture. The mixture was heated at 20 ℃ under N₂Stirred under atmosphere for 3 hours. TLC (PE/EtOAc ═ 3/1, R_f0.38) indicates that a major new blob is detected. Ice water (30mL) was added to the mixture and the mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 3/1, R_f0.38) to yield 2- [1- (phenylsulfonyl) indol-3-yl as a yellow solid]Propionitrile (420mg, 1.14mmol, 41.6% yield, 84.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.03(d，J＝8.3Hz，1H)，7.94-7.89(m，2H)，7.62-7.55(m，3H)，7.52-7.46(m，2H)，7.42-7.37(m，1H)，7.34-7.29(m，1H)，4.13(q，J＝7.1Hz，1H)，1.75(d，J＝7.1Hz，3H)；ES-LCMS m/z 311.1[M+H]⁺。

Step 3: 2- [1- (phenylsulfonyl) indol-3-yl]Propan-1-amines

To 2- [1- (phenylsulfonyl) indol-3-yl]To a solution of propionitrile (420mg, 1.14mmol, 1 equiv) in MeOH (10mL) were added Raney nickel (453.70mg, 5.30mmol, 4.66 equiv.) and NH₃·H₂O (910.00mg, 6.49mmol, 1mL, 5.71 equiv.). The mixture is degassed and treated with H₂Purify 3 times and stir at 25 ℃ for 16 hours. TLC (PE/EtOAc ═ 3/1, R_f0.16) indicates that a major new spot has been detectedAnd (4) point. The reaction mixture was filtered and concentrated to give 2- [1- (phenylsulfonyl) indol-3-yl as a white solid]Propan-1-amine (330mg, 818.70 μmol, 72.0% yield, 78.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.01(d，J＝8.3Hz，1H)，7.87(d，J＝7.5Hz，2H)，7.58-7.51(m，2H)，7.48-7.40(m，2H)，7.38-7.30(m，2H)，7.26-7.21(m，1H)，4.93(brs，2H)，3.08-2.93(m，2H)，2.92-2.86(m，1H)，1.34(d，J＝6.8Hz，3H)；ES-LCMS m/z 315.1[M+H]⁺。

Step 4: 2- (1H-indol-3-yl) propan-1-amine

To 2- [1- (phenylsulfonyl) indol-3-yl]To a solution of propan-1-amine (330mg, 818.70 μmol, 1 eq) in MeOH (10mL) was added NaOH (327.46mg, 8.19mmol, 10 eq). Mixing the mixture in N₂Stirred under an atmosphere at 50 ℃ for 4 hours. TLC (DCM/MeOH ═ 10/1, R)_f0.20) indicates that a major new blob is detected. The mixture was concentrated and water (10mL) was added. The mixture was extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration gave 2- (1H-indol-3-yl) propan-1-amine (130mg, 746.09 μmol, 91.1% yield, crude material) as a white solid which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm8.05(br s，1H)，7.67(d，J＝8.1Hz，1H)，7.42-7.36(m，1H)，7.21(t，J＝7.5Hz，1H)，7.12(t，J＝7.6Hz，1H)，7.03(d，J＝2.0Hz，1H)，3.18-3.10(m，1H)，3.05-2.92(m，2H)，1.40-1.36(m，3H)。

Step 5: 5- (5-fluoro-3-pyridinyl) -N- [ (2S) -2- (1H-indol-3-yl) propyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine and 5- (5-fluoro-3-pyridinyl) -N- [ (2R) -2- (1H-indol-3-yl) propyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amines (I-160a, I-160b)

To 2- (1H-indol-3-yl) propan-1-amine (130mg, 746.09 μmol, 1 eq) and 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Mixture of pyrimidine (200.59mg, 746.09. mu. mol, 1 equiv.) in/-PrOH (10mL) DIEA (289.28mg, 2.24mmol, 389.87. mu.L, 3 equiv.) was added. Mixing the mixture in N₂Stirring at 80 ℃ for 15 h under atmosphere and concentration under reduced pressure gave a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.34) to yield 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) propyl ester as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (300mg, 689.22. mu. mol, 92.4% yield, 92.0% purity) was passed through SFC (column: xylonite CHIRALCEL OJ (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃·H₂OEtOH](ii) a B%: 40% -40%, min). The solution was concentrated to give the crude product which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 48% -68%, 8min) followed by lyophilization gave the enantiomer as a yellow solid (27.27mg, 57.61 μmol, 8.4% yield, 100.0% purity, 2HCl, SFC: r_t＝3.079min，ee＝98.49％，OR：[α]^23.9 _D＝+48.385(MeOH，c＝0.110g/100mL))。¹H NMR(400MHz，CD₃OD)δppm8.73(d，J＝2.7Hz，1H)，8.39(s，1H)，8.09(s，1H)，7.54(d，J＝8.1Hz，2H)，7.11(d，J＝8.1Hz，1H)，7.05(s，1H)，6.91(t，J＝7.6Hz，1H)，6.76(t，J＝7.1Hz，1H)，5.74(s，1H)，4.00-3.94(m，2H)，3.58-3.51(m，1H)，2.27(s，3H)，1.59(d，J＝7.1Hz，3H)；ES-LCMS m/z 401.1[M+H]⁺(ii) a And the other enantiomer as a yellow solid (64.75mg, 136.78 μmol, 19.85% yield, 100% purity, 2HCl, SFC: R_t＝3.374min，ee＝98.93％，OR：[α]^23.8 _D＝-32.08(MeOH，c＝0.120g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝2.7Hz，1H)，8.39(s，1H)，8.09(s，1H)，7.57-7.51(m，2H)，7.12(d，J＝8.3Hz，1H)，7.06(s，1H)，6.92(t，J＝7.6Hz，1H)，6.76(t，J＝7.5Hz，1H)，5.75(s，1H)，4.02-3.92(m，2H)，3.59-3.51(m，1H)，2.28(s，3H)，1.60(d，J＝7.1Hz，3H)；ES-LCMS m/z 401.1[M+H]⁺。

Example 137

Synthesis I-162

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-162)

A mixture of 6-chloro-2- (5-fluoro-3-pyridyl) -9-isopropyl-purine (60mg, 187.17 μmol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (38.35mg, 205.89 μmol, 1.1 equivalents) and DIEA (72.57mg, 561.51 μmol, 97.81 μ L, 3 equivalents) in i-PrOH (6mL) was degassed and N-PrOH (6mL) was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 80 ℃ for 15 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 8min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) -9-isopropyl-purin-6-yl as a yellow solid]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (30.19mg, 58.51 μmol, 31.3% yield, 99.7% purity, 2HCl, [ α ]]^22.3 _D＝-22.78(MeOH，c＝0.149g/100mL)。¹H NMR(400MHz，CD₃OD)δppm 9.57(br s，1H)，9.40(s，1H)，9.14(J＝8.0Hz，1H)，8.99(br s，1H)，7.31(J＝7.5Hz，1H)，7.23(d，J＝8.0Hz，1H)，7.00(t，J＝7.5Hz，1H)，6.94-6.87(m，1H)，5.23-5.12(m，1H)，5.01(m，1H)，3.28(J＝5.0Hz，1H)，3.01-2.94(m，2H)，2.90(J＝6.8，15.3Hz，1H)，2.42-2.32(m，1H)，2.27(td，J＝7.0，13.7Hz，1H)，1.78-1.74(m，6H)；ES-LCMS m/z 442.1[M+H]⁺。

Example 138

Synthesis I-163

The synthesis scheme is as follows:

step 1: 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (70mg, 260.36. mu. mol, 1 eq), 2-amino-1- (1H-indol-3-yl) ethanol (53.72mg, 260.36. mu. mol, 1 eq), DIEA (100.95mg, 781.09. mu. mol, 136.05. mu.L, 3 eq) in i-PrOH (15mL) was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (pure DCM to DCM/MeOH-10/1, TLC: DCM/MeOH-10/1, R_f0.60) to give 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a brown solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanol (80mg, 152.08 μmol, 58.4% yield, 76.5% purity).¹HNMR(400MHz，CDCl₃)δppm 8.77(s，1H)，8.46(s，1H)，8.24(s，1H)，7.91(d，J＝8.3Hz，1H)，7.82(s，1H)，7.78(d，J＝7.6Hz，1H)，7.35(d，J＝8.1Hz，1H)，7.20(d，J＝2.2Hz，1H)，6.83-6.76(m，1H)，6.07(s，1H)，5.38(t，J＝5.4Hz，1H)，3.92(t，J＝5.9Hz，2H)，2.35(s，3H)；ES-LCMS m/z 403.2[M+H]⁺。

Step 2: 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanone (I-163)

To 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]To a solution of (E) -1- (1H-indol-3-yl) ethanol (80mg, 152.08. mu. mol, 1 eq) in DCM (10mL) was added MnO₂(396.64mg, 4.56mmol, 30 equiv.). The reaction mixture was stirred at 20 ℃ for 12 hours. The reaction mixture was concentrated to give a residue which was purified twice by preparative HPLC (column: Aigerl DuraShell150 mm-25 mm-5 μm; mobile phase: water (0.05% HCl) -ACN; B%: 40% -70%, 8min) followed by lyophilization to give 2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]-1- (1H-indol-3-yl) ethanone (13.82mg, 27.88 μmol, 18.3% yield, 95.5% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.95(s，1H)，8.76(d，J＝2.7Hz，1H)，8.38(d，J＝3.2Hz，1H)，8.28-8.24(m，1H)，8.23-8.18(m，2H)，7.48(d，J＝7.1Hz，1H)，7.29-7.20(m，2H)，6.87(s，1H)，5.24(s，2H)，2.40(s，3H)；ES-LCMS m/z 401.2[M+H]⁺。

Example 139

Synthesis I-164

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-8-methyl-pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-164)

To 4-chloro-2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazine (50mg, 182.24. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (32.12mg, 200.47. mu. mol, 1.1 eq) in i-PrOH (10mL) was added DIEA (188.43mg, 1.46mmol, 253.95. mu.L, 8 eq). The mixture was stirred at 50 ℃ for 3 hours. TLC (PE/EtOAc ═ 3/1, R_f0.2) indicates complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: AigelDuraShell 150 mm-25 mm-5 um; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 9 min). The desired fractions were lyophilized to give 2- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a yellow solid]-8-methyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (22.72mg, 48.65. mu. mol, 26.7% yield, 98.6% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.15(s，1H)，8.83(br s，1H)，8.59(d，J＝9.0Hz，1H)，7.95(s，1H)，7.68(dd，J＝2.4，6.1Hz，1H)，7.20-7.12(m，1H)，7.05-6.91(m，3H)，4.05(t，J＝6.7Hz，2H)，3.19(t，J＝6.7Hz，2H)，2.29(s，3H)；ES-LCMS m/z 388.2[M+H]⁺。

Example 140

Synthesis I-165

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-165)

4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]A mixture of triazine (44.89mg, 172.65. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (39.30mg, 189.92. mu. mol, 1.1 equivalents) and DIEA (66.94mg, 517.95. mu. mol, 90.22. mu.L, 3 equivalents) in i-PrOH (3mL) was degassed and N was used to degas₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 80 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 8min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (20.39mg, 42.52 μmol, 24.6% yield, 98.5% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.46(s，1H)，8.90(d，J＝9.0Hz，1H)，8.82(s，1H)，8.13(d，J＝2.2Hz，1H)，7.35(d，J＝7.8Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.06-6.98(m，1H)，6.97-6.91(m，1H)，6.57(d，J＝2.0Hz，1H)，4.89(m，1H)，3.31-3.26(m，1H)，3.11-2.88(m，3H)，2.42-2.34(m，1H)，2.33-2.21(m，1H)；ES-LCMS m/z 400.2[M+H]⁺Optical rotation ([ α)]^21.4 _D＝0.396(MeOH，c＝0.102g/100mL)。

Example 141

Synthesis I-166

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -8-isopropyl-N- [2- (1H-pyrrol-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (i-166)

To 4-chloro-2- (5-fluoro-3-pyridine)Yl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine (50mg, 168.66. mu. mol, 1 eq.) to a solution of i-PrOH (3mL) was added DIEA (21.80mg, 168.66. mu. mol, 29.38. mu.L, 1 eq.) and 2- (1H-pyrrol-3-yl) ethylamine (27.87mg, 252.99. mu. mol, 1.5 eq.). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 8min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -8-isopropyl-N- [2- (1H-pyrrol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (15.28mg, 32.18. mu. mol, 19.1% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.52(s，1H)，9.39(s，1H)，8.93(t，J＝5.6Hz，1H)，8.73(d，J＝2.9Hz，1H)，8.41(d，J＝8.8Hz，1H)，8.11(s，1H)，6.65(d，J＝2.4Hz，2H)，5.98(s，1H)，3.84-3.75(m，2H)，3.23-3.16(m，1H)，2.84(t，J＝7.3Hz，2H)，1.35(d，J＝6.8Hz，6H)；ES-LCMS m/z 366.2[M+H]⁺。

Example 142

Synthesis I-169

The synthesis scheme is as follows:

step 1: 3- (5-fluoro-3-pyridinyl) -2-methyl-3-oxo-propionic acid methyl ester

To a solution of (Z) -methyl 3- (5-fluoro-3-pyridyl) -3-hydroxy-prop-2-enoate (600.00mg, 2.83. mu. mol, 1 eq.) and MeI (401.71mg, 2.83. mu. mol, 176.19. mu.L, 1 eq.) in DMF (20mL) was added K₂CO₃(391.14mg, 2.83. mu. mol, 1 eq.).The mixture was stirred at 20 ℃ for 3 hours. The reaction mixture is purified by addition of H₂O (50mL) was quenched and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/1, TLC: PE/EtOAc: 10/1, R_f0.37) to yield the product, methyl 3- (5-fluoro-3-pyridyl) -2-methyl-3-oxo-propionate, as a yellow oil (605mg, 2.69 μmol, 95.0% yield, 93.9% purity).¹H NMR(400MHz CDCl₃)δppm 9.00(d，J＝1.5Hz，1H)，8.78-8.61(m，1H)，8.03-7.90(m，1H)，4.36(q，J＝7.1Hz，1H)，3.71(s，3H)，1.57-1.52(m，3H)；ES-LCMS m/z 212.1[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -3, 6-dimethyl-pyrazolo [1, 5-a]Pyrimidin-7-ols

3- (5-fluoro-3-pyridyl) -2-methyl-3-oxo-propionic acid methyl ester (300mg, 1.33. mu. mol, 1 eq), 4-methyl-1H-pyrazol-5-amine (647.37mg, 6.67. mu. mol, 5 eq) in AcOH (5mL) was placed in a microwave tube. The sealed tube was heated at 150 ℃ for 1 hour under microwave. The mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridinyl) -3, 6-dimethyl-pyrazolo [1, 5-a ] pyrimidin-7-ol (300mg, 1.16 μmol, 87.14% yield) as a white solid, which was used in the next step without further purification.

Step 3: 7-chloro-5- (5-fluoro-3-pyridinyl) -3, 6-dimethyl-pyrazolo [1, 5-a]Pyrimidines

Reacting 5- (5-fluoro-3-pyridyl) -3, 6-dimethyl-pyrazolo [1, 5-a)]Pyrimidin-7-ol (270mg, 1.05. mu. mol, 1 eq.) in POCl₃(8.25g, 53.80. mu. mol, 5.00mL, 51.46 equivalents) was stirred at 110 ℃ for 3 hours. The reaction mixture was poured into ice water (50g) and extracted with DCM (50 mL. times.3)And (6) taking. The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.51) to yield 7-chloro-5- (5-fluoro-3-pyridinyl) -3, 6-dimethyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (200mg, 337.55. mu. mol, 32.3% yield, 46.7% purity).¹H NMR(400MHz，CDCl₃)δppm9.01(d，J＝1.2Hz，1H)，8.68(s，1H)，8.61(s，1H)，8.08(s，1H)，2.65(s，3H)，2.63(s，3H)；ES-LCMS m/z 277.1[M+H]⁺。

Step 4: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3, 6-dimethyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-169)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3, 6-dimethyl-pyrazolo [1, 5-a]To a solution of pyrimidine (100mg, 168.78. mu. mol, 1 eq) and 2- (1H-indol-3-yl) ethylamine (40.56mg, 253.17. mu. mol, 1.5 eq) in i-PrOH (4mL) was added DIEA (87.25mg, 675.11. mu. mol, 117.59. mu.L, 4 eq). The mixture was stirred at 70 ℃ for 3 hours and concentrated to give a residue which was purified by preparative HPLC (Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 50% -80%, 8min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3, 6-dimethyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (33.61mg, 83.93 μmol, 49.7% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 8.49(d，J＝2.7Hz，1H)，8.13(s，1H)，7.89(s，1H)，7.52(d，J＝7.8Hz，1H)，7.30-7.26(m，1H)，7.20(d，J＝8.1Hz，1H)，7.07(t，J＝7.5Hz，1H)，6.98(d，J＝7.8Hz，1H)，6.71(s，1H)，4.16-4.12(m，2H)，3.12-3.09(m，2H)，2.26(s，3H)，1.88(s，3H)；ES-LCMS m/z 401.2[M+H]⁺。

Example 143

Synthesis I-171

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) propyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-171)

To 2- (1H-indol-3-yl) propan-1-amine (30mg, 172.17 μmol, 1 eq) and 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (46.29mg, 172.17. mu. mol, 1 eq.) in i-PrOH (6mL) was added DIEA (66.76mg, 516.52. mu. mol, 89.97. mu.L, 3 eq.). Mixing the mixture in N₂Stirred at 80 ℃ for 15 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 48% -68%, 8min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) propyl ] as an orange solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (18.71mg, 39.52. mu. mol, 23.0% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.80(br s，1H)，8.44(br s，1H)，8.09(s，1H)，7.64(br s，1H)，7.56(d，J＝8.1Hz，1H)，7.12(d，J＝8.1Hz，1H)，7.05(s，1H)，6.92(t，J＝7.3Hz，1H)，6.80-6.74(m，1H)，5.75(s.1H)，4.04-3.92(m，2H)，3.59-3.50(m，1H)，2.28(s，3H)，1.59(d，J＝7.3Hz，3H)；ES-LCMSm/z 401.1[M+H]⁺。

Example 144

Synthesis I-172

The synthesis scheme is as follows:

step 1: 7-methoxy-1H-indole-3-carbaldehyde

At 0 ℃ to POCl₃(1.13g, 7.37mmol, 684.85. mu.L, 1.08 equiv.) to a solution in DMF (12mL) was added 7-methoxy-1H-indole (1g, 6.79mmol, 884.96. mu.L, 1 equiv.). Mixing the mixture in N₂Stirring at 0-20 deg.C for 3 hr under atmosphere. TLC (PE/EtOAc ═ 3/1, R_f0.25) indicates that a major new blob is detected. The pH of the mixture is adjusted to 10-12 by 2N NaOH. The mixture was extracted with DCM (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 5/2, TLC: PE/EtOAc: 3/1, R_f0.25) to give 7-methoxy-1H-indole-3-carbaldehyde (900mg, 5.03mmol, 74.1% yield, 98.0% purity) as a pink solid.¹H NMR(400MHz，CDCl₃)δppm 10.07(s，1H)，9.18(br s，1H)，7.89(d，J＝7.9Hz，1H)，7.81(d，J＝3.1Hz，1H)，7.24(t，J＝7.9Hz，1H)，6.78(d，J＝7.7Hz，1H)，3.98(s，3H)；ES-LCMS m/z 176.1[M+H]⁺。

Step 2: 7-methoxy-3- [ (E) -2-nitrovinyl group]-1H-indoles

To 7-methoxy-1H-indole-3-carbaldehyde (900mg, 5.03mmol, 1 eq.) and NH₄A mixture of OAc (504.52mg, 6.55mmol, 1.3 equiv.) in THF (10mL) was added CH₃NO₂(11.30g, 185.12mmol, 10mL, 36.77 equiv.). The mixture is degassed and treated with N₂Purification 3 times and in N₂At 80 ℃ under an atmosphereStirred for 19 hours. TLC (PE/EtOAc ═ 1/1, R_f0.60) indicates that a major new blob is detected. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 5/2, TLC: PE/EtOAc: 1/1, R_f0.60) to give 7-methoxy-3- [ (E) -2-nitrovinyl) as an orange solid]-1H-indole (660mg, 2.87mmol, 57.1% yield, 95.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.92(br s，1H)，8.29(d，J＝13.5Hz，1H)，7.79(d，J＝13.5Hz，1H)，7.63(d，J＝3.1Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.26-7.24(m，1H)，6.80(d，J＝7.7Hz，1H)，4.00(s，3H)。

Step 3: 2- (7-methoxy-1H-indol-3-yl) ethylamine

To 7-methoxy-3- [ (E) -2-nitrovinyl group]To a solution of (E) -1H-indole (300mg, 1.31mmol, 1 equiv.) in THF (10mL) was added LiAlH₄(247.86mg, 6.53mmol, 5 equiv.). Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.10) indicates that a major new blob is detected. 2mL of H₂O and 1mL of 2N NaOH were added to the mixture. The mixture was filtered and concentrated to give 2- (7-methoxy-1H-indol-3-yl) ethylamine (240mg, 1.20mmol, 91.8% yield, 95.0% purity) as a yellow solid, which was used in the next step without further purification.¹HNMR(400MHz，CDCl₃)δppm 8.22(br s，1H)，7.23(d，J＝7.8Hz，1H)，7.07-7.01(m，2H)，6.66(d，J＝7.6Hz，1H)，3.97(s，3H)，3.06-3.01(m，2H)，2.93-2.87(m，2H)。

Step 4: 5- (5-fluoro-3-pyridinyl) -N- [2- (7-methoxy-1H-indol-3-yl) ethyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

Reacting 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (230mg, 855.48. mu. mol, 1 eq), 2- (7-methoxy-1H-indol-3-yl) ethylamine (217.00mg, 1.03mmol, 1.2 eq) and DIEA (331.70mg, 2.57mmol, 447.03. mu.L, 3 eq) in i-PrOH (10mL) was degassed and N₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl DuraShell150 mm-25 mm-5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (7-methoxy-1H-indol-3-yl) ethyl as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (240mg, 490.42 μmol, 57.3% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.72(d，J＝2.7Hz，1H)，8.30(s，1H)，8.10(s，1H)，7.43(td，J＝2.3，9.0Hz，1H)，7.15(d，J＝7.8Hz，1H)，6.87(s，1H)，6.80(t，J＝7.8Hz，1H)，6.48(d，J＝7.6Hz，1H)，5.62(s，1H)，4.04-3.98(m，2H)，3.81(s，3H)，3.21-3.16(m，2H)，2.29(s，3H)；ES-LCMS m/z 417.1[M+H]⁺。

Step 5: 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-7-ol (I-172)

To 5- (5-fluoro-3-pyridyl) -N- [2- (7-methoxy-1H-indol-3-yl) ethyl at 0 DEG C]-3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidin-7-amine (200mg, 480.25. mu. mol, 1 eq.) in DCM (10mL) was added BBr₃(240.63mg, 960.50. mu. mol, 92.55. mu.L, 2 equiv.). Mixing the mixture in N₂Stirring for 0.5 hour at 0-20 deg.C under atmosphere. 1mL MeOH was added to the mixture. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 8min) and then lyophilized to give 3- [2- [ [5- (5-fluoro-3) as an orange solid-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-7-ol (22.74mg, 45.54. mu. mol, 9.5% yield, 95.2% purity, 2 HCl).¹HNMR(400MHz，CD₃OD)δppm 8.71(d，J＝2.7Hz，1H)，8.35(s，1H)，8.10(s，1H)，7.43(J＝9.0Hz，1H)，7.04(d，J＝7.8Hz，1H)，6.87(s，1H)，6.69(td，J＝3.8，7.9Hz，1H)，6.36(d，J＝7.6Hz，1H)，5.65(s，1H)，4.04-3.98(m，2H)，3.21-3.15(m，2H)，2.29(s，3H)；ES-LCMS m/z403.1[M+H]⁺。

Example 145

Synthesis I-175

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N3, N3-dimethyl-N7- [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Pyrazolo [1, 5-a]Pyrimidine-3, 7-diamine (I-175)

To 7-chloro-5- (5-fluoro-3-pyridyl) -N, N-dimethyl-pyrazolo [1, 5-a]To a solution of pyrimidin-3-amine (50mg, 171.40 μmol, 1 eq) in i-PrOH (5mL) was added DIEA (66.46mg, 514.21 μmol, 89.56 μ L, 3 eq) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (35.12mg, 188.54 μmol, 1.1 eq). Mixing the mixture in N₂Stirring was carried out at 90 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl DuraShell150 mm-25 mm-5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 8min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N3, N3-dimethyl-N7- [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as a yellow solid]Pyrazolo [1, 5-a]Pyrimidine-3, 7-diamines(22.71mg, 43.35. mu. mol, 25.3% yield, 98.2% purity, 2 HCl).¹H NMR(400MHz，DMSO-d₆)δppm 10.82(s，1H)，9.41(s，1H)，8.72(s，1H)，8.66-8.55(m，2H)，8.49(br s，1H)，7.36(d，J＝7.6Hz，1H)，7.31-7.25(m，2H)，7.04-6.98(m，1H)，6.96-6.91(m，1H)，4.56(br s，1H)，3.37(s，6H)，3.18-3.01(m，2H)，2.99-2.82(m，2H)，2.28-2.09(m，2H)；ES-LCMS m/z 442.3[M+H]⁺。

Example 146

Synthesis I-177

The synthesis scheme is as follows:

step 1: 2- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Propan-2-ol (I-177)

In N₂To MeLi (1.3M, 5mL, 57.13 equiv.) was added 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino dropwise at-20 ℃ under an atmosphere]Pyrazolo [1, 5-a]Pyrimidin-3-yl]A solution of ethanone (50mg, 113.77. mu. mol, 1 eq.) in THF (2 mL). Mixing the mixture in N₂Stirred at-20 ℃ for 0.5 hour under an atmosphere. The reaction was quenched with water (10mL) and extracted with EtOAc (50 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Aigerl Durashell C18150X 305 u; mobile phase: [ water (10mM NH) ]₄HCO₃)-ACN](ii) a B%: 40% -60%, 9 min). Lyophilizing the desired fractions to obtain 2- [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino ] as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Propan-2-ol (13.48mg, 31.31. mu. mol,27.5% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm8.69(s，1H)，8.43(d，J＝2.8Hz，1H)，7.98(s，1H)，7.74(td，J＝2.0，9.6Hz，1H)，7.68(dd，J＝2.8，6.0Hz，1H)，7.24-7.16(m，1H)，7.09-7.02(m，2H)，6.98(s，1H)，6.00(s，1H)，3.86(t，J＝6.0Hz，2H)，3.18(t，J＝6.0Hz，2H)，1.72(s，6H)；ES-LCMS m/z 431.1[M+H]⁺。

Example 147

Synthesis I-179

The synthesis scheme is as follows:

step 1: 7-methoxy-1H-indole-3-carbaldehyde

Step 2: 7-methoxy-3- [ (E) -2-nitrovinyl group]-1H-indoles

To 7-methoxy-1H-indole-3-carbaldehyde (900mg, 5.03mmol, 1 eq.) and NH₄A mixture of OAc (504.52mg, 6.55mmol, 1.3 equiv.) in THF (10mL) was added CH₃NO₂(11.30g, 185.12mmol, 10mL, 36.77 equiv.). The mixture is degassed and treated with N₂Purification 3 times and in N₂Stirred at 80 ℃ for 19 hours under an atmosphere. TLC (PE/EtOAc ═ 1/1, R_f0.60) indicates that a major new blob is detected. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 5/2, TLC: PE/EtOAc: 1/1, R_f0.60) to give 7-methoxy-3- [ (E) -2-nitrovinyl) as an orange solid]-1H-indole (660mg, 2.87mmol, 57.1% yield, 95.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.92(br s，lH)，g.29(d，J＝13.5Hz，1H)，7.79(d，J＝13.5Hz，1H)，7.63(d，J＝3.1Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.26-7.24(m，1H)，6.80(d，J＝7.7Hz，1H)，4.00(s，3H)。

Step 3: 2- (7-methoxy-1H-indol-3-yl) ethylamine

To 7-methoxy-3- [ (E) -2-nitrovinyl group]To a solution of (E) -1H-indole (300mg, 1.31mmol, 1 equiv.) in THF (10mL) was added LiAlH₄(247.86mg, 6.53mmol, 5 equiv.). Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 2 hours. TLC (PE/EtOAc ═ 3/1, R_f0.10) indicates that a major new blob is detected. Addition of H₂O (2mL), followed by 2N NaOH (1mL) to the mixture. The mixture was filtered and concentrated to give 2- (7-methoxy-1H-indol-3-yl) ethylamine (240mg, 1.20mmol, 91) as a yellow solid8% yield, 95.0% purity) which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.22(br s，1H)，7.23(d，J＝7.8Hz，1H)，7.07-7.01(m，2H)，6.66(d，J＝7.6Hz，1H)，3.97(s，3H)，3.06-3.01(m，2H)，2.93-2.87(m，2H)。

Step 4: 5- (5-fluoro-3-pyridinyl) -N- [2- (7-methoxy-1H-indol-3-yl) ethyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-179)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (230mg, 855.48. mu. mol, 1 eq), 2- (7-methoxy-1H-indol-3-yl) ethylamine (217.00mg, 1.03mmol, 1.2 eq) and DIEA (331.70mg, 2.57mmol, 447.03. mu.L, 3 eq) in i-PrOH (10mL) was degassed and N₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl DuraShell150 mm-25 mm-5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (7-methoxy-1H-indol-3-yl) ethyl as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (240mg, 490.42 μmol, 57.3% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.72(d，J＝2.7Hz，1H)，8.30(s，1H)，8.10(s，1H)，7.43(td，J＝2.3，9.0Hz，1H)，7.15(d，J＝7.8Hz，1H)，6.87(s，1H)，6.80(t，J＝7.8Hz，1H)，6.48(d，J＝7.6Hz，1H)，5.62(s，1H)，4.04-3.98(m，2H)，3.81(s，3H)，3.21-3.16(m，2H)，2.29(s，3H)；ES-LCMS m/z 417.1[M+H]⁺。

Example 148

Synthesis of I-180

The synthesis scheme is as follows:

step 1: 2- (1H-pyrazol-3-yl) acetonitrile

To 3- (chloromethyl) -1H-pyrazole (350mg, 2.29mmol, 1 eq, HCl) in CH₃To a solution in CN (5mL) were added KCN (300mg, 4.61mmol, 197.37. mu.L, 2.01 equiv.) and H₂O (1 mL). The mixture was stirred at 50 ℃ for 12 hours. TLC (DCM/MeOH ═ 10/1, R)_f0.4) indicates complete consumption of the starting material and formation of a new spot. Subjecting the reaction mixture to hydrogenation with H₂O (10mL) was diluted and extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 2- (1H-pyrazol-3-yl) acetonitrile (150mg, 1.33mmol, 58.2% yield, 95.0% purity) as a yellow oil, which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆) δ ppm 12.84(s, 1H), 7.73(s, 1H), 6.23(s, 1H), 3.95(s, 2H); ES-LCMS: the correct quality was not found.

Step 2: 2- (1H-pyrazol-3-yl) ethylamine

To a solution of 2- (1H-pyrazol-3-yl) acetonitrile (150mg, 1.33mmol, 1 eq) in MeOH (10mL) under Ar atmosphere was added raney nickel (600mg, 7.00mmol, 5.26 eq). The suspension is degassed and treated with H₂And purifying for 3 times. Mixing the mixture in H₂(15psi) at 20 ℃ for 12 hours. TLC (DCM/MeOH ═ 10/1, R)_f0.4) indicates complete consumption of the starting material. The reaction mixture was filtered and concentrated under reduced pressure to give 2- (1H-pyrazol-3-yl) ethylamine (100mg, 899.73 μmol, 67.6% yield, crude) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆) δ ppm 12.64(s, 1H), 7.42-7.35(m, 1H), 5.98(s, 1H), 3.10-2.94(m, 2H), 2.82(d, J ═ 17.6Hz, 2H); ES-LCMS: the correct quality was not found.

Step 3: 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (1H-pyrazol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-180)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (75mg, 279.53. mu. mol, 1 eq) in i-PrOH (3mL) was added DIEA (180.64mg, 1.40mmol, 243.45. mu.L, 5 eq.) and 2- (1H-pyrazol-3-yl) ethylamine (62.14mg, 559.07. mu. mol, 2 eq.). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 15% -45%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (1H-pyrazol-3-yl) ethyl as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-7-amine (21.84mg, 48.89 μmol, 17.5% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.07(s，1H)，8.88(d，J＝2.4Hz，1H)，8.45(td，J＝2.3，8.9Hz，1H)，8.21(d，J＝2.7Hz，1H)，8.16(s，1H)，7.01(s，1H)，6.80(d，J＝2.7Hz，1H)，4.16(t，J＝7.0Hz，2H)，3.37(t，J＝7.0Hz，2H)，2.40(s，3H)；ES-LCMS m/z 338.1[M+H]⁺。

Example 149

Synthesis I-186

The synthesis scheme is as follows:

step (ii) of1: 2- (5-fluoro-3-pyridinyl) -8-methyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-186)

To 4-chloro-2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]To a solution of triazine (50mg, 189.64. mu. mol, 1 eq) in i-PrOH (5mL) was added DIEA (73.53mg, 568.92. mu. mol, 99.09. mu.L, 3 eq.) and 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (40mg, 248.13. mu. mol, 1.31 equiv.). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 10% -40%, 9 min). Lyophilizing the desired fractions to obtain 2- (5-fluoro-3-pyridyl) -8-methyl-N- [2- (1H-pyrrolo [3, 2-b ] as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (30.06mg, 60.39 μmol, 31.8% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.37(d，J＝1.3Hz，1H)，8.92(d，J＝2.3Hz，1H)，8.82(d，J＝8.8Hz，1H)，8.48(d，J＝5.8Hz，1H)，8.40(d，J＝8.3Hz，1H)，7.98(d，J＝10.5Hz，2H)，7.55(dd，J＝5.9，8.2Hz，1H)，4.19(t，J＝6.3Hz，2H)，3.38(t，J＝6.4Hz，2H)，2.29(s，3H)；ES-LCMS m/z 389.1[M+H]⁺。

Example 150

Synthesis of I-187b

The synthesis scheme is as follows:

step 1: (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]-3- (1H-indol-3-yl) propionic acid

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (100mg, 380.71. mu. mol, 1 eq), (2S) -2-amino-3- (1H-indol-3-yl) propionic acid (77.75mg, 380.71. mu. mol, 1 eq), DIEA (147.61mg, 1.14mmol, 198.93. mu.L, 3 eq) in i-PrOH (10mL) was stirred at 80 ℃ for 12H. The reaction mixture was concentrated to give (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a brown oil]Pyrimidin-7-yl]Amino group]-3- (1H-indol-3-yl) propionic acid (160mg, 371.72 μmol, 97.6% yield, 100.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 10.69(s，1H)，8.91(s，1H)，8.57(d，J＝2.7Hz，1H)，7.96(d，J＝10.0Hz，1H)，7.88(s，1H)，7.59-7.50(m，2H)，7.19(d，J＝8.1Hz，1H)，7.02-6.94(m，2H)，6.91-6.85(m，1H)，6.29(s，1H)，4.62(s，1H)，3.58-3.54(m，1H)，2.94(s，2H)，2.21(s，3H)；ES-LCMS m/z 431.2[M+H]⁺。

Step 2: (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]-3- (1H-indol-3-yl) -N, N-dimethyl-propionamide (I-187b)

To (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]To a solution of (E) -3- (1H-indol-3-yl) propionic acid (80mg, 183.26. mu. mol, 1 eq) and N-methylmethylamine hydrochloride (29.89mg, 366.52. mu. mol, 2.0 eq) in DMF (20mL) was added HATU (139.36mg, 366.52. mu. mol, 2.0 eq) and Et₃N (92.72mg, 916.30. mu. mol, 127.54. mu.L, 5.0 equiv.). The mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 9min) and then lyophilized to give (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]-3- (1H-indol-3-yl) -N, N-dimethyl-propionamide (17.77mg, 32.74 μmol, 17.9% yield, 97.7% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.73(d，J＝2.3Hz，1H)，8.39(s，1H)，8.11(s，1H)，7.57(d，J＝8.3Hz，1H)，7.45(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，7.01(s，1H)，6.91(t，J＝7.4Hz，1H)，6.84-6.77(m，1H)，5.83(s，1H)，5.40(d，J＝8.5Hz，1H)，3.52(dd，J＝3.0，14.6Hz，1H)，3.31(s，3H)，3.13-3.07(m，1H)，3.04(s，3H)，2.27(s，3H)；ES-LCMS m/z 458.3[M+H]⁺。

Example 151

Synthesis I-192

The synthesis scheme is as follows:

step 1: 3-bromo-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-192)

To 3-bromo-7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (100mg, 305.31. mu. mol, 1 eq.) in i-PrOH (5mL) was added 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (50mg, 310.17 μmol, 1.02 equiv.) and DIEA (118.38mg, 915.92 μmol, 159.54 μ L, 3 equiv.). Mixing the mixture in N₂Stirring was carried out at 60 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN]；B％：25％-55％，9min) and then lyophilized to give 3-bromo-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (37.41mg, 65.74 μmol, 21.5% yield, 98.7% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.11(s，1H)，8.72(d，J＝2.5Hz，1H)，8.50-8.47(m，2H)，8.46(s，1H)，8.12(s，1H)，8.05(s，1H)，7.62(dd，J＝5.9，8.2Hz，1H)，6.69(s，1H)，4.03(t，J＝6.7Hz，2H)，3.39(t，J＝6.8Hz，2H)；ES-LCMS m/z 452.0，454.0[M+H]⁺。

Example 152

Synthesis I-195

The synthesis scheme is as follows:

step 1: n- [2- [4- (methanesulfonamido) phenyl]Ethyl radical]Carbamic acid tert-butyl ester

To the N- [2- (4-aminophenyl) ethyl group]To a solution of tert-butyl carbamate (150mg, 634.76. mu. mol, 1 eq) in DCM (10mL) was added MsCl (327.20mg, 2.86mmol, 221.08. mu.L, 4.5 eq) and TEA (321.16mg, 3.17mmol, 441.76. mu.L, 5 eq). The mixture was stirred at 20 ℃ for 20 hours. The reaction mixture was purified by addition of saturated NaHCO₃Quenched (50mL) and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.37) to yield N- [2- [4- (methanesulfonamido) phenyl ] oil as a colorless oil]Ethyl radical]Tert-butyl carbamate (190mg, 186.13. mu. mol, 29.3% yield, 30.8%)Purity).¹H NMR(400MHz，CDCl₃)δppm 7.25-7.11(m，4H)，6.45(br s，1H)，4.58-4.49(m，1H)，3.37(d，J＝6.8Hz，2H)，3.01(s，3H)，2.79(t，J＝7.0Hz，2H)，1.44(s，9H)；ES-LCMS m/z 337.1[M+Na]⁺。

Step 2: n- [4- (2-aminoethyl) phenyl]Methane sulfonamides

To the N- [2- [4- (methanesulfonamido) phenyl group]Ethyl radical]To a solution of tert-butyl carbamate (190mg, 186.13 μmol, 1 eq) in DCM (3mL) was added TFA (212.23mg, 1.86mmol, 137.81 μ L, 10 eq). The mixture was stirred at 20 ℃ for 20 minutes. TLC (PE/EtOAc ═ 1/1, R_f0.06) showed starting material consumption. The reaction mixture was concentrated under reduced pressure to give crude N- [4- (2-aminoethyl) phenyl ] amine as a yellow oil]Methanesulfonamide (61mg, crude, TFA), which was used in the next step without further purification.

Step 3: n- [4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenyl radical]Methanesulfonamide (I-195)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (48.80mg, 185.80. mu. mol, 1 eq) in i-PrOH (10mL) was added DIEA (120.07mg, 929.01. mu. mol, 161.81. mu.L, 5 eq) and N- [4- (2-aminoethyl) phenyl]Methanesulfonamide (61mg, 185.80. mu. mol, 1 eq, TFA). The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 9min) and subsequent lyophilization to yield N- [4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenyl radical]Methanesulfonamide (50.35mg, 95.81)μ mol, 51.5% yield, 97.7% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.89(s，1H)，8.85(d，J＝2.3Hz，1H)，8.27-8.22(m，1H)，8.14(s，1H)，7.26(d，J＝8.3Hz，2H)，7.08(d，J＝8.5Hz，2H)，6.53(s，1H)，4.01(t，J＝6.7Hz，2H)，3.08(t，J＝6.7Hz，2H)，2.87(s，3H)，2.36(s，3H)；ES-LCMS m/z 441.0[M+H]⁺。

Example 153

Synthesis I-196

The synthesis scheme is as follows:

step 1: 3- [ (E) -2-nitrovinyl group]-1H-pyrrole

To 1H-pyrrole-3-carbaldehyde (1g, 10.52mmol, 1 eq.) in CH₃NO₂NH was added to a solution of (10mL) and THF (10mL)₄OAc (891.60mg, 11.57mmol, 1.1 equiv.). The mixture was stirred at 80 ℃ for 12 hours. TLC (TLC: PE/EtOAc: 3/1, R_f0.45) indicates that no starting material remained and that one major new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.45) to yield the product 3- [ (E) -2-nitrovinyl) as a yellow solid]-1H-pyrrole (1.2g, 7.82mmol, 74.4% yield, 90.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.64(brs，1H)，8.03(d，J＝13.4Hz，1H)，7.44(d，J＝13.3Hz，1H)，7.22(td，J＝1.6，2.8Hz，1H)，6.88(q，J＝2.4Hz，1H)，6.49-6.43(m，1H)。

Step 2: 2- (1H-pyrrol-3-yl) ethylamine

In ice bath to produce 3- [ (E) -2-nitrovinyl group]To a solution of (E) -1H-pyrrole (300mg, 1.95mmol, 1 equiv.) in THF (20mL) was added LiAlH₄(370.96mg, 9.77mmol, 5.0 equiv.). The mixture was stirred at 80 ℃ for 2 hours. TLC (TLC: PE/EtOAc: 3/1, R_f0.56) indicates that no starting material remains and one major new spot with greater polarity is detected. The reaction mixture was cooled down on ice by addition of H₂O (1.5mL), 1N NaOH (1.5mL) and H₂O (1.5mL) was quenched, filtered and concentrated under reduced pressure to give the crude product 2- (1H-pyrrol-3-yl) ethylamine (180mg, 1.63mmol, 83.6% yield, crude purity) as a brown oil, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.12(br s，1H)，6.80-6.72(m，1H)，6.63(d，J＝1.3Hz，1H)，6.14-6.08(m，1H)，2.93-2.85(m，2H)，2.63(t，J＝6.7Hz，2H)。

Step 3: 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (1H-pyrrol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-196)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 190.35. mu. mol, 1 eq) and 2- (1H-pyrrol-3-yl) ethylamine (41.94mg, 380.71. mu. mol, 2.0 eq) in i-PrOH (10mL) was added DIEA (73.81mg, 571.06. mu. mol, 99.47. mu.L, 3.0 eq). The mixture was stirred at 70 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 9min) to give a residue which was purified by preparative HPLC (column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 35% -65%, 10min), followed by lyophilization to give 5-, (b) as a yellow solid5-fluoro-3-pyridinyl) -3-methyl-N- [2- (1H-pyrrol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (15.72mg, 46.73 μmol, 24.6% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.03(s，1H)，8.53(d，J＝2.7Hz，1H)，8.19(d，J＝9.5Hz，2H)，7.87(s，1H)，6.80(d，J＝2.4Hz，1H)，6.72(s，1H)，6.48(br s，1H)，6.27(s，1H)，6.19(br s，1H)，3.69(q，J＝6.4Hz，2H)，2.99(t，J＝6.8Hz，2H)，2.39(s，3H)；ES-LCMSm/z 337.2[M+H]⁺。

Example 154

Synthesis I-197

The synthesis scheme is as follows:

step 1: [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Methanol (I-197)

To 5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino at 0 deg.C]Pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (50mg, 110.71. mu. mol, 1 eq.) in THF (8mL) was added LAH (50mg, 1.32mmol, 11.90 eq.). Mixing the mixture in N₂Stirred at 80 ℃ for 12 hours under an atmosphere. The reaction mixture was diluted with THF (40mL) and quenched at 0 deg.C by the sequential addition of water (0.5mL), 10% NaOH (0.5mL), and water (1.5 mL). After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xbridge 150X 30mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 25% -55%, 8min) and then lyophilized to give [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino) as a yellow solid]Pyrazolo ring[1，5-a]Pyrimidin-3-yl]Methanol (6mg, 14.91 μmol, 13.5% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 8.65(s，1H)，8.47(d，J＝2.7Hz，1H)，8.06(s，1H)，7.74(d，J＝9.8Hz，1H)，7.71-7.66(m，1H)，7.24-7.18(m，1H)，7.12-7.02(m，2H)，6.98(s，1H)，6.00(s，1H)，4.80(s，2H)，3.88(t，J＝6.2Hz，2H)，3.20(t，J＝6.1Hz，2H)；ES-LCMS m/z 403.2[M+H]⁺。

Example 155

Synthesis of I-198a, I-198b and I-198c

The synthesis scheme is as follows:

step 1: (3R) -N- [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

Reacting 3-bromo-7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]A mixture of pyrimidine (440mg, 1.34mmol, 1 eq), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (274.54mg, 1.47mmol, 1.1 eq) and DIEA (519.56mg, 4.02mmol, 700.21. mu.L, 3 eq) in i-PrOH (10mL) was stirred at 80 ℃ for 12H. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 2/1, TLC: PE/EtOAc: 2/1, R_f0.25) to give (3R) -N- [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (520mg, 1.06mmol, 79.2% yield, 97.4% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.76(s，1H)，9.30(s，1H)，8.65(d，J＝2.9Hz，1H)，8.46(td，J＝2.2，10.4Hz，1H)，8.32-8.24(m，2H)，7.33(d，J＝7.5Hz，1H)，7.24(d，J＝7.9Hz，1H)，7.15(s，1H)，7.02-6.86(m，2H)，4.49(td，J＝4.8，9.4Hz，1H)，3.14-2.98(m，2H)，2.94-2.79(m，2H)，2.23-2.10(m，2H)；ES-LCMS m/z 477.1，479.1[M+H]⁺。

Step 2: (3R) -3- [ [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Reacting (3R) -N- [ 3-bromo-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (500mg, 1.02mmol, 1 equiv.), Boc₂A mixture of O (556.67mg, 2.55mmol, 585.97 μ L, 2.5 equivalents) and DMAP (373.93mg, 3.06mmol, 3 equivalents) in 1, 4-dioxane (10mL) was stirred at 110 ℃ for 5 hours. The reaction mixture was concentrated to give a residue which was purified by flash chromatography on silica gel (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 3/1, R_f0.7) to give (3R) -3- [ [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (600mg, 664.15 μmol, 65.1% yield, 75.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.06(s，1H)，8.60(d，J＝3.0Hz，1H)，8.26-8.18(m，2H)，8.06(d，J＝8.0Hz，1H)，7.29(s，1H)，7.25-7.13(m，3H)，4.86-4.76(m，1H)，3.26-3.16(m，2H)，2.66(d，J＝10.5Hz，1H)，2.36(m，1H)，2.10-1.92(m，2H)，1.64(s，9H)，1.34(s，9H)；ES-LCMS m/z 677.2，679.2[M+H]⁺。

Step 3: (3R) -3- [ [ 3-acetyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Reacting (3R) -3- [ [ 3-bromo-5-)(5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonyl-amino]-tert-butyl 1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (550mg, 608.80. mu. mol, 1 eq.), tributyl (1-ethoxyvinyl) stannane (1.02g, 2.82mmol, 953.27. mu.L, 4.64 eq.), and Pd (dppf) Cl₂(89.09mg, 121.76. mu. mol, 0.2 eq.) in toluene (8mL) was placed in a microwave tube and then treated with N₂And purifying for 1 minute. The sealed tube was heated at 120 ℃ for 5 hours under microwave (1 bar). To the mixture was added aqueous KF solution (10mL, 1g/10 mL). The mixture was stirred at 25 ℃ for 30 min and extracted with EtOAc (30 mL. times.3). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated to give a residue which was purified by flash chromatography on silica gel (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 3/1, R_f0.45) to give (3R) -3- [ [ 3-acetyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-tert-butoxycarbonylamino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (340mg, 524.83 μmol, 91.0% yield, 98.9% purity).¹H NMR(400MHz，CDCl₃)δppm 9.12(s，1H)，8.73(s，1H)，8.64(d，J＝2.5Hz，1H)，8.15(d，J＝9.5Hz，1H)，8.05(d，J＝8.0Hz，1H)，7.28(s，1H)，7.25-7.19(m，1H)，7.18-7.13(m，1H)，4.83(s，1H)，3.27-3.11(m，3H)，2.90(s，3H)，2.72-2.62(m，1H)，2.37(s，1H)，2.13-2.06(m，1H)，2.05(s，1H)，1.64(s，9H)，1.34(s，9H)；ES-LCMS m/z 641.4[M+H]⁺。

Step 4: 1- [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanones

To (3R) -3- [ [ 3-acetyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]To a solution of tert-butyl (340mg, 524.83 μmol, 1 eq) 1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate in DCM (8mL) was added TFA (3.08g, 27.01mmol, 2mL, 51.47 eq). The reaction mixture was stirred at 20 ℃ for 30 minutes. Mixing the reactionThe compound was concentrated. The residue was dissolved in water (10mL) and saturated NaHCO was used₃The aqueous solution was basified until pH 8 and extracted with DCM (30mL × 3). The organic layer was washed with Na₂SO₄Drying, filtering and concentrating to obtain 1- [5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanone (250mg, 515.36 μmol, 98.2% yield, 90.8% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.11(s，1H)，8.58(d，J＝2.9Hz，1H)，8.49(s，1H)，8.20(td，J＝2.4，9.4Hz，1H)，7.90(s，1H)，7.44(d，J＝7.9Hz，1H)，7.33(d，J＝8.2Hz，1H)，7.17(t，J＝7.6Hz，1H)，7.13-7.07(m，1H)，6.76(d，J＝8.4Hz，1H)，6.63(s，1H)，4.34(s，1H)，3.38(dd，J＝4.9，15.0Hz，1H)，3.02-2.91(m，3H)，2.84(s，3H)，2.35(m，1H)，2.31-2.23(m，1H)；ES-LCMS m/z441.3[M+H]⁺。

Step 5: (1R) -1- [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (I-198a) and (1S) -1- [5- (5-fluoro-3-pyridinyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (I-198b)

To 1- [5- (5-fluoro-3-pyridyl) -7- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] at 20 deg.C]Amino group]Pyrazolo [1, 5-a]Pyrimidin-3-yl]A solution of ethanone (100mg, 206.14. mu. mol, 1 eq) in MeOH (2.5mL) and EtOH (2.5mL) was added NaBH in portions₄(31.19mg, 824.57. mu. mol, 4 equiv.). The reaction mixture was stirred at 20 ℃ for 0.5 h. Addition of H₂O (10mL) quenched the reaction and was extracted with DCM (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to give a residue which is purified by preparative HPLC (column: Gemini 150X 255 u; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 55% -70%, 8min) and then freeze-drying to obtain the final productEnantiomer (12.50mg, 28.25 μmol, 13.7% yield, 100.0% purity) as a yellow solid (SFC: Rt 6.742, ee 100%).¹H NMR(400MHz，DMSO-d₆)δppm 10.79(s，1H)，9.34(s，1H)，8.66(d，J＝2.8Hz，1H)，8.50(td，J＝2.2，10.4Hz，1H)，8.12(s，1H)，7.99(d，J＝9.3Hz，1H)，7.37(d，J＝7.8Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.07(s，1H)，7.04-6.98(m，1H)，6.97-6.91(m，1H)，5.20-5.12(m，1H)，5.05(d，J＝4.5Hz，1H)，4.50(d，J＝8.8Hz，1H)，3.18-3.00(m，2H)，2.98-2.82(m，2H)，2.24-2.13(m，2H)，1.57(d，J＝6.3Hz，3H)；ES-LCMS m/z 443.2[M+H]⁺(ii) a And the other enantiomer as a yellow solid (18.17mg, 40.22 μmol, 19.5% yield, 97.9% purity) (SFC: Rt ═ 5.398, ee ═ 82.9%).¹H NMR(400MHz，DMSO-d₆)δppm 10.75(s，1H)，9.30(s，1H)，8.62(d，J＝2.7Hz，1H)，8.50-8.43(m，1H)，8.08(s，1H)，7.95(d，J＝9.3Hz，1H)，7.32(d，J＝7.8Hz，1H)，7.24(d，J＝7.8Hz，1H)，7.03(s，1H)，7.00-6.94(m，1H)，6.93-6.87(m，1H)，5.16-5.08(m，1H)，4.99(d，J＝4.4Hz，1H)，4.46(d，J＝8.8Hz，1H)，3.13-2.98(m，2H)，2.92-2.79(m，2H)，2.14(m，2H)，1.53(d，J＝6.4Hz，3H)；ES-LCMS m/z 443.2[M+H]⁺。

Example 156

Synthesis of I-200

The synthesis scheme is as follows:

step 1: 5-fluoro-N' - (1H-pyrazol-5-yl) pyridine-3-carboxamidine

5-Fluoropyridine-3-carbonitrile (1g, 7.78mmol, 1 mm)Amount) and 1H-pyrazol-5-amine (775.80mg, 9.34mmol, 1.2 equiv.) in xylene (15mL) were stirred at 70 ℃ for 30 minutes, followed by the one-shot addition of AlMe at 70 ℃₃(2M, 7.78mL, 2 equiv) (2M in toluene, 19.45mL, 1 equiv). The mixture was stirred at 100 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (DCM/MeOH ═ 100/1 to 10/1, TLC: DCM/MeOH ═ 10/1, R_f0.3) to yield 5-fluoro-N' - (1H-pyrazol-5-yl) pyridine-3-carboxamidine as a yellow solid (700mg, 2.73mmol, 35.1% yield, 80.0% purity).¹H NMR(400MHz，CD₃OD)δppm 8.89(s，1H)，8.59(d，J＝2.7Hz，1H)，8.06(d，J＝9.3Hz，1H)，7.56(d，J＝2.2Hz，1H)，6.16(d，J＝2.2Hz，1H)；ES-LCMS m/z206.3[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazine-4-ols

A mixture of 5-fluoro-N' - (1H-pyrazol-5-yl) pyridine-3-carboxamidine (600mg, 2.34mmol, 1 eq.), CDI (758.62mg, 4.68mmol, 2 eq.), and DMAP (142.89mg, 1.17mmol, 0.5 eq.) in DMSO (10mL) was stirred at 130 ℃ for 12 hours. The mixture was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 15% -43%, 9min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-ol (150mg, 627.42 μmol, 26.8% yield, 96.7% purity).¹H NMR(400MHz，CD₃OD)δppm 9.17(s，1H)，8.82(d，J＝2.4Hz，1H)，8.55-8.36(m，1H)，8.10(d，J＝2.0Hz，1H)，6.65(d，J＝2.0Hz，1H)；ES-LCMS m/z 232.1[M+H]⁺。

Step 3: 4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazine

2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-ol (150mg, 627.42. mu. mol, 1 eq.) and N, N-dimethylaniline (304.12mg, 2.51mmol, 318.12. mu.L, 4 eq.) in POCl₃(59.33g, 386.94mmol, 35.96mL, 616.72 equiv.) the mixture was degassed and treated with N₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with ice water followed by addition of saturated NaHCO₃To the above solution until pH 8, extract with EtOAc (30mL × 3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAC ═ 100/1 to 3/1, TLC: PE/EtOAC ═ 3/1, R_f0.5) to give 4-chloro-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazine (50mg, 172.65 μmol, 27.5% yield, 86.2% purity).¹H NMR(400MHz，CDCl₃)δppm9.51(s，1H)，8.65(d，J＝2.7Hz，1H)，8.50-8.42(m，1H)，8.34(d，J＝2.2Hz，1H)，6.86(d，J＝2.2Hz，1H)；ES-LCMS m/z 250.0，252.1[M+H]⁺。

Step 4: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-200)

4-chloro-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]A mixture of triazine (50mg, 172.65. mu. mol, 1 eq), 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (57.03mg, 224.45. mu. mol, 1.3 eq, HCl) and DIEA (111.57mg, 863.27. mu. mol, 150.37. mu.L, 5 eq) in i-PrOH (2mL) was degassed and N was used₂And purifying for 3 times. The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN]；B％：55％-85％，9min) and then lyophilized to give N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl ] as a white solid]-2- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (19.54mg, 40.85 μmol, 23.7% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.15(s，1H)，8.53(d，J＝2.9Hz，1H)，8.12(d，J＝9.5Hz，1H)，8.05(d，J＝2.0Hz，1H)，7.33(d，J＝7.8Hz，1H)，6.86(dt，J＝4.6，7.8Hz，1H)，6.61(dd，J＝7.8，11.2Hz，1H)，6.43(d，J＝2.0Hz，1H)，3.98(t，J＝6.8Hz，2H)，3.13(t，J＝6.8Hz，2H)，2.26(s，3H)；ES-LCMS m/z 406.1[M+H]⁺。

Example 157

Synthesis I-201

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-201)

Reacting 4-chloro-2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (11mg, 24.27. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (5.43mg, 29.13. mu. mol, 1.2 equivalents) and DIEA (15.69mg, 121.37. mu. mol, 21.14. mu.L, 5 equivalents) in i-PrOH (2mL) was stirred at 80 ℃ for 12H. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 60% -90%, 9min) and then lyophilized to give (3R) -N- [2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (4.32mg, 8.72 μmol, 35.9% yield, 98.2% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.48(s，1H)，8.94(d，J＝9.2Hz，1H)，8.82(br s，1H)，7.96(s，1H)，7.34(d，J＝7.6Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.04-6.98(m，1H)，6.96-6.90(m，1H)，4.86(m，1H)，3.25(d，J＝5.6Hz，1H)，3.12-2.84(m，3H)，2.40-2.33(m，1H)，2.32(s，3H)，2.29-2.17(m，1H)；ES-LCMS m/z 414.2[M+H]⁺。

Example 158

Synthesis I-202

The synthesis scheme is as follows:

step 1: 5-fluoro-N' - (4-methyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine

A mixture of 5-fluoropyridine-3-carbonitrile (1g, 6.55mmol, 1 eq) and 4-methyl-1H-pyrazol-5-amine (707.02mg, 6.55mmol, 1 eq) in xylene (10mL) was stirred at 70 ℃ for 0.5H. Followed by the reaction of AlMe at 100 ℃₃(2M, 3.93mL, 1.2 equiv.) was added to the mixture in one portion. The mixture was stirred at 100 ℃ for 16 hours. The mixture was quenched with MeOH (30mL) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH ═ 1/0 to 5/1, TLC: DCM/MeOH ═ 5/1, R_f0.40) to yield the product 5-fluoro-N' - (4-methyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine as a yellow oil (1.09g, 3.86mmol, 58.9% yield, 77.7% purity).¹H NMR(400MHz，CD₃OD)δppm 8.98(s，1H)，8.60(d，J＝2.4Hz，1H)，7.38(s，1H)，7.17(s，1H)，2.14(s，3H)；ES-LCMSm/z 220.2[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazine-4-ols

A mixture of 5-fluoro-N' - (4-methyl-1H-pyrazol-5-yl) pyridine-3-carboxamidine (600mg, 2.46mmol, 1 eq.), CDI (799.20mg, 4.93mmol, 2 eq.), and DMAP (301.07mg, 2.46mmol, 1 eq.) in DMSO (15mL) was placed in N₂Stirring was carried out at 130 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 14% -44%, 9min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-ol (120mg, 412.82 μmol, 16.8% yield, 96.9% purity, HCl).¹H NMR(400MHz，CD₃OD)δppm 9.12(s，1H)，8.72(s，1H)，8.34(s，1H)，7.95(s，1H)，2.28(s，3H)；ES-LCMS m/z246.1[M+H]⁺。

Step 3: 4-chloro-2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazine

2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-ol (150mg, 422.79. mu. mol, 1 eq, 2HCl), N-dimethylaniline (69.12mg, 570.36. mu. mol, 72.30. mu.L, 1.35 eq) and POCl₃(11.40g, 74.38mmol, 6.91mL, 175.91 equivalents) was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure. Ice water (50mL) was added to the residue. NaHCO for the mixture₃Basified until pH 8 and extracted with EtOAc (50mL × 3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 2/1, TLC: PE/EtOAc: 2/1, R_f0.40) to yield 4-chloro-2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazine (100mg, 379.28 μmol, 89.7% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.52(s，1H)，8.63(d，J＝2.8Hz，1H)，8.46(d，J＝9.2Hz，1H)，8.19(s，1H)，2.44(s，3H)；ES-LCMS m/z 264.0，266.0[M+H]⁺。

Step 4: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-202)

Reacting 4-chloro-2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (20mg, 75.86. mu. mol, 1 eq), 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (21.20mg, 83.44. mu. mol, 1.1 eq, HCl) and DIEA (49.02mg, 379.28. mu. mol, 66.06. mu.L, 5 eq) in i-PrOH (2mL) was stirred at 90 ℃ for 10 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 9min) to obtain N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl) as a yellow solid]-2- (5-fluoro-3-pyridinyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (4.66mg, 9.21. mu. mol, 12.1% yield, 97.3% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.17(s，1H)，8.53(d，J＝2.0Hz，1H)，8.18(d，J＝8.8Hz，1H)，7.88(s，1H)，7.33(d，J＝7.6Hz，1H)，6.92-6.76(m，1H)，6.60(dd，J＝7.6，11.2Hz，1H)，3.95(t，J＝6.8Hz，2H)，3.10(t，J＝6.8Hz，2H)，2.27(s，3H)，2.23(s，3H)；ES-LCMS m/z 420.2[M+H]⁺。

Example 159

Synthesis I-203

The synthesis scheme is as follows:

step 1: n- (4-Nitro-1H-pyrazol-5-yl) carbamic acid tert-butyl ester

To a solution of 4-nitro-1H-pyrazole-5-carboxylic acid (14g, 89.12mmol, 1 eq) in toluene (280mL) at 25 deg.C were added TEA (22.55g, 222.81mmol, 31.01mL, 2.5 eq) and DPPA (26.98g, 98.04mmol, 21.24mL, 1.1 eq). The mixture was stirred at 25 ℃ for 1.5 hours. t-BuOH (66.06g, 891.24mmol, 85.24mL, 10 equiv.) was added to the above solution and the mixture was stirred under N₂Stirring was continued at 130 ℃ for 12 hours. TLC (PE/EtOAc ═ 1/1, R_f0.49) showed complete consumption of starting material and formation of the main spot. The reaction mixture was purified by addition of saturated NaHCO₃Quenched (100mL) and extracted with EtOAc (80 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.49) to yield tert-butyl N- (4-nitro-1H-pyrazol-5-yl) carbamate as a white solid (6.0g, 21.03mmol, 23.6% yield, 80% purity).¹H NMR(400MHz，DMSO-d₆)δppm 13.80-13.47(m，1H)，9.35(br s，1H)，8.58-7.94(m，1H)，1.44(br s，9H)。

Step 2: n- (4-amino-1H-pyrazol-5-yl) carbamic acid tert-butyl ester

N- (4-Nitro-1H-pyrazol-5-yl) carbamic acid tert-butyl ester (5g, 17.53mmol, 1 eq), Raney's nickel (5g in water) and NH₃·H₂O(2.19g，17.53mmol，2.41mL, 28%, 1 eq) in MeOH (100mL) and degassed with H₂Purifying for 3 times, and adding the mixture in H₂(15psi) at 20 ℃ for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product tert-butyl N- (4-amino-1H-pyrazol-5-yl) carbamate (3.47g, 16.44mmol, 93.7% yield, 93.9% purity) as a purple solid, which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 11.65(br s，1H)，8.76(br s，1H)，7.00(s，1H)，3.50(br s，2H)，1.50-1.36(m，9H)；ES-LCMS m/z 143.1[M-t-Bu+H]⁺。

Step 3: n- [4- (dimethylamino) -1H-pyrazol-5-yl]Carbamic acid tert-butyl ester

To a solution of tert-butyl N- (4-amino-1H-pyrazol-5-yl) carbamate (1.5g, 7.11mmol, 1 eq) in MeOH (30mL) was added HCHO (938.76mg, 31.26mmol, 4.4 eq) and NaBH₃CN (4.47g, 71.06mmol, 10 equiv.). The mixture was stirred at 50 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was quenched by addition of water (100mL) and extracted with EtOAc (80mL × 3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 0/1, TLC: PE/EtOAc: 1/1, R_f0.20) to yield N- [4- (dimethylamino) -1H-pyrazol-5-yl) as a reddish brown oil]Tert-butyl carbamate (1.2g, 3.87mmol, 54.4% yield, 73.0% purity).¹H NMR(400MHz，CD₃OD)δppm 7.29(s，1H)，2.64(s，6H)，1.49(s，9H)。

Step 4: n4, N4-dimethyl-1H-pyrazole-4, 5-diamine

Mixing N- [4- (dimethylamino)-1H-pyrazol-5-yl]A mixture of tert-butyl carbamate (1.2g, 3.87mmol, 1 eq) in HCl/MeOH (4M, 15mL) was degassed and N was used₂Purifying for 3 times, and adding the mixture in N₂Stirring was carried out at 15 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product N4, N4-dimethyl-1H-pyrazole-4, 5-diamine (629mg, crude, HCl) as a white solid, which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm8.47(s，1H)，3.32(s，6H)。

Step 5: 3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

N4, N4-dimethyl-1H-pyrazole-4, 5-diamine (300mg, 1.57mmol, 1 eq, HCl) was dissolved in MeOH (10mL) followed by adjustment of the pH to 9-10 by 2N aqueous NaOH. The mixture was concentrated under reduced pressure to give a residue. The residue and (z) -3- (5-fluoro-3-pyridyl) -3-hydroxy-prop-2-enoic acid methyl ester (332.44mg, 1.57mmol, 1 eq) in AcOH (15mL) were stirred at 120 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product 3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a as a yellow solid]Pyrimidin-7-ol (616mg, crude, 2HOAC), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 10.71(s，1H)，9.05(s，1H)，8.89(d，J＝1.5Hz，1H)，8.30(s，1H)，7.97(s，1H)，6.37(s，1H)，2.72-2.52(m，6H)；ES-LCMSm/z 274.2[M+H]⁺。

Step 6: 7-chloro-5- (5-fluoro-3-pyridinyl) -N, N-dimethyl-pyrazolo [1, 5-a]Pyrimidin-3-amines

Reacting 3- (dimethylamino) -5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (616mg, 1.57mmol, 1 eq, 2HOAC) in POCl₃(16.50g, 10mL) solution was strippedGas and with N₂Purifying for 3 times, and adding the mixture in N₂Stirred under an atmosphere at 110 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was quenched by addition of ice water (100mL) at 0 ℃ by saturated NaHCO₃The pH was adjusted to 9-10 and extracted with EtOAc (80 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 3/1, R_f0.21) to yield 7-chloro-5- (5-fluoro-3-pyridinyl) -N, N-dimethyl-pyrazolo [1, 5-a) as a red solid]Pyrimidin-3-amine (190mg, 651.33 μmol, 41.5% yield, 100% purity).¹H NMR(400MHz，CDCl₃)δppm 9.08(s，1H)，8.57(d，J＝2.8Hz，1H)，8.18-8.10(m，1H)，7.87(s，1H)，7.30(s，1H)，3.10(s，6H)；ES-LCMS m/z 292.2，294.2[M+H]⁺。

Step 7: 5- (5-fluoro-3-pyridinyl) -N7- [2- (1H-indol-3-yl) ethyl]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamine (I-203)

To 7-chloro-5- (5-fluoro-3-pyridyl) -N, N-dimethyl-pyrazolo [1, 5-a]To a solution of pyrimidin-3-amine (40mg, 137.12 μmol, 1 eq) in i-PrOH (5mL) was added DIEA (53.17mg, 411.37 μmol, 71.65 μ L, 3 eq) and 2- (1H-indol-3-yl) ethylamine (28.56mg, 178.26 μmol, 1.3 eq). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena GeminiC 18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 25% -55%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N7- [2- (1H-indol-3-yl) ethyl ] as a yellow solid]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamine (27.03mg, 55.35. mu. mol, 40.3% yield, 100% purity, 2 HCl).¹HNMR(400MHz，CD₃OD)δppm 8.87(d，J＝1.0Hz，1H)，8.82(d，J＝1.2Hz，1H)，8.36(s，1H)，8.17-8.12(m，1H)，7.71-7.67(m，1H)，7.17-7.11(m，1H)，7.07-7.00(m，2H)，6.98(s，1H)，6.18(s，1H)，3.96(t，J＝6.1Hz，2H)，3.48(s，6H)，3.21(t，J＝6.0Hz，2H)；ES-LCMS m/z416.1[M+H]⁺。

Example 160

Synthesis I-204a

The synthesis scheme is as follows:

step 1: (2E) -2-hydroxyimino-5-methoxy-indan-1-one

A solution of 5-methoxyindan-1-one (5g, 30.83mmol, 1 equiv.) in MeOH (500mL) is heated to 45 deg.C and isoamyl nitrite (5.42g, 46.24mmol, 6.23mL, 1.5 equiv.) and concentrated HCl (12M, 5.14mL, 2 equiv.) are added. The mixture was stirred at 45 ℃ for 2 hours. The mixture was concentrated under reduced pressure to give a residue and MeOH (30mL) was added. The slurry was filtered and dried in vacuo to give (2E) -2-hydroxyimino-5-methoxy-indan-1-one (5.0g, 22.75mmol, 73.8% yield, 87.0% purity) as a brown solid, which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 12.47(s，1H)，7.68(d，J＝8.5Hz，1H)，7.14(d，J＝2.0Hz，1H)，7.01(dd，J＝2.3，8.5Hz，1H)，3.92-3.84(m，3H)，3.71(s，2H)；ES-LCMS m/z 192.1[M+H]⁺。

Step 2: (2R) -5-methoxyindan-2-amine

To (2E) -2-hydroxyimino-5-methoxy-indan-1-one (5g, 22.75mmol, 1 eq) in AcOH (250mL) and concentrated H₂SO₄To the solution in (3.5mL) was added Pd/C (1g, 10%). Mixing the mixture in H₂(15psi) at 25 ℃ for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was poured into ice water (200mL), adjusted to pH 10-11 with 2N NaOH and extracted with EtOAc (150 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude 5-methoxyindan-2-amine (2.0g, 11.48mmol, 50.4% yield, 93.7% purity) as a brown solid. 5-Methoxyindan-2-amine (1g, 5.74mmol) was passed through chiral SFC (column: AD-3_ EtOH (DEA), AD (250 mm. times.30 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O IPA](ii) a B%: 55% -55%, min) to give (2R) -5-methoxyindan-2-amine (220mg, 1.35mmol, 23.4% yield, 100% purity) (R) as a brown oil_t＝3.581min，ee＝100％，[α]²² _D＝24.733(13.5mg/10mL，CHCl₃))。¹H NMR(400MHz，CDCl₃)δppm 7.11(d，J＝8.2Hz，1H)，6.78(s，1H)，6.72(dd，J＝2.5，8.3Hz，1H)，3.88-3.81(m，1H)，3.79(s，3H)，3.15(dt，J＝6.7，14.6Hz，2H)，2.71-2.59(m，2H)；ES-LCMS m/z 164.2[M+H]⁺. And (2S) -5-methoxyindan-2-amine (350mg, 2.14mmol, 37.3% yield, 100% purity) as a brown oil (R)_t＝3.762min，ee＝100％，[α]²² _D＝-16.666(10.3mg/10mL，CHCl₃))。¹H NMR(400MHz，CDCl₃)δppm7.11(d，J＝7.9Hz，1H)，6.78(s，1H)，6.72(dd，J＝2.5，8.3Hz，1H)，3.87-3.81(m，1H)，3.79(s，3H)，3.15(dt，J＝6.8，14.7Hz，2H)，2.71-2.57(m，2H)；ES-LCMS m/z 164.2[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -N7- [ (2R) -5-methoxyindan-2-yl]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamines

To 7-chloro-5- (5-fluoro-3-pyridyl) -N, N-dimethyl-pyrazolo [1, 5-a]To a solution of pyrimidin-3-amine (50mg, 171.40 μmol, 1 eq) in i-proH (5mL) was added DIEA (66.46mg, 514.21 μmol, 89.56 μ L, 3 eq) and (2R) -5-methoxyindan-2-amine (36.37mg, 222.82 μmol, 1.3 eq). The mixture was stirred at 70 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude 5- (5-fluoro-3-pyridinyl) -N7- [ (2R) -5-methoxyindan-2-yl as a red brown oil]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamine (71mg, 123.18 μmol, 71.9% yield, 72.6% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.01(s，1H)，8.44(d，J＝2.7Hz，1H)，8.17-8.10(m，1H)，7.58(s，1H)，7.10(d，J＝8.3Hz，1H)，6.75(s，1H)，6.71(dd，J＝2.3，8.2Hz，1H)，6.43(d，J＝7.6Hz，1H)，6.29(s，1H)，4.63-4.55(m，1H)，3.73(s，3H)，3.58-3.54(m，2H)，3.46-3.37(m，2H)，2.93(s，6H)；ES-LCMSm/z 419.2[M+H]⁺。

Step 4: (2R) -2- [ [3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-204a)

In N₂Reacting 5- (5-fluoro-3-pyridyl) -N7- [ (2R) -5-methoxyindan-2-yl group under an atmosphere]-N3, N3-dimethyl-pyrazolo [1, 5-a]A solution of pyrimidine-3, 7-diamine (71mg, 123.18. mu. mol, 1 equiv.) in aqueous HBr (5mL, 60%) was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 23% -53%, 8min) and then lyophilized to give (2R) -2- [ [3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (33.84mg, 67.84. mu. mol, 55.1% yield, 95.7% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.68(s，1H)，9.31(d，J＝9.0Hz，1H)，9.12(s，1H)，8.43(s，1H)，7.24(s，1H)，7.07(d，J＝8.1Hz，1H)，6.72(s，1H)，6.65(d，J＝8.1Hz，1H)，4.97-4.94(m，1H)，3.54(s，6H)，3.52-3.43(m，2H)，3.19-3.02(m，2H)；ES-LCMS m/z 405.2[M+H]⁺。

Example 161

Synthesis I-204b

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N7- [ (2S) -5-methoxyindan-2-yl]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamines

To 7-chloro-5- (5-fluoro-3-pyridyl) -N, N-dimethyl-pyrazolo [1, 5-a]To a solution of pyrimidin-3-amine (50mg, 171.40 μmol, 1 eq) in i-proH (5mL) was added DIEA (66.46mg, 514.20 μmol, 89.56 μ L, 3 eq) and (2S) -5-methoxyindan-2-amine (27.98mg, 171.40 μmol, 1 eq). The mixture was stirred at 70 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude 5- (5-fluoro-3-pyridinyl) -N7- [ (2S) -5-methoxyindan-2-yl group as a red brown oil]-N3, N3-dimethyl-pyrazolo [1, 5-a]Pyrimidine-3, 7-diamine (71mg, 128.27 μmol, 74.8% yield, 75.6% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.12-9.05(m，1H)，8.52(d，J＝2.7Hz，1H)，8.21(td，J＝2.2，9.8Hz，1H)，7.66(s，1H)，7.18(d，J＝8.3Hz，1H)，6.86-6.76(m，2H)，6.51(d，J＝7.6Hz，1H)，6.37(s，1H)，4.72-4.57(m，1H)，3.81(s，3H)，3.66(d，J＝4.9Hz，2H)，3.50(ddd，J＝7.0，12.6，15.9Hz，2H)，3.01(s，6H)；ES-LCMS m/z 419.2[M+H]⁺。

Step 2: (2S) -2- [ [3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-204b)

Reacting 5- (5-fluoro-3-pyridyl) -N7- [ (2S) -5-methoxyindan-2-yl]-N3, N3-dimethyl-pyrazolo [1, 5-a]A solution of pyrimidine-3, 7-diamine (71mg, 128.27. mu. mol, 1 equiv.) in aqueous HBr (5mL, 60%) was stirred at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 8min) and then lyophilized to give (2S) -2- [ [3- (dimethylamino) -5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (32.5mg, 77.95. mu. mol, 60.7% yield, 97.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.64(s，1H)，9.25(d，J＝9.3Hz，1H)，9.08(s，1H)，8.43(s，1H)，7.22(s，1H)，7.08(d，J＝8.1Hz，1H)，6.72(s，1H)，6.65(d，J＝8.1Hz，1H)，4.97-4.92(m，1H)，3.54(s，6H)，3.44-3.41(m，2H)，3.18-3.03(m，2H)；ES-LCMS m/z 405.2[M+H]⁺。

Example 162

Synthesis I-208

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-208)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]Pyrimidine (60mg, 225.62. mu. mol, 1 equiv.), 2- (1H-pyrrolo [3, 2-b ]]A mixture of pyridin-3-yl) ethylamine (43.65mg, 270.75. mu. mol, 1.2 equivalents), DIEA (87.48mg, 676.87. mu. mol, 117.90. mu.L, 3 equivalents) in i-PrOH (10mL) was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 5% -35%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-pyrrolo [3, 2-b) as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (37.11mg, 75.38. mu. mol, 33.4% yield, 98.7% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.99(s，1H)，8.82(s，1H)，8.56-8.50(m，2H)，8.35(d，J＝8.8Hz，1H)，8.26(s，1H)，8.10(s，1H)，7.69-7.63(m，1H)，7.04(s，1H)，6.65(d，J＝2.0Hz，1H)，4.22-4.13(m，2H)，3.46(t，J＝6.6Hz，2H)；ES-LCMS m/z 374.2[M+H]⁺。

Example 163

Synthesis I-209

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-methyl-N- [2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-209)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidine (60mg, 228.42. mu. mol, 1 equivalent) in i-PrOHTo a solution (5mL) were added DIEA (88.56mg, 685.27. mu. mol, 119.36. mu.L, 3 equivalents) and 2- (1H-pyrrolo [3, 2-b ]]Pyridin-3-yl) ethylamine (45mg, 279.15. mu. mol, 1.22 eq). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 15% -45%, 9 min). Lyophilizing the desired fractions to obtain 5- (5-fluoro-3-pyridyl) -3-methyl-N- [2- (1H-pyrrolo [3, 2-b ] as a yellow solid]Pyridin-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (28.89mg, 56.64 μmol, 24.8% yield, 97.4% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.94(s，1H)，8.79(d，J＝2.7Hz，1H)，8.57-8.50(m，2H)，8.31-8.24(m，1H)，8.09(d，J＝7.6Hz，2H)，7.71-7.63(m，1H)，6.80(s，1H)，4.12(t，J＝7.0Hz，2H)，3.43(t，J＝6.8Hz，2H)，2.37(s，3H)；ES-LCMS m/z 388.2[M+H]⁺。

Example 164

Synthesis I-210

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridyl) -N- [2- (3-methoxyphenyl) ethyl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 190.35. mu. mol, 1 eq) in i-PrOH (3mL) was added 2- (3-methoxyphenyl) ethylamine (43.17mg, 285.53. mu. mol, 41.92. mu.L, 1.5 eq) and DIEA (73.81mg, 571.06. mu. mol, 99.47. mu.L, 3 eq). Mixing the mixture in N₂Under the atmosphere ofStirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give 5- (5-fluoro-3-pyridyl) -N- [2- (3-methoxyphenyl) ethyl group as a yellow solid]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (70mg, 185.47 μmol, 97.4% yield), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 9.01(s，1H)，8.54(d，J＝2.5Hz，1H)，8.25-8.18(m，1H)，7.89(s，1H)，7.18-7.10(m，1H)，6.89-6.83(m，2H)，6.73-6.65(m，1H)，6.36(s，1H)，3.83(t，J＝6.8Hz，2H)，3.67(s，3H)，3.03(t，J＝6.8Hz，2H)，2.33(s，3H)；ES-LCMS m/z 378.2[M+H]⁺。

Step 2: 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (I-210)

Reacting 5- (5-fluoro-3-pyridyl) -N- [2- (3-methoxyphenyl) ethyl]-3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidin-7-amine (70mg, 185.47. mu. mol, 1 eq.) and aqueous HBr (4.47g, 33.15mmol, 3mL, 60% purity, 178.72 eq.) was degassed and treated with N₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 120 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10min) and then lyophilized to give 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (40.74mg, 93.37 μmol, 50.3% yield, 100% purity, 2 HCl).¹H NMR(400MHz，CO₃OD)δppm 8.87-8.85(m，2H)，8.22(d，J＝8.8Hz，1H)，8.14(s，1H)，7.06-6.95(m，1H)，6.77-6.68(m，2H)，6.60-6.51(m，1H)，6.44(s，1H)，4.01(t，J＝6.5Hz，2H)，3.02(t，J＝6.4Hz，2H)，2.36(s，3H)；ES-LCMS m/z 364.1[M+H]⁺。

Example 165

Synthesis I-211

The synthesis scheme is as follows:

step 1: n- [2- (4-aminophenyl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-211)

To a solution of 4- (2-aminoethyl) aniline (25.92mg, 190.35 μmol, 1 eq) in i-PrOH (3mL) was added 7-chloro-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a [ ] -]Pyrimidine (50mg, 190.35. mu. mol, 1 equivalent) and DIEA (73.81mg, 571.06. mu. mol, 99.47. mu.L, 3 equivalents). The mixture was stirred at 50 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 20% -50%, 8min) and then freeze-dried to give N- [2- (4-aminophenyl) ethyl group as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (73.99mg, 155.10 μmol, 81.5% yield, 98.9% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.94(s，1H)，8.80(d，J＝2.7Hz，1H)，8.28(td，J＝2.4，8.9Hz，1H)，8.11(s，1H)，7.54(d，J＝8.6Hz，2H)，7.35(d，J＝8.3Hz，2H)，6.80(s，1H)，4.02(t，J＝7.2Hz，2H)，3.19(t，J＝7.2Hz，2H)，2.37(s，3H)；ES-LCMS m/z 363.3[M+H]⁺。

Example 166

Synthesis I-213

The synthesis scheme is as follows:

step 1: 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (I-213)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (60mg, 228.42. mu. mol, 1 eq.) and 4- (2-aminoethyl) phenol (37.60mg, 274.11. mu. mol, 1.2 eq.) in i-PrOH (12mL) was added DIEA (88.57mg, 685.27. mu. mol, 119.36. mu.L, 3 eq.). Mixing the mixture in N₂Stirred at 75 ℃ for 19 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 9min) and then lyophilized to give 4- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Phenol (55.37mg, 126.91. mu. mol, 55.6% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.84(br s，2H)，8.23-8.12(m，2H)，7.06(d，J＝8.6Hz，2H)，6.63-6.57(m，2H)，6.36(s，1H)，3.96(t，J＝6.5Hz，2H)，2.99(t，J＝6.5Hz，2H)，2.36(s，3H)；ES-LCMS m/z 364.0[M+H]⁺。

Example 167

Synthesis I-214

The synthesis scheme is as follows:

step 1: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) pyriproxyfenAzolo [1, 5-a ]]Pyrimidine-7-amine (I-214)

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]A mixture of pyrimidine (100mg, 376.04. mu. mol, 1 eq) in DIEA (5mL) and i-PrOH (3mL) was added 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (95.55mg, 376.04. mu. mol, 1 eq, HCl). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150X 255 u; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 45% -75%, 8min) and then lyophilized to give N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (58.73mg, 141.11 μmol, 37.5% yield, 97.2% purity).¹H NMR(400MHz，CDCl₃)δppm 8.70(s，1H)，8.44(d，J＝2.8Hz，1H)，7.93(d，J＝2.4Hz，1H)，7.81-7.76(m，1H)，7.25(d，J＝7.6Hz，1H)，6.99(dt，J＝4.8，8.0Hz，1H)，6.83-6.79(m，1H)，6.47(d，J＝2.4Hz，1H)，5.99(s，1H)，3.72(q，J＝6.4Hz，2H)，3.11(t，J＝6.4Hz，2H)，2.24(s，3H)；ES-LCMS m/z 405.2[M+H]⁺。

Example 168

Synthesis I-215

The synthesis scheme is as follows:

step 1: 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-5-ol (I-215)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (60mg, 228.42. mu. mol, 1 eq) and 3- (2-aminoethyl) -1H-indol-5-ol (60.37mg, 283.87. mu. mol, 1.24 eq, HCl) in i-PrOH (5mL) was added DIEA (147.61mg, 1.14. mu. mol, 198.94. mu.L, 5 eq). The mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.25) to yield the product 3- [2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]-1H-indol-5-ol (73.19mg, 179.69. mu. mol, 78.7% yield, 98.8% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.52(br s，1H)，9.16(s，1H)，8.77-8.55(m，2H)，8.27(d，J＝9.7Hz，1H)，8.07-7.93(m，2H)，7.20-7.02(m，2H)，6.91(d，J＝1.8Hz，1H)，6.65(s，1H)，6.62-6.58(m，1H)，3.91-3.74(m，2H)，3.03(t，J＝7.1Hz，2H)，2.28(s，3H)；ES-LCMS m/z 403.2[M+H]⁺。

Example 169

Synthesis I-216a

The synthesis scheme is as follows:

step 1: (3R) -8-fluoro-N- [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-216a)

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidine (50mg, 190.35 μmol, 1 equivalent), (3R) -8-fluoro-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (47.36mg, 209.39 μmol, 1.1 equivalent) and DA mixture of IEA (123.01mg, 951.76. mu. mol, 165.78. mu.L, 5 equivalents) in i-PrOH (2mL) was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 10 min). Lyophilizing the desired fractions to obtain (3R) -8-fluoro-N- [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (21.98mg, 51.06 μmol, 26.8% yield, 100.0% purity) (SFC: Rt ═ 2.106, ee ═ 97.3%).¹H NMR(400MHz，CD₃OD)δppm 8.97(s，1H)，8.75(d，J＝2.4Hz，1H)，8.29(td，J＝2.0，9.2Hz，1H)，8.13(s，1H)，7.16(d，J＝8.0Hz，1H)，7.00(s，1H)，6.89(dt，J＝4.8，8.0Hz，1H)，6.76(dd，J＝8.0，11.6Hz，1H)，4.62(m，1H)，3.32(s，1H)，3.16-3.06(m，1H)，3.03-2.95(m，2H)，2.37(s，3H)，2.36-2.23(m，2H)；ES-LCMS m/z 431.2[M+H]⁺。

Example 170

Synthesis I-218

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-methyl-N- (2-phenylethyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-218)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]To a solution of pyrimidine (50mg, 190.35. mu. mol, 1 eq.) in i-PrOH (3mL) was added DIEA (73.80mg, 571.06. mu. mol, 99.47. mu.L, 3 eq.) and 2-phenylethylamine (34.60mg, 285.53. mu. mol, 35.86. mu.L, 1.5 eq.). Stirring the mixture at 60 deg.CStirring for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 9min) and then lyophilized to give 5- (5-fluoro-3-pyridinyl) -3-methyl-N- (2-phenylethyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-amine (37.43mg, 89.05. mu. mol, 46.78% yield, 100% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.83-8.78(m，2H)，8.17-8.13(m，2H)，7.32-7.27(m，2H)，7.23(t，J＝7.3Hz，2H)，7.18-7.13(m，1H)，6.51(s，1H)，4.01(t，J＝6.7Hz，2H)，3.09(t，J＝6.7Hz，2H)，2.34(s，3H)；ES-LCMS m/z 348.2[M+H]⁺。

Example 171

Synthesis I-219

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [ (2S) -5-methoxyindan-2-yl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 190.35. mu. mol, 1 equivalent), (2S) -5-methoxyindan-2-amine (33.05mg, 190.35. mu. mol, 1 equivalent), DIEA (73.80mg, 571.06. mu. mol, 99.47. mu.L, 3 equivalents) in i-PrOH (10mL) was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to give 5- (5-fluoro-3-pyridyl) -N- [ (2S) -5-methoxyindan-2-yl group as a brown oil]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 122.03 μmol, 64.1% yield, 79.2% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.06-8.95(m，1H)，8.58-8.43(m，1H)，8.22-8.09(m，1H)，7.79(s，1H)，7.15-7.00(m，1H)，6.80-6.61(m，2H)，6.53(d，J＝7.1Hz，1H)，6.32(s，1H)，4.59(s，1H)，3.74(s，3H)，3.60(d，J＝6.4Hz，2H)，3.06-3.02(m，2H)，2.31(s，3H)；ES-LCMSm/z 390.2[M+H]⁺。

Step 2: (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-219)

Adding 5- (5-fluoro-3-pyridyl) -N- [ (2S) -5-methoxyindan-2-yl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 122.03. mu. mol, 1 eq.) in HBr (5mL, 60% in water) was stirred at 120 ℃ for 2 h. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Feilomen Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10min) and then lyophilized to give (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (23.51mg, 52.44 μmol, 43.0% yield, 100.0% purity, 2HCl) ((SFC: Rt 2.090, ee 100%).¹HNMR(400MHz，CD₃OD)δppm 9.08(s，1H)，8.90(s，1H)，8.45(d，J＝9.0Hz，1H)，8.16(s，1H)，7.09(d，J＝8.0Hz，1H)，7.01(s，1H)，6.73(s，1H)，6.66(dd，J＝2.0，8.0Hz，1H)，5.11-5.02(m，1H)，3.54-3.42(m，2H)，3.28-3.14(m，2H)，2.41(s，3H)；ES-LCMS m/z 376.2[M+H]⁺。

Example 172

Synthesis I-220

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (2S) -5-methoxyindan-2-yl]Pyrazolo [1, 5-a]Pyrimidin-7-amines

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 154.79. mu. mol, 1 equivalent), (2S) -5-methoxyindan-2-amine (26.88mg, 154.79. mu. mol, 1 equivalent) and DIEA (60.02mg, 464.36. mu. mol, 80.88. mu.L, 3 equivalents) in i-PrOH (10mL) was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to give 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [ (2S) -5-methoxyindan-2-yl group as a brown oil]Pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 115.69 μmol, 74.7% yield, 80.5% purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 9.06-8.93(m，1H)，8.54-8.42(m，1H)，8.13(d，J＝7.3Hz，1H)，7.79(s，1H)，7.10(d，J＝7.9Hz，1H)，6.79-6.58(m，2H)，6.51(d，J＝7.3Hz，1H)，6.33(s，1H)，4.57(s，1H)，3.75-3.62(m，3H)，3.59(d，J＝6.8Hz，2H)，3.02(d，J＝8.6Hz，3H)，1.15(d，J＝2.2Hz，6H)；ES-LCMS m/z 418.2[M+H]⁺。

Step 2: (2S) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-220)

Adding 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [ (2S) -5-methoxyindan-2-yl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 115.69. mu. mol, 1 eq.) in HBr (5mL, 60% in water) was stirred at 120 ℃ for 2 h. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Feilomen Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 40% -70%, 10min) and then lyophilized to give (2S) -2- [ [5- (5-fluoro-3-pyridinyl) as a yellow solid) -3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Indan-5-ol (17.20mg, 36.11 μmol, 31.2% yield, 100.0% purity, 2HCl) (SFC: Rt ═ 2.050, ee ═ 99.374%).¹H NMR(400MHz，CD₃OD)δppm 9.04(s，1H)，8.86(d，J＝2.0Hz，1H)，8.40(d，J＝9.0Hz，1H)，8.26(s，1H)，7.09(d，J＝8.0Hz，1H)，6.99(s，1H)，6.73(s，1H)，6.66(dd，J＝2.5，8.0Hz，1H)，5.09-5.01(m，1H)，3.54-3.43(m，2H)，3.39(td，J＝6.8，13.9Hz，1H)，3.26-3.15(m，2H)，1.41(d，J＝7.0Hz，6H)；ES-LCMS m/z 404.2[M+H]⁺。

Example 173

Synthesis of I-222a, I-222b and I-222c

The synthesis scheme is as follows:

step 1: 7-chloro-5- (5-fluoro-3-pyridinyl) -3-iodo-pyrazolo [1, 5-a]Pyrimidines

To 7-chloro-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a]To a solution of pyrimidine (600mg, 2.24mmol, 1 eq) in DCM (25mL) and MeCN (25mL) was added NIS (1.01g, 4.48mmol, 2 eq) in portions and the mixture was stirred at 20 ℃ for 24 h. TLC (PE/EtOAc ═ 3/1, R_f0.41) showed complete consumption of starting material. The reaction mixture was saturated with Na₂S₂O₃Quenched (100mL) and concentrated under reduced pressure to remove DCM and MeCN. The residue was extracted with EtOAc (100 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 4/1, TLC: PE/EtOAc: 3/1, R_f0.41) to give 7-chloro-5- (5-Fluoro-3-pyridinyl) -3-iodo-pyrazolo [1, 5-a]Pyrimidine (1.03g, 2.75mmol, 61.4% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 9.12(s，1H)，8.64(d，J＝2.8Hz，1H)，8.34-8.26(m，2H)，7.53-7.45(m，1H)；ES-LCMS m/z 374.9[M+H]⁺。

Step 2: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-iodo-pyrazolo [1, 5-a]Pyrimidin-7-amines

Reacting 7-chloro-5- (5-fluoro-3-pyridyl) -3-iodo-pyrazolo [1, 5-a]A mixture of pyrimidine (650mg, 1.74mmol, 1 equiv.), 2- (1H-indol-3-yl) ethylamine (333.66mg, 2.08mmol, 1.2 equiv.) and DIEA (672.89mg, 5.21mmol, 906.86. mu.L, 3 equiv.) in i-PrOH (50mL) was stirred at 60 ℃ for 12H. TLC (PE/EtOAc ═ 2/1, R_f0.30) showed complete consumption of starting material. The reaction mixture was cooled to 20 ℃ and filtered. The solid was washed with i-PrOH (5mL) and dried under reduced pressure to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-iodo-pyrazolo [1, 5-a]Pyrimidin-7-amine (620mg, 1.24mmol, 71.3% yield, 99.3% purity).¹H NMR(400MHz，CDCl₃)δppm 8.78(s，1H)，8.52(d，J＝2.4Hz，1H)，8.10-7.90(m，3H)，7.68(d，J＝7.6Hz，1H)，7.39-7.32(m，1H)，7.24-7.18(m，2H)，7.06(s，1H)，6.57(br s，1H)，6.12(s，1H)，3.86(q，J＝6.4Hz，2H)，3.27(t，J＝6.4Hz，2H)；ES-LCMS m/z 499.1[M+H]⁺。

Step 3: 3- [2- [ tert-Butoxycarbonyl- [5- (5-fluoro-3-pyridinyl) -3-iodo-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

Reacting 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]-3-iodo-pyrazolo [1, 5-a]Pyrimidin-7-amine (900mg, 1.81mmol, 1 eq.), Boc₂O(1.58A mixture of g, 7.22mmol, 1.66mL, 4 equivalents) and DMAP (1.10g, 9.03mmol, 5 equivalents) in 1, 4-dioxane (60mL) was stirred at 120 ℃ for 12 hours. TLC (PE/EtOAc ═ 3/1, R_f0.60) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 5/1, TLC: PE/EtOAc: 3/1, R_f0.60) to yield 3- [2- [ tert-butoxycarbonyl- [5- (5-fluoro-3-pyridinyl) -3-iodo-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (1g, 1.41mmol, 78.2% yield, 98.7% purity).¹H NMR(400MHz，CDCl₃)δppm 8.73(s，1H)，8.55(d，J＝2.4Hz，1H)，8.15(s，1H)，7.98(br s，1H)，7.90(d，J＝7.6Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.25-7.23(m，2H)，7.19-7.12(m，1H)，6.55(s，1H)，4.24-4.18(m，2H)，3.15-3.06(m，2H)，1.59(s，9H)，1.39(s，9H)；ES-LCMS m/z 699.2[M+H]⁺。

Step 4: 3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

Reacting 3- [2- [ tert-butyloxycarbonyl- [5- (5-fluoro-3-pyridyl) -3-iodo-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (200mg, 282.60. mu. mol, 1 eq.), tributyl (1-ethoxyvinyl) stannane (880mg, 2.44mmol, 822.43. mu.L, 8.62 eq.), and Pd (dppf) Cl₂A mixture of (206.78mg, 282.60. mu. mol, 1 eq.) in toluene (6mL) was treated with N₂Bubbled for 2 minutes and sealed. The reaction mixture was irradiated under microwave (1 bar) at 100 ℃ for 2 hours. The reaction was carried out 5 times in parallel. KF (100mL, 2M) was added to the combined mixture. The mixture was stirred at 25 ℃ for 1 hour and extracted with EtOAc (100 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 1/0 to 4/1, TLC: PE/EtOAc: 3/1, R_f＝040) to give 3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (450mg, 732.11. mu. mol, 51.8% yield, 100.0% purity).¹HNMR(400MHz，CDCl₃)δppm 8.79(s，1H)，8.66(s，1H)，8.61(d，J＝2.4Hz，1H)，7.97(d，J＝6.4Hz，1H)，7.80(td，J＝2.4，9.2Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.26-7.20(m，2H)，7.17-7.11(m，1H)，6.65(s，1H)，4.30(t，J＝6.4Hz，2H)，3.18-3.12(m，2H)，2.84(s，3H)，1.59(s，9H)，1.43(s，9H)；ES-LCMS m/z 615.3[M+H]⁺。

Step 5: 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanones

To 3- [2- [ [ 3-acetyl-5- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a ] at 20 DEG C]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (450mg, 732.11. mu. mol, 1 eq.) in MeOH (50mL) was added HCl/H₂O (6M, 150mL, 1229.33 eq). The mixture was stirred at 35 ℃ for 3 hours. The mixture was basified with aqueous NaOH (15%) until pH 8 and concentrated under reduced pressure to remove MeOH. The residue was extracted with EtOAc (50 mL. times.3). The organic layer was washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure to give 1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino as a yellow solid]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanone (300mg, 723.88 μmol, 98.9% yield, 100.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 10.77(br s，1H)，9.11(s，1H)，8.67(d，J＝2.4Hz，1H)，8.60(t，J＝6.0Hz，1H)，8.49(s，1H)，8.18(d，J＝10.4Hz，1H)，7.61(d，J＝7.6Hz，1H)，7.24(d，J＝7.6Hz，1H)，7.16(d，J＝1.6Hz，1H)，7.05-6.99(m，1H)，6.98-6.93(m，1H)，6.82(s，1H)，3.84(q，J＝6.4Hz，2H)，3.09(t，J＝6.8Hz，2H)，2.67(s，3H)；ES-LCMS m/z 415.1[M+H]⁺。

Step 6: (1S) -1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (I-222b) and (1R) -1- [5- (5-fluoro-3-pyridinyl) -7- [2- (1H-indol-3-yl) ethylamino]Pyrazolo [1, 5-a]Pyrimidin-3-yl]Ethanol (I-222a)

To 1- [5- (5-fluoro-3-pyridyl) -7- [2- (1H-indol-3-yl) ethylamino at 20 deg.C]Pyrazolo [1, 5-a]Pyrimidin-3-yl]To a solution of ethanone (250mg, 603.23. mu. mol, 1 eq.) in THF (50mL) and EtOH (20mL) was added NaBH in portions₄(114.11mg, 3.02mmol, 5 equiv.). The mixture was stirred at 20 ℃ for 3 hours. The reaction mixture was quenched with water (50mL) and concentrated under reduced pressure at 30 ℃ to remove EtOH and THF. The residue was extracted with EtOAc (80 mL. times.3) over Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was passed through chiral SFC (column: xylonite CHIRALPAKAD-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃·H₂O/EtOH](ii) a B%: 40% -40%) of the seed. Peak 1 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 40% -70%, 10 min). The desired fractions were lyophilized to give the enantiomer as a white solid (32.78mg, 76.81 μmol, 12.7% yield, 97.6% purity) (SFC: Rt ═ 6.825, ee ═ 98.8%; [ a ] optical rotation]^22.3 _D-9.540(10.04mg/10mL in MeOH)).¹H NMR(400MHz，CDCl₃)δppm 8.78(s，1H)，8.51(d，J＝2.4Hz，1H)，8.07(br s，1H)，7.95(s，1H)，7.87-7.80(m，1H)，7.68(d，J＝7.6Hz，1H)，7.40-7.32(m，1H)，7.26-7.18(m，2H)，7.06(s，1H)，6.56(brs，1H)，6.08(s，1H)，5.34(d，J＝6.0Hz，1H)，3.89-3.83(m，2H)，3.29-3.24(m，3H)，1.70(d，J＝6.4Hz，3H)；ES-LCMS m/z 417.2[M+H]⁺. Peak 2 was concentrated under reduced pressure to giveThe residue was purified by preparative HPLC (column: Feilomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 40% -70%, 10 min). The desired fractions were lyophilized to give a residue which was passed again through chiral SFC (column: xylonite CHIRALPAK AD-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃·H₂O/EtOH](ii) a B%: 40% -40%) of the seed. The desired fractions were concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 42% -72%, 10 min). The desired fractions were lyophilized to give the other enantiomer as a white solid (30.13mg, 72.35 μmol, 12.0% yield, 100.0% purity) (SFC: Rt ═ 7.042, ee ═ 99.0%; [ a ] optical rotation]^22.2 _D1.916(6.44mg/10mL in MeOH)).¹H NMR(400MHz，CDCl₃)δppm 8.77(s，1H)，8.51(d，J＝2.4Hz，1H)，8.11(br s，1H)，7.95(s，1H)，7.83(td，J＝2.0，9.6Hz，1H)，7.68(d，J＝7.6Hz，1H)，7.36(d，J＝8.0Hz，1H)，7.27-7.18(m，2H)，7.06(d，J＝2.0Hz，1H)，6.58(t，J＝5.6Hz，1H)，6.07(s，1H)，5.42-5.26(m，1H)，3.85(q，J＝6.4Hz，2H)，3.34-3.22(m，3H)，1.70(d，J＝6.4Hz，3H)；ES-LCMS m/z417.2[M+H]⁺。

Example 174

Synthesis I-224

The synthesis scheme is as follows:

step 1: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo (I-224)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (60mg, 228.42. mu. mol, 1 eq) and 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (79.89mg, 296.95. mu. mol, 1.3 eq, HCl) in i-PrOH (10mL) was added DIEA (88.57mg, 685.27. mu. mol, 119.36. mu.L, 3 eq) and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl Durashell C18150X 255 u; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 12min) to give the product, which was purified by preparative HPLC (column: gemini150 × 255 u; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 55% -85%, 8min) and then lyophilized to give N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (16.79mg, 40.13 μmol, 17.6% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm8.80(s，1H)，8.50(d，J＝2.6Hz，1H)，8.00(br s，1H)，7.95-7.82(m，2H)，7.32(d，J＝7.9Hz，1H)，7.10-7.03(m，1H)，6.89(dd，J＝8.2，11.0Hz，1H)，6.49(br s，1H)，6.01(s，1H)，3.78(q，J＝6.5Hz，2H)，3.21-3.13(m，2H)，2.38(s，3H)，2.29(s，3H)；ES-LCMS m/z 419.2[M+H]⁺。

Example 175

Synthesis I-225

The synthesis scheme is as follows:

step 1: 7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester

To a solution of 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (50mg, 196.77. mu. mol, 1 eq, HCl) in i-PrOH (5mL) was added 7-chloro-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (63.52mg, 196.77 μmol, 1 equivalent) and DIEA (76.29mg, 590.31 μmol, 102.82 μ L, 3 equivalents). Mixing the mixture in N₂Stirred at 60 ℃ for 3 hours under an atmosphere. The mixture was concentrated under reduced pressure and water (50mL) was added. The mixture was extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtering and concentrating to give 7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino as a yellow solid]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid methyl ester (90mg, 173.79 μmol, 88.3% yield, 89.3% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.51-8.46(m，2H)，8.41(s，1H)，7.72-7.65(m，1H)，7.38(d，J＝8.0Hz，1H)，6.98-6.92(m，1H)，6.69-6.60(m，1H)，5.85(s，1H)，3.88(s，3H)，3.83(br s，2H)，3.16-3.07(m，2H)，2.08(s，3H)；ES-LCMS m/z 463.2[M+H]⁺。

Step 2: 7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid

To 7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid methyl ester (90mg, 173.79 μmol, 1 eq) in MeOH (5mL) was added NaOH (2M, 4.96mL, 57.09 eq). Mixing the mixture in N₂Stirred under an atmosphere at 50 ℃ for 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water (50mL), adjusted to pH 3 by 1N HCl solution, and extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtering and concentrating to obtain 7- [2- (7-fluoro) compound as yellow solid-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxylic acid (80mg, 160.56 μmol, 92.4% yield, 90.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.48(s，2H)，8.41(s，1H)，7.68(d，J＝9.8Hz，1H)，7.38(d，J＝7.8Hz，1H)，6.95(dt，J＝4.5，7.9Hz，1H)，6.68-6.60(m，1H)，5.85(s，1H)，3.89-3.83(m，2H)，3.15-3.08(m，2H)，2.08(s，3H)；ES-LCMS m/z 449.2[M+H]⁺。

Step 3: [7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]-morpholinyl-methanone (I-225)

To 7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]To a solution of pyrimidine-3-carboxylic acid (80mg, 160.56. mu. mol, 1 eq) in DCM (10mL) was added morpholine (20.98mg, 240.84. mu. mol, 21.19. mu.L, 1.5 eq), HATU (91.58mg, 240.84. mu. mol, 1.5 eq) and TEA (32.49mg, 321.12. mu. mol, 44.70. mu.L, 2 eq). Mixing the mixture in N₂Stirred under an atmosphere at 20 ℃ for 1 hour. The mixture was concentrated under reduced pressure and water (30mL) was added. The mixture was extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (30mL) and Na₂SO₄Dried, filtered and concentrated to give a residue which is purified by preparative HPLC (column: Philomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 33% -63%, 10min) and then lyophilized to give [7- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamino ] as a yellow solid]-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-3-yl]Morpholinyl-methanone (29.09mg, 56.21. mu. mol, 35.0% yield, 100% purity).¹H NMR(400MHz，CD₃OD)δppm 8.78(d，J＝2.5Hz，1H)，8.60(s，1H)，8.38(s，1H)，7.79-7.70(m，1H)，7.34(d，J＝8.0Hz，1H)，6.87(dt，J＝4.7，7.8Hz，1H)，6.60(dd，J＝7.7，11.4Hz，1H)，5.88(s，1H)，4.01-3.93(m，2H)，3.76(s，8H)，3.20-3.14(m，2H)，2.12(s，3H)；ES-LCMSm/z 518.3[M+H]⁺。

Example 176

Synthesis I-226

The synthesis scheme is as follows:

step 1: 3- [2- [ [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

To 3-bromo-5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]To a solution of pyrimidin-7-amine (750mg, 1.63mmol, 1 equiv.) in 1, 4-dioxane (30mL) was added DMAP (596.31mg, 4.88mmol, 3 equiv.) and (Boc)₂O (887.73mg, 4.07mmol, 934.45. mu.L, 2.5 equiv.). The mixture was stirred at 110 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.75) to yield 3- [2- [ [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (950mg, 1.46mmol, 89.6% yield, 100.0% purity).¹H NMR(400MHz，CDCl3)δppm 8.73(s，1H)，8.57(d，J＝2.8Hz，1H)，8.16(s，1H)，8.00(d，J＝7.0Hz，1H)，7.91(td，J＝2.1，9.3Hz，1H)，7.45(d，J＝7.8Hz，1H)，7.27-7.21(m，2H)，7.21-7.14(m，1H)，6.57(s，1H)，4.24(t，J＝6.8Hz，2H)，3.12(t，J＝6.7Hz，2H)，1.62(s，9H)，1.42(s，9H)；ES-LCMS m/z 651.2，652.2[M+H]⁺。

Step 2: 3- [2- [ tert-Butoxycarbonyl- [5- (5-fluoro-3-pyridinyl) -3-tetrahydrofuran-2-yl-pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

4-tert-butyl-2- (4-tert-butyl-2-pyridyl) pyridine (24.72mg, 92.09. mu. mol, 0.1 eq.) and nickel dichloride 1, 2-dimethoxyethane (20.23mg, 92.09. mu. mol, 0.1 eq.) were added to THF (4 mL). Mixing the mixture in N₂Stirring was carried out at 50 ℃ under an atmosphere until a green solution was obtained. In N₂Under the atmosphere, [ Ir { dFCF [ ]₃ppy}₂(bpy)]PF₆(51.66mg, 46.05. mu. mol, 0.05 eq.), K₂HPO₄(320.81mg, 1.84mmol, 2 equiv.) and 3- [2- [ [ 3-bromo-5- (5-fluoro-3-pyridinyl) pyrazolo [1, 5-a ]]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]A solution of tert-butyl indole-1-carboxylate (600mg, 920.92. mu. mol, 1 eq.) in THF (20mL) was added to the above mixture. The resulting mixture was stirred and irradiated with a standard 72W LED ribbon bulb for 12 hours at 25 ℃. The reaction mixture was concentrated to give a residue, which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.45) to yield 3- [2- [ tert-butoxycarbonyl- [5- (5-fluoro-3-pyridinyl) -3-tetrahydrofuran-2-yl-pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (190mg, 274.04. mu. mol, 29.8% yield, 92.7% purity).¹H NMR(400MHz，CDCl₃)δppm 8.83-8.76(m，1H)，8.55(s，1H)，8.18(s，1H)，8.05(s，1H)，7.90-7.79(m，1H)，7.47(t，J＝6.9Hz，1H)，7.31(d，J＝8.8Hz，1H)，7.19(t，J＝7.6Hz，2H)，6.59(s，1H)，5.38-5.29(m，1H)，4.21-4.15(m，2H)，4.10(m，1H)，4.01-3.92(m，1H)，3.11(t，J＝6.9Hz，2H)，2.45-2.35(m，1H)，2.33-2.24(m，1H)，2.23-2.16(m，1H)，2.15-2.07(m，1H)，1.60(s，9H)，1.46-1.39(m，9H)；ES-LCMS m/z 643.3[M+H]⁺。

Step 3: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-tetrahydrofuran-2-yl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-226)

To a stirred solution of 3- [2- [ tert-butoxycarbonyl- [5- (5-fluoro-3-pyridyl) -3-tetrahydrofuran-2-yl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]Amino group]Ethyl radical]A solution of tert-butyl indole-1-carboxylate (70mg, 100.96. mu. mol, 1 eq.) in DCM (8mL) was added ZnBr₂(2.27g, 10.10mmol, 100 equiv.). The reaction mixture was stirred at 25 ℃ for 15 hours. TLC (PE/EtOAc ═ 1/1, R_f0.35) indicates that a major new blob is detected. MeOH (30mL) was added to the reaction mixture and diluted with water (50mL) and saturated NaHCO₃The solution was adjusted to pH 8-9 and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by flash silica gel chromatography (PE/EtOAc: 100/1 to 2/1, TLC: PE/EtOAc: 1/1, R_f0.35) to yield a residue which was purified by preparative HPLC (basic conditions; column: gemini150 × 255 u; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 55% -75%, 8min) and then purifying. The desired fractions were lyophilized to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] e as a white solid]-3-tetrahydrofuran-2-yl-pyrazolo [1, 5-a]Pyrimidin-7-amine (5.91mg, 12.85 μmol, 12.7% yield, 96.2% purity).¹H NMR(400MHz，CDCl₃)δppm 8.80(s，1H)，8.50(s，1H)，8.03(s，2H)，7.85(d，J＝9.5Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.36(d，J＝7.7Hz，1H)，7.26-7.18(m，2H)，7.05(d，J＝2.0Hz，1H)，6.54(s，1H)，6.07(s，1H)，5.29(t，J＝7.3Hz，1H)，4.12(q，J＝7.3Hz，1H)，3.99-3.90(m，1H)，3.85(q，J＝6.3Hz，2H)，3.25(t，J＝6.5Hz，2H)，2.39-2.28(m，2H)，2.24-2.15(m，1H)，2.14-2.04(m，1H)；ES-LCMS m/z 443.2[M+H]⁺。

Example 177

Synthesis I-227

The synthesis scheme is as follows:

step 1: 1, 3-benzodioxol-4-yl (trimethyl) stannanes

To a solution of 4-iodo-1, 3-benzodioxole (100mg, 403.20 μmol, 1 eq) in 1, 4-dioxane (5mL) was added trimethyl (trimethylstannyl) stannane (132.10mg, 403.20 μmol, 83.61 μ L, 1 eq) and 4-diphenylphosphinobutyl (diphenyl) phosphane (17.20mg, 40.32 μmol, 0.1 eq) with N₂And purifying for 15 minutes. Addition of Pd (OAc)₂(9.05mg, 40.32. mu. mol, 0.1 eq.) and the mixture was stirred at 110 ℃ for 3 hours. TLC (PE/EtOAc ═ 10/1, R_f0.44) indicates that one major new blob with a lower polarity is detected. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.44) to yield the product 1, 3-benzodioxol-4-yl (trimethyl) stannane (80mg, 252.70 μmol, 62.7% yield, 90.0% purity) as a colorless oil.¹H NMR(400MHz，CDCl₃)δppm 6.88-6.76(m，3H)，5.91(s，2H)，0.42-0.26(s，9H)。

Step 2: 3- [2- [ [5- (1, 3-benzodioxol-4-yl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

1, 3-benzodioxol-4-yl (trimethyl) stannane (50mg, 157.94. mu. mol, 1 equivalent) and 3- [2- [ tert-butyloxycarbonyl [ ] -- (5-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]Ethyl radical]A solution of tert-butyl indole-1-carboxylate (75.06mg, 134.25. mu. mol, 0.85 eq.) in DMF (5mL) was taken with N₂And purifying for 25 minutes. Addition of Pd (dppf) Cl₂(10.98mg, 15.00. mu. mol, 0.095 equiv.) and CuI (2.86mg, 15.00. mu. mol, 0.095 equiv.) and the mixture was stirred under microwave at 110 ℃ for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (TLC: PE/EtOAc ═ 10/1, R)_f0.46) to yield the product 3- [2- [ [5- (1, 3-benzodioxol-4-yl) -3-isopropyl-pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (80mg, 106.42. mu. mol, 67.4% yield, 85.1% purity).¹H NMR(400MHz，CDCl₃)δppm 8.03(s，2H)，7.99(s，1H)，7.87(d，J＝7.7Hz，1H)，7.50(d，J＝7.1Hz，1H)，7.39(br s，2H)，7.23-7.14(m，1H)，7.03-6.96(m，1H)，6.95-6.90(m，1H)，6.09-6.04(m，2H)，4.19(t，J＝7.5Hz，2H)，3.46-3.37(m，1H)，3.06(t，J＝6.9Hz，2H)，1.63(s，9H)，1.45(d，J＝6.4Hz，6H)，1.36(s，9H)；ES-LCMS m/z 640.4[M+H]⁺。

Step 3: 5- (1, 3-benzodioxol-4-yl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-227)

3- [2- [ [5- (1, 3-benzodioxol-4-yl) -3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl]-tert-butoxycarbonylamino]Ethyl radical]A solution of tert-butyl indole-1-carboxylate (80mg, 106.42. mu. mol, 1 eq) in HCl/MeOH (4M, 5mL, 187.94 eq.) was stirred at 25 ℃ for 12 h. LC-MS showed incomplete consumption of starting material. The mixture was stirred at 25 ℃ for a further 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 9min), followed by lyophilization,to give 5- (1, 3-benzodioxol-4-yl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (47.73mg, 100.08 μmol, 94.0% yield, 99.8% purity, HCl).¹H NMR(400MHz，CD₃OD)δppm 8.16(s，1H)，7.51(d，J＝7.8Hz，1H)，7.14(d，J＝8.0Hz，1H)，7.05-7.00(m，2H)，6.97-6.92(m，2H)，6.86-6.80(m，1H)，6.53(d，J＝8.0Hz，1H)，6.07(s，2H)，5.76(s，1H)，3.96(t，J＝5.8Hz，2H)，3.23-3.18(m，3H)，1.33(d，J＝6.8Hz，6H)；ES-LCMS m/z 440.3[M+H]⁺。

Example 178

Synthesis I-229

The synthesis scheme is as follows:

step 1: (3R) -3- [ tert-Butoxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Reacting (3R) -3- [ tert-butyloxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (200mg, 316.66 μmol, 1 equivalent), pyrimidin-5-ylboronic acid (47.08mg, 379.99 μmol, 1.2 equivalents), Cs₂CO₃(309.52mg, 949.98. mu. mol, 3 equiv.) and Pd (dppf) Cl₂(23.17mg, 31.67. mu. mol, 0.1 equiv.) in 1, 4-dioxane (6mL) and H₂O (2mL) was placed in the microwave tube. The sealed tube was heated under microwave (2 bar) at 110 ℃ for 1 hour. The mixture was concentrated and then saturated NaHCO was added₃(10mL) and extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentratingCondensation to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.30) to give (3R) -3- [ tert-butoxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a) as a yellow gum]Pyrimidin-7-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (180mg, 288.58 μmol, 91.1% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.39(s，2H)，9.22(s，1H)，8.14(s，1H)，7.94(d，J＝7.9Hz，1H)，7.46(s，1H)，7.19(br s，1H)，7.14-7.02(m，2H)，4.79(m，1H)，3.48(m，1H)，3.43-3.36(m，2H)，3.18-3.08(m，2H)，2.36-2.28(m，2H)，1.63(s，9H)，1.45(d，J＝7.1Hz，6H)，1.30(s，9H)；ES-LCMS m/z 624.4[M+H]⁺。

Step 2: (3R) -N- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-229)

To (3R) -3- [ tert-butyloxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]To a solution of tert-butyl (180mg, 288.58 μmol, 1 eq) of-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate in DCM (5mL) was added TFA (1 mL). The mixture is degassed and treated with N₂Purifying for 3 times, and adding the mixture in N₂Stirred under an atmosphere at 20 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 9min) to give a residue which was purified by preparative HPLC (column: feilomen Gemini150 × 25mm × 10 μm; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 56% -86%, 10min) and then lyophilized to give (3R) -N- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (12mg, 28.33 μmol, 9.8% yield, 100.0% purity).¹H NMR(400MHz，CD₃OD)δppm 9.51(s，2H)，9.21(s，1H)，7.95(s，1H)，7.39(d，J＝7.7Hz，1H)，7.27(d，J＝8.2Hz，1H)，7.07-7.01(m，1H)，6.99-6.93(m，1H)，6.84(s，1H)，4.47(m，J＝8.6Hz，1H)，3.37-3.34(m，2H)，3.14-3.03(m，1H)，3.00-2.88(m，2H)，2.41-2.33(m，1H)，2.28-2.19(m，1H)，1.42(d，J＝6.8Hz，6H)；ES-LCMS m/z 424.2[M+H]⁺。

Example 179

Synthesis I-230

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]-3-vinyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-230)

Reacting 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]-3-iodo-pyrazolo [1, 5-a]Pyrimidin-7-amine (55mg, 109.71 μmol, 1 eq), 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxolane (50.69mg, 329.14 μmol, 55.83 μ L, 3 eq), Cs₂CO₃(178.74mg, 548.57. mu. mol, 5 equiv.) and Pd (dppf) Cl₂(40.14mg, 54.86. mu. mol, 0.5 eq.) in 1, 4-dioxane (3mL) and H₂Mixture in O (1.5mL) with N₂Bubbled for 2 minutes and sealed. The reaction mixture was irradiated under microwave (2 bar) at 120 ℃ for 2 hours. Subjecting the reaction mixture to hydrogenation with H₂O (10mL) was diluted and extracted with EtOAc (10 mL. times.3). The organic layer was washed with Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc ═ 2/1, R)_f0.23) and then purified by preparative HPLC (column: gemini150 × 255 u; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -ACN](ii) a B%: 60% -90%, 8 min). Freeze-drying stationThe fractions were eluted to give 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] ethyl as a yellow solid]-3-vinyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (15.4mg, 38.65 μmol, 35.2% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.82(s，1H)，8.51(d，J＝2.4Hz，1H)，8.06(s，2H)，7.95-7.88(m，1H)，7.69(d，J＝7.6Hz，1H)，7.39-7.33(m，1H)，7.27-7.18(m，2H)，7.06(d，J＝2.0Hz，1H)，6.90(dd，J＝11.2，17.6Hz，1H)，6.55(t，J＝6.4Hz，1H)，6.11(s，1H)，6.07(dd，J＝1.6，17.6Hz，1H)，5.27(dd，J＝2.0，11.2Hz，1H)，3.85(q，J＝6.4Hz，2H)，3.27(t，J＝6.4Hz，2H)；ES-LCMS m/z399.2[M+H]⁺。

Example 180

Synthesis I-232

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -N- [ (2R) -5-methoxyindan-2-yl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 190.35. mu. mol, 1 eq), (2R) -5-methoxyindan-2-amine (38.01mg, 190.35. mu. mol, 1 eq, HCl) in i-PrOH (5mL) was added DIEA (73.80mg, 571.06. mu. mol, 99.47. mu.L, 3 eq). The mixture was stirred at 80 ℃ for 12 hours. Concentrating the mixture to obtain crude compound 5- (5-fluoro-3-pyridyl) -N- [ (2R) -5-methoxyindan-2-yl]-3-methyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (70mg, 130.90 μmol, 68.8% yield, 72.8% purity), which was used in the next step without further purification; ES-LCMS M/z 390.2[ M + H ]]⁺。

Step 2: (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-232)

Reacting 5- (5-fluoro-3-pyridyl) -N- [ (2R) -5-methoxyindan-2-yl]-3-methyl-pyrazolo [1, 5-a]A mixture of pyrimidin-7-amine (70mg, 130.90. mu. mol, 1 eq.) in HBr solution (7.45g, 55.25mmol, 5mL, 60%, 422.06 eq.) was stirred at 80 ℃ for 1 h. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 30% -60%, 6 min). Lyophilizing the desired fractions to obtain (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-methyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (17.22mg, 38.27 μmol, 29.2% yield, 99.6% purity, 2HCl, ee ═ 98.2%).¹H NMR(400MHz，CD₃OD)δppm 8.98(s，1H)，8.80(d，J＝2.4Hz，1H)，8.29(td，J＝2.4，9.2Hz，1H)，8.11(s，1H)，7.06(d，J＝8.0Hz，1H)，6.94(s，1H)，6.69(s，1H)，6.63(dd，J＝2.4，8.0Hz，1H)，5.07-4.96(m，1H)，3.47-3.39(m，2H)，3.23-3.15(m，2H)，2.36(s，3H)；ES-LCMS m/z 376.1[M+H]⁺。

Example 181

Synthesis I-234

The synthesis scheme is as follows:

step 1: 5- (5-fluoro-3-pyridinyl) -3-isopropyl-N- [ (2R) -5-methoxyindan-2-yl]Pyrazolo [1, 5-a]Pyrimidin-7-amines

To 7-chloro-5- (5-fluoro-3-pyridyl) -3-isopropyl-pyrazolo [1, 5-a]A mixture of pyrimidine (50mg, 154.79. mu. mol, 1 equivalent), (2R) -5-methoxyindan-2-amine (27.79mg, 170.27. mu. mol, 1.1 equivalents) in i-PrOH (5mL) was added DIEA (60.01mg, 464.36. mu. mol, 80.88. mu.L, 3 equivalents). The mixture was stirred at 80 ℃ for 12 hours. Concentrating the mixture to obtain the product 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [ (2R) -5-methoxyindan-2-yl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (60mg, 102.65 μmol, 66.3% yield, 71.4% pure), which was used in the next step without further purification. ES-LCMS M/z 418.2[ M + H ]]⁺。

Step 2: (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Indan-5-ol (I-234)

Reacting 5- (5-fluoro-3-pyridyl) -3-isopropyl-N- [ (2R) -5-methoxyindan-2-yl]Pyrazolo [1, 5-a]A mixture of pyrimidin-7-amine (60mg, 102.04. mu. mol, 1 eq.) in HBr solution (5.29g, 39.22mmol, 3.55mL, 60%, 384.39 eq.) was stirred at 120 ℃ for 2 h. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 45% -75%, 9 min). Lyophilizing the desired fractions to obtain (2R) -2- [ [5- (5-fluoro-3-pyridinyl) -3-isopropyl-pyrazolo [1, 5-a ] as a yellow solid]Pyrimidin-7-yl]Amino group]Indan-5-ol (13.92mg, 31.34. mu. mol, 30.7% yield, 99.0% purity, HCl) (97.1% ee).¹H NMR(400MHz，CD₃OD)δppm 8.98(s，1H)，8.80(d，J＝2.0Hz，1H)，8.32-8.29(m，1H)，8.21(s，1H)，7.05(d，J＝8.0Hz，1H)，6.92(s，1H)，6.62(dd，J＝2.4，8.4Hz，1H)，6.61(m，1H)，5.02-4.93(m，1H)，3.49-3.40(m，2H)，3.37-3.31(m，1H)，3.21-3.09(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 404.3[M+H]⁺。

Example 182

Synthesis of I-235

The synthesis scheme is as follows:

step 1: n- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl]-5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-235)

To 7-chloro-5- (5-fluoro-3-pyridyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]To a solution of pyrimidine (30mg, 87.92. mu. mol, 1 eq) and 2- (7-fluoro-2-methyl-1H-indol-3-yl) ethylamine (24.15mg, 105.51. mu. mol, 1.2 eq) in i-PrOH (5mL) was added DIEA (34.09mg, 263.77. mu. mol, 45.94. mu.L, 3.0 eq). The mixture was stirred at 80 ℃ for 9 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 10min) and then lyophilized to give N- [2- (7-fluoro-2-methyl-1H-indol-3-yl) ethyl as a yellow solid]-5- (5-fluoro-3-pyridinyl) -3- (trifluoromethyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (10.90mg, 19.97 μmol, 22.7% yield, 99.9% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.86(dd，J＝1.3，2.5Hz，1H)，8.74(d，J＝1.5Hz，1H)，8.34(s，1H)，7.94(td，J＝2.3，8.7Hz，1H)，7.42(d，J＝8.0Hz，1H)，6.98(dt，J＝4.8，7.9Hz，1H)，6.67(dd，J＝7.9，11.4Hz，1H)，5.92(s，1H)，3.98-3.91(m，2H)，3.21-3.14(m，2H)，2.13-2.05(m，3H)；ES-LCMS m/z 473.2[M+H]⁺。

Example 183

Synthesis I-237

The synthesis scheme is as follows:

step 1: 3-Ethyl-5- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrazolo [1, 5-a]Pyrimidine-7-amine (I-237)

Reacting 5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl]-3-vinyl-pyrazolo [1, 5-a]Mixture of pyrimidin-7-amine (140mg, 196.77. mu. mol, 1 eq.) and Pd/C (50mg, 10% purity) in EtOAc (20mL) in H₂(15psi) at 25 ℃ for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10 min). Lyophilizing the desired fractions to obtain 3-ethyl-5- (5-fluoro-3-pyridyl) -N- [2- (1H-indol-3-yl) ethyl ] ethyl]Pyrazolo [1, 5-a]Pyrimidin-7-amine (7.13mg, 15.06 μmol, 7.7% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.65(d，J＝2.4Hz，1H)，8.37(s，1H)，8.11(s，1H)，7.53(d，J＝8.0Hz，1H)，7.50-7.46(m，1H)，7.14(d，J＝8.0Hz，1H)，6.99(s，1H)，6.96(t，J＝7.6Hz，1H)，6.87-6.82(m，1H)，5.78(s，1H)，3.98(t，J＝5.6Hz，2H)，3.20(t，J＝5.6Hz，2H)，2.72(q，J＝7.6Hz，2H)，1.28(t，J＝7.6Hz，3H)；ES-LCMS m/z 401.2[M+H]⁺。

Example 184

Synthesis I-240

The synthesis scheme is as follows:

step 1: 3- [2- [ tert-Butoxycarbonyl- [ 3-isopropyl-5- (2-methoxyphenyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

To 3- [2- [ tert-butoxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]Ethyl radical]To a solution of indole-1-carboxylic acid tert-butyl ester (100mg, 178.86 μmol, 1 eq) in 1, 4-dioxane (6mL) and water (2mL) was added (2-methoxyphenyl) boronic acid (81.53mg, 536.57 μmol, 3 eq), K₃PO₄(113.89mg, 536.57. mu. mol, 3 equivalents) and sphos cyclopalladium (13.61mg, 17.89. mu. mol, 0.1 equivalents). Mixing the mixture in N₂Stirred under an atmosphere at 110 ℃ for 1 hour. The mixture was concentrated under reduced pressure, followed by addition of water (30 mL). The mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated to give 3- [2- [ tert-butoxycarbonyl- [ 3-isopropyl-5- (2-methoxyphenyl) pyrazolo [1, 5-a) as a yellow oil]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (200mg, 164.28 μmol, 91.8% yield, 51.4% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.96(s，1H)，7.92-7.87(m，1H)，7.73(dd，J＝1.7，7.6Hz，1H)，7.65-7.60(m，1H)，7.47(dd，J＝1.4，8.7Hz，1H)，7.19-7.13(m，2H)，7.07(s，1H)，6.97-6.94(m，1H)，6.94-6.91(m，2H)，4.1(m，2H)，3.81(s，3H)，3.36(s，1H)，3.06(t，J＝6.4Hz，2H)，1.61-1.55(m，9H)，1.48-1.45(m，6H)，1.37-1.35(m，9H)；ES-LCMS m/z 626.4[M+H]⁺。

Step 2: n- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-5- (2-methoxyphenyl) pyrazolo [1, 5-a]Pyrimidine-7-amine (I-240)

To 3- [2- [ tert-butoxycarbonyl- [ 3-isopropyl-5- (2-methoxyphenyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]Amino group]Ethyl radical]To a solution of indole-1-carboxylic acid tert-butyl ester (185mg, 151.96. mu. mol, 1 eq.) in DCM (10mL) was added TFA (3.08g, 27.01mmol, 2mL, 177.76 eq.). Mixing the mixture in N₂Stirring was carried out under an atmosphere at 25 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 23% -53%, 10min) and subsequent lyophilization to yield N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-5- (2-methoxyphenyl) pyrazolo [1, 5-a]Pyrimidin-7-amine (27.57mg, 63.69 μmol, 41.9% yield, 98.3% purity).¹H NMR(400MHz，CD₃OD)δppm 8.11(s，1H)，7.57-7.47(m，2H)，7.25(d，J＝8.0Hz，1H)，7.13(d，J＝8.3Hz，1H)，7.06-6.95(m，3H)，6.84(t，J＝7.5Hz，2H)，5.79(s，1H)，3.93(t，J＝6.1Hz，2H)，3.83(s，3H)，3.21(t，J＝6.1Hz，2H)，3.19-3.12(m，1H)，1.33(d，J＝6.8Hz，6H)；ES-LCMS m/z 426.2[M+H]⁺。

Example 185

Synthesis I-241

The synthesis scheme is as follows:

step 1: 3- [2- [ tert-Butoxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

Reacting 3- [2- [ tert-butyloxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (100mg, 178.86. mu. mol, 1 eq.), pyrimidin-5-ylboronic acid (22.16mg, 178.86. mu. mol, 1 eq.), Pd (dppf) Cl₂(13.09mg, 17.89. mu. mol, 0.1 equiv.) and Cs₂CO₃(174.82mg, 536.57. mu. mol, 3 equivalents) in H₂O (2mL) and 1, 4-dioxane (6mL) were placed in a microwave tube. The sealed tube was heated at 110 ℃ for 1 hour under microwave. The mixture was concentrated and saturated NaHCO was added₃(10mL) and extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtering and concentrating to give 3- [2- [ tert-butoxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a) as a brown solid]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (100mg, 167.31 μmol, 93.5% yield, crude), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 9.23-9.22(m，1H)，9.21-9.20(m，1H)，8.97(s，1H)，7.81(d，J＝7.6Hz，1H)，7.45(d，J＝7.6Hz，2H)，7.41(d，J＝8.4Hz，1H)，7.09-7.02(m，2H)，6.93(t，J＝8.0Hz，1H)，4.33(d，J＝6.4Hz，2H)，4.30(s，1H)，3.11(t，J＝6.4Hz，2H)，1.59(s，9H)，1.39(s，6H)，1.37(s，9H)；ES-LCMS m/z 598.4[M+H]⁺。

Step 2: n- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-241)

To 3- [2- [ tert-butyloxycarbonyl- (3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl) amino]Ethyl radical]To a solution of indole-1-carboxylic acid tert-butyl ester (100mg, 167.31. mu. mol, 1 eq.) in DCM (7.5mL) was added TFA (1.5 mL). The mixture is degassed and treated with N₂Purify 3 times and in N₂Stirred under an atmosphere at 20 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase:[ Water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10 min). The desired fractions were lyophilized to give N- [2- (1H-indol-3-yl) ethyl ] as a yellow solid]-3-isopropyl-5-pyrimidin-5-yl-pyrazolo [1, 5-a]Pyrimidin-7-amine (17.94mg, 34.12. mu. mol, 20.4% yield, 96.4% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.31(s，1H)，8.68(s，2H)，8.18(s，1H)，7.50(d，J＝7.9Hz，1H)，7.16(d，J＝8.0Hz，1H)，7.03(s，1H)，6.99-6.92(m，1H)，6.83-6.77(m，1H)，5.83(s，1H)，4.04-3.97(m，2H)，3.25-3.16(m，3H)，1.35(d，J＝6.8Hz，6H)；ES-LCMS m/z 398.1[M+H]⁺。

Example 186

Synthesis I-242

The synthesis scheme is as follows:

step 1: n- (2-bromo-4, 6-difluoro-phenyl) carbamic acid tert-butyl ester

Reacting 3- [2- [ tert-butyloxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (100mg, 178.86. mu. mol, 1 eq), (3-fluorophenyl) boronic acid (75.08mg, 536.57. mu. mol, 3 eq), Pd (dppf) Cl₂(13.09mg, 17.89. mu. mol, 0.1 equiv.), Cs₂CO₃(174.82mg, 536.57. mu. mol, 3 equivalents) and H₂O (2mL) in 1, 4-dioxane (6mL) was placed in the microwave tube. The sealed tube was heated at 110 ℃ for 1 hour under microwave. The reaction mixture was concentrated under reduced pressure to give a residue which was taken up in NaHCO₃Aqueous (20mL) was diluted and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure to give a mixture of3- [2- [ tert-Butoxycarbonyl- [5- (3-fluorophenyl) -3-isopropyl-pyrazolo [1, 5-a ] as a brown solid]Pyrimidin-7-yl]Amino group]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (100mg, 97.77 μmol, 54.7% yield, 60.0% purity), which was used in the next step without further purification.¹HNMR(400MHz，CD₃OD)δppm 7.98(s，1H)，7.94(d，J＝7.6Hz，1H)，7.59(d，J＝1.2Hz，1H)，7.56(d，J＝2.4Hz，1H)，7.53(s，1H)，7.51(s，1H)，7.48(d，J＝3.6Hz，1H)，7.46(d，J＝2.0Hz，1H)，7.26(s，1H)，7.19-7.15(m，1H)，6.65-6.57(m，1H)，4.24-4.21(m，2H)，3.58-3.44(m，1H)，3.11(t，J＝6.4Hz，2H)，1.56(s，9H)，1.50-1.45(m，6H)，1.37(s，9H)；ES-LCMS m/z614.3[M+H]⁺。

Step 2: 5- (3-fluorophenyl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-242)

Reacting 3- [2- [ tert-butyloxycarbonyl- [5- (3-fluorophenyl) -3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl]Amino group]Ethyl radical]A solution of tert-butyl indole-1-carboxylate (80mg, 78.21. mu. mol, 1 eq) in HCl/MeOH (4M, 3mL, 153.43 eq.) in N₂Stirring was carried out under an atmosphere at 25 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Feilomena Gemini C18250X 50mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 10min) and then lyophilized to give 5- (3-fluorophenyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (38.32mg, 76.97 μmol, 98.4% yield, 97.7% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.16(s，1H)，7.55-7.46(m，2H)，7.31-7.36(m，1H)，7.20(d，J＝8.0Hz，1H)，7.10(d，J＝8.8Hz，1H)，7.06-6.92(m，3H)，6.85(t，J＝7.6Hz，1H)，5.74(s，1H)，4.08-3.92(m，2H)，3.29-3.24(m，1H)，3.24-3.19(m，2H)，1.34(d，J＝6.8Hz，6H)；ES-LCMS m/z 414.2[M+H]⁺。

Example 187

Synthesis I-245

The synthesis scheme is as follows:

step 1: 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ols

A mixture of methyl 3-oxo-3- (3-pyridyl) propionate (440mg, 2.46mmol, 1 eq) and 4-isopropyl-1H-pyrazol-5-amine (307.39mg, 2.46mmol, 1 eq) in AcOH (20mL) was stirred at 120 ℃ for 0.5H. The reaction mixture was concentrated under reduced pressure to give 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a as a brown oil]Pyrimidin-7-ol (600mg, 1.60mmol, 65.3% yield, crude, 2HOAC), was used in the next step without further purification.¹HNMR(400MHz，CDCl₃)δppm 9.19-9.17(m，1H)，8.83-8.78(m，1H)，8.27(td，J＝1.9，8.0Hz，1H)，7.50-7.42(m，2H)，7.14(s，1H)，2.84-2.75(m，1H)，1.22(d，J＝2.0Hz，6H)；ES-LCMS m/z 255.1[M+H]⁺。

Step 2: 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidines

3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-ol (600mg, 1.60mmol, 1 eq, 2HOAC) in POCl₃The solution in (15mL) was degassed and N was used₂And purifying for 3 times. The mixture was stirred at 110 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was adjusted to pH 7-8 with TEA. Subjecting the residue to silica gel column chromatography(PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.35) to give 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a) as a green solid]Pyrimidine (100mg, 322.66 μmol, 20.1% yield, 88.0% purity).¹HNMR(400MHz，CDCl₃)δppm 9.33(d，J＝1.8Hz，1H)，8.74(dd，J＝1.5，4.9Hz，1H)，8.46(td，J＝2.0，7.9Hz，1H)，8.13(s，1H)，7.50(dd，J＝4.7，8.0Hz，1H)，7.40(s，1H)，3.42(td，J＝6.9，13.8Hz，1H)，1.46(d，J＝7.1Hz，6H)；ES-LCMS m/z 273.0[M+H]⁺。

Step 3: (3R) -N- [ 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-245)

Reacting 7-chloro-3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a]A mixture of pyrimidine (60mg, 193.60. mu. mol, 1 equivalent), (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (36.06mg, 193.60. mu. mol, 1 equivalent) and DIEA (75.06mg, 580.79. mu. mol, 101.16. mu.L, 3 equivalents) in i-PrOH (10mL) was degassed and N was used₂And purifying for 3 times. Mixing the mixture in N₂Stirred at 80 ℃ for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 42% -70%, 7min) and then lyophilized to give (3R) -N- [ 3-isopropyl-5- (3-pyridyl) pyrazolo [1, 5-a) as a red solid]Pyrimidin-7-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (40.65mg, 76.42 μmol, 39.5% yield, 100.0% purity, 3 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.52(s，1H)，9.17(J＝8.2Hz，1H)，8.97(J＝5.3Hz，1H)，8.21-8.15(m，2H)，7.34(d，J＝7.7Hz，1H)，7.23(d，J＝7.9Hz，1H)，7.10(s，1H)，7.00(t，J＝7.2Hz，1H)，6.95-6.88(m，1H)，4.62(br s，1H)，3.41(td，J＝7.0，13.8Hz，1H)，3.27(J＝4.9Hz，1H)，3.13(J＝9.7Hz，1H)，3.01-2.91(m，2H)，2.42-2.22(m，2H)，1.42(dd，J＝3.1，6.8Hz，6H)；ES-LCMS m/z 423.2[M+H]⁺。

Example 188

Synthesis I-246

The synthesis scheme is as follows:

step 1: 3-isopropyl-4H-pyrazolo [1, 5-a)]Pyrimidine-5, 7-diones

Na (367.33mg, 15.98mmol, 2 equiv.) was added to EtOH (25mL) and the mixture was stirred at 24 ℃ for 2 h. 4-isopropyl-1H-pyrazol-5-amine (1g, 7.99mmol, 1 equiv.) and diethyl malonate (1.41g, 8.79mmol, 1.33mL, 1.1 equiv.) were added to the above reaction mixture and stirred at 80 ℃ for 5 hours. The solution was cooled to room temperature and filtered. The resulting solid was washed with EtOH and dissolved in water (20 mL). The solution was then acidified in an ice bath to pH 1-2 with concentrated hydrochloric acid. The precipitate was filtered, washed with water and dried under reduced pressure to give 3-isopropyl-4H-pyrazolo [1, 5-a as a yellow solid]Pyrimidine-5, 7-dione (300mg, 1.55mmol, 19.4% yield, 100.0% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 7.80-7.73(m，2H)，3.02(td，J＝6.7，13.7Hz，1H)，1.28(d，J＝7.1Hz，6H)；ES-LCMS m/z 194.2[M+H]⁺。

Step 2: 5, 7-dichloro-3-isopropyl-pyrazolo [1, 5-a ]]Pyrimidines

3-isopropyl-4H-pyrazolo [1, 5-a)]Pyrimidine-5, 7-dione (285mg, 1.48mmol, 1 am)Amount) to POCl₃(20 mL). The reaction mixture was stirred at 110 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 5/1, TLC: PE/EtOAc: 10/1, R_f0.30) to yield 5, 7-dichloro-3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidine (300mg, 1.30mmol, 88.4% yield, 100.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.10(s，1H)，6.94-6.90(m，1H)，3.37-3.26(m，1H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 230.1，232.1[M+H]⁺。

Step 3: 5-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amines

To 5, 7-dichloro-3-isopropyl-pyrazolo [1, 5-a ]]To a solution of pyrimidine (200mg, 869.21. mu. mol, 1 eq) in i-PrOH (6mL) was added DIEA (337.02mg, 2.61mmol, 454.20. mu.L, 3 eq.) and 2- (1H-indol-3-yl) ethylamine (167.11mg, 1.04mmol, 1.2 eq.). The mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.60) to yield 5-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (240mg, 672.83 μmol, 77.4% yield, 99.2% purity).¹H NMR(400MHz，CDCl₃)δppm 8.11(s，1H)，7.81(s，1H)，7.62(d，J＝7.8Hz，1H)，7.41(d，J＝8.3Hz，1H)，7.27-7.22(m，1H)，7.20-7.13(m，1H)，7.11(d，J＝2.3Hz，1H)，6.45(s，1H)，5.88(s，1H)，3.71(q，J＝6.6Hz，2H)，3.33-3.18(m，3H)，1.33(d，J＝7.0Hz，6H)；ES-LCMS m/z 354.1，355.1[M+H]⁺。

Step 4: 3- [2- [ tert-Butoxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester

To 5-chloro-N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]To a solution of pyrimidin-7-amine (120mg, 336.42 μmol, 1 eq) in 1, 4-dioxane (6mL) was added DMAP (123.30mg, 1.01mmol, 3 eq) and (Boc)₂O (183.56mg, 841.04. mu. mol, 193.22. mu.L, 2.5 equiv). The mixture was stirred at 110 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.75) to yield 3- [2- [ tert-butoxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a) as a yellow solid]Pyrimidin-7-yl) amino]Ethyl radical]Indole-1-carboxylic acid tert-butyl ester (150mg, 262.33. mu. mol, 77.9% yield, 96.9% purity).¹H NMR(400MHz，CDCl₃)δppm 8.09(d，J＝6.4Hz，1H)，7.97(s，1H)，7.43(d，J＝7.9Hz，1H)，7.35(s，1H)，7.32-7.27(m，1H)，7.20-7.13(m，1H)，6.39(s，1H)，4.21-4.15(m，2H)，3.28(td，J＝7.0，13.9Hz，1H)，3.06(t，J＝7.4Hz，2H)，1.67(s，9H)，1.41(s，9H)，1.36(d，J＝7.1Hz，6H)；ES-LCMS m/z 554.3，556.3[M+H]⁺。

Step 5: 5- (1, 3-benzodioxol-5-yl) -N- [2- (1H-indol-3-yl) ethyl]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidine-7-amine (I-246)

To 3- [2- [ tert-butoxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1, 5-a)]Pyrimidin-7-yl) amino]Ethyl radical]To a solution of indole-1-carboxylic acid tert-butyl ester (100mg, 174.88 μmol, 1 eq) in 1, 4-dioxane (6mL) and water (2mL) was added K₃PO₄(111.37mg, 524.65. mu. mol, 3 equivalents), sphos cyclopalladium (13.30mg, 17.49. mu. mol, 0.1 equivalents) and 1, 3-benzodioxol-5-ylboronic acid (87.06mg, 524.65. mu. mol, 3 equivalents). The mixture is degassed and treated with N₂Purifying for three times and stirring at 110 deg.C under microwaveStirring for 1 hour. The reaction mixture was diluted with EtOAc (50mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in DCM (1mL) and HCl/EtOAc (1mL, 4M) was added. The reaction mixture was stirred at 25 ℃ for 14 hours. The reaction mixture was diluted with water (50mL) and adjusted to pH 2 by 10% aqueous NaOH. The mixture was extracted with EtOAc (50 mL. times.3) over anhydrous Na₂SO₄Drying, filtration and concentration of the filtrate gave a residue which was purified by preparative HPLC (HCl conditions; column: Philomena Gemini 150X 25mm X10 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 30% -60%, 10 min). The desired fractions were lyophilized to give 5- (1, 3-benzodioxol-5-yl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]-3-isopropyl-pyrazolo [1, 5-a]Pyrimidin-7-amine (22.10mg, 43.13 μmol, 25.1% yield, 100.0% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 8.09(s，1H)，7.56(d，J＝7.9Hz，1H)，7.22(d，J＝8.2Hz，1H)，7.08-7.02(m，2H)，6.92-6.86(m，2H)，6.80(d，J＝1.8Hz，1H)，6.73(dd，J＝1.9，8.3Hz，1H)，6.08(s，2H)，5.70(s，1H)，3.99-3.93(m，2H)，3.28-3.18(m，3H)，1.33(d，J＝6.8Hz，6H)；ES-LCMS m/z 440.2[M+H]⁺。

Example 189

Synthesis of I-249a, I-249b and I-249c

The synthesis scheme is as follows:

step 1: 1- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) pyrrolidine

In N₂1, 4-dioxaspiro [4.5 ] under atmosphere]Decan-8-one (18g, 115.25mmol, 1)Equiv.), TsOH (198.47mg, 1.15mmol, 0.01 equiv.) in toluene (200mL) was added pyrrolidine (12.30g, 172.88mmol, 14.43mL, 1.5 equiv.). Mixing the mixture in N₂Stirring was carried out at 110 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated to give 1- (1, 4-dioxaspiro [4.5 ] spiro as a brown oil]Dec-7-en-8-yl) pyrrolidine (24g, 103.21mmol, 89.6% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 4.17(t，J＝3.7Hz，1H)，4.11(s，2H)，4.07-4.05(m，2H)，3.12(t，J＝6.5Hz，2H)，2.97(t，J＝6.2Hz，2H)，2.59(t，J＝7.1Hz，2H)，2.54-2.49(m，1H)，2.45-2.43(m，1H)，2.09(t，J＝7.1Hz，2H)，1.94-1.90(m，2H)，1.87-1.73(m，2H)。

Step 2: 7-benzoylmethyl-1, 4-dioxaspiro [4.5 ]]Decan-8-ones

In N₂1- (1, 4-dioxaspiro [4.5 ] under atmosphere]A solution of dec-7-en-8-yl) pyrrolidine (24g, 103.21mmol, 1 eq) in toluene (200mL) was heated to reflux and toluene (60mL) containing 2-bromo-1-phenyl-ethanone (20.54g, 103.21mmol, 1 eq) was added slowly. Mixing the mixture in N₂Stirred under an atmosphere at 110 ℃ for 2 hours. Followed by the addition of H₂O (60mL) and the mixture in N₂Stirring was continued for a further 2 hours at 110 ℃ under an atmosphere. The mixture was concentrated and water (50mL) was added, followed by extraction with EtOAc (100 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 2/1, TLC: PE/EtOAc: 3/1, R_fNot 0.4) to yield 7-phenacyl-1, 4-dioxaspiro [4.5 ] as a yellow solid]Decan-8-one (13g, 42.65mmol, 41.3% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 8.01-7.93(m，2H)，7.59-7.53(m，1H)，7.49-7.43(m，2H)，4.17-4.06(m，2H)，4.05-3.96(m，2H)，3.64-3.45(m，2H)，2.85-2.68(m，2H)，2.48-2.39(m，1H)，2.25-2.14(m，1H)，2.13-2.02(m，2H)，1.89-1.77(m，1H)；ES-LCMS m/z 275.1[M+H]⁺。

Step 3: 2 '-phenylspiro [1, 3-dioxolane-2, 5' -1, 4, 6, 7-tetrahydroindole]

In a sealed tube, 7-phenacyl-1, 4-dioxaspiro [4.5 ]]Decan-8-one (5g, 16.40mmol, 1 eq.) and (NH)₄)₂CO₃(5.00g, 52.04mmol, 5.56mL, 3.17 equiv.) of the mixture in N₂Stirred under an atmosphere at 110 ℃ for 2 hours. Water (50mL) was added to the mixture, which was extracted with EtOAc (100 mL. times.2). The combined organic layers were washed with brine (40mL) and Na₂SO₄Drying, filtering and concentrating to obtain 2 '-phenylspiro [1, 3-dioxolane-2, 5' -1, 4, 6, 7-tetrahydroindole as brown solid](4g, 14.10mmol, 86.0% yield, 90% purity).¹H NMR(400MHz，CDCl₃)δppm 8.07-7.86(m，1H)，7.40(d，J＝7.8Hz，2H)，7.36-7.29(m，2H)，7.20-7.10(m，1H)，6.25(d，J＝2.4Hz，1H)，4.08-3.99(m，4H)，2.84(t，J＝6.6Hz，2H)，2.80(s，2H)，2.02(t，J＝6.5Hz，2H)；ES-LCMS m/z 256.1[M+H]⁺。

Step 4: 2-phenyl-1, 4, 6, 7-tetrahydroindol-5-ones

To 2 '-phenylspiro [1, 3-dioxolane-2, 5' -1, 4, 6, 7-tetrahydroindole](3.9g, 13.75mmol, 1 equiv.) to a solution in acetone (30mL) was added HCl (1M, 13.75mL, 1 equiv.) and the mixture was stirred at 50 ℃ for 3 h. The mixture was concentrated and diluted with saturated NaHCO₃The solution was adjusted to pH 7 and extracted with EtOAc (80 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 2/1, TLC: PE/EtOAc: 3/1, R_fNot 0.3) to give 2-phenyl as a yellow solid-1, 4, 6, 7-tetrahydroindol-5-one (0.7g, 2.32mmol, 16.9% yield, 70.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.15(s，1H)，7.44(d，J＝7.6Hz，2H)，7.36(t，J＝7.7Hz，2H)，7.23-7.17(m，1H)，6.29(d，J＝2.4Hz，1H)，3.45(s，2H)，3.09-3.03(m，2H)，2.74(t，J＝6.8Hz，2H)；ES-LCMS m/z 212.1[M+H]⁺。

Step 5: 2-phenyl-1, 4, 6, 7-tetrahydroindol-5-ketoxime

To a solution of 2-phenyl-1, 4, 6, 7-tetrahydroindol-5-one (600mg, 1.99mmol, 1 equiv.) in THF (15mL) was added NaOAc (244.64mg, 2.98mmol, 1.5 equiv.) and NH₂OH HCl (165.78mg, 2.39mmol, 1.2 equiv.). The mixture was stirred at 60 ℃ for 3 hours. The mixture was filtered. The filtrate was concentrated to give a residue which was subjected to silica gel column chromatography (pure PE to PE/EtOAc-1/1, TLC: PE/EtOAc-1/1, R_f0.4) to give 2-phenyl-1, 4, 6, 7-tetrahydroindol-5-one oxime as a red solid (350mg, 1.24mmol, 62.2% yield, 80% purity).¹H NMR(400MHz，CDCl₃)δppm 8.02(s，1H)，7.47-7.41(m，2H)，7.38-7.33(m，2H)，7.21-7.16(m，1H)，6.32(d，J＝2.4Hz，1H)，3.66(s，2H)，2.89-2.81(m，2H)，2.71-2.63(m，1H)；ES-LCMS m/z 227.1[M+H]⁺。

Step 6: 2-phenyl-4, 5, 6, 7-tetrahydro-1H-indol-5-amines

In N₂To a solution of 2-phenyl-1, 4, 6, 7-tetrahydroindol-5-one oxime (350mg, 1.24mmol, 1 eq) in MeOH (6mL) was added raney nickel (200mg, 2.33mmol, 1.89 eq) under atmosphere. Mixing the mixture in H₂Stirring was carried out at 20 ℃ for 1 hour under an atmosphere of (15 psi). The mixture was filtered. The filtrate was concentrated to give 2-phenyl-4, 5, 6, 7-tetrakis (phenyl-4-phenyl-7-tetra-ethyl) as a dark brown solidhydro-1H-indol-5-amine (250mg, 942.11. mu. mol, 76.1% yield, 80% purity).¹H NMR(500MHz，CD₃OD)δppm 7.50-7.46(m，2H)，7.26(t，J＝7.9Hz，2H)，7.09-7.03(m，1H)，6.18(s，1H)，3.12-3.04(m，1H)，2.86-2.63(m，3H)，2.30(dd，J＝8.9，14.8Hz，1H)，2.05-1.97(m，1H)，1.73-1.64(m，1H)；ES-LCMS m/z 213.2[M+H]⁺。

Step 7: 2- (5-fluoro-3-pyridinyl) -8-isopropyl-N- [ (5R) -2-phenyl-4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (I-249b) and 2- (5-fluoro-3-pyridyl) -8-isopropyl-N- [ (5S) -2-phenyl-4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-249a)

To a solution of 2-phenyl-4, 5, 6, 7-tetrahydro-1H-indol-5-amine (207.84mg, 783.24. mu. mol, 1.2 equivalents) and DIEA (253.07mg, 1.96mmol, 341.07. mu.L, 3 equivalents) in i-PrOH (15mL) was added 4-chloro-2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a ]][1，3，5]Triazine (200mg, 652.70. mu. mol, 1 equivalent). The mixture was stirred at 50 ℃ for 2 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 2/1, TLC: PE/EtOAc: 2/1, R_f0.5) to yield a residue which was purified by SFC (column: xylonite CHIRALCEL OJ-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O EtOH](ii) a B%: 40% -40%, min) to obtain peak 1 and peak 2. Peak 1 was concentrated and purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN]75% -100% for B), followed by lyophilization to give the enantiomer as a yellow solid (18.68mg, 31.16 μmol, 4.8% yield, 96.249% purity, 3HCl, SFC: Rt 5.229min, ee 95.522%, [ α%, (8 min)]^26.5 _D＝+24.339，(CHCl₃，c＝0.1015g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.89(s，1H)，9.38(s，1H)，8.89(d，J＝8.6Hz，1H)，8.70(d，J＝2.9Hz，1H)，8.43(td，J＝2.2，9.8Hz，1H)，8.18-8.07(m，1H)，7.55(d，J＝7.6Hz，2H)，7.30(t，J＝7.7Hz，2H)，7.14-7.03(m，1H)，6.27(d，J＝2.2Hz，1H)，4.77-4.60(m，1H)，3.26-3.15(m，1H)，2.93-2.71(m，4H)，2.17-2.00(m，2H)，1.36(d，J＝7.1Hz，6H)；ES-LCMS m/z 468.3[M+H]⁺. Peak 2 concentration gave a residue, which was dissolved in MeCN (20mL), 1M HCl solution (1.2mL) and H₂O (40mL) followed by lyophilization afforded the other-enantiomer as a yellow solid (23.41mg, 40.58 μmol, 6.2% yield, 100% purity, 3HCl, SFC: Rt 6.074min, ee 100%, [ α%]^26.5 _D＝-26.002，(CHCl₃，c＝0.1002g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.90(br s，1H)，9.38(s，1H)，8.89(d，J＝8.6Hz，1H)，8.70(d，J＝2.7Hz，1H)，8.43(d，J＝9.8Hz，1H)，8.23-8.04(m，1H)，7.55(d，J＝7.6Hz，2H)，7.30(t，J＝7.8Hz，2H)，7.17-7.03(m，1H)，6.27(d，J＝2.2Hz，1H)，4.68(d，J＝5.1Hz，1H)，3.27-3.13(m，1H)，2.92-2.66(m，4H)，2.19-2.00(m，2H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 468.3[M+H]⁺。

Example 190

Synthesis of I-252a, I-252b and I-252c

The synthesis scheme is as follows:

step 1: 2-chloro-N- (4, 5, 6, 7-tetrahydro-1H-indol-5-yl) pyrido [3, 2-d]Pyrimidin-4-amines

2, 4-dichloropyrido [3, 2-d ]]Pyrimidine (150mg, 749.91. mu. mol, 1 equiv.), 4, 5, 6, 7-tetrahydro-1H-indol-5-amine (113.48mg, 74 mg)A mixture of 9.91. mu. mol, 1 eq) and DIEA (387.68mg, 3.00mmol, 522.48. mu.L, 4 eq) in i-PrOH (10mL) was stirred at 55 ℃ for 2 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 3/1 to 1/1, TLC: PE/EtOAc: 1/1, R_f0.50) to yield 2-chloro-N- (4, 5, 6, 7-tetrahydro-1H-indol-5-yl) pyrido [3, 2-d) as a yellow solid]Pyrimidin-4-amine (120mg, 397.52 μmol, 53.0% yield, 99.3% purity).¹H NMR(400MHz，CDCl₃)δppm 8.64(dd，J＝1.5，4.3Hz，1H)，8.01(dd，J＝1.5，8.5Hz，1H)，7.85(s，1H)，7.64(dd，J＝4.3，8.3Hz，1H)，7.44(d，J＝8.5Hz，1H)，6.70(t，J＝2.6Hz，1H)，6.04(t，J＝2.6Hz，1H)，4.80-4.70(m，1H)，3.10(dd，J＝5.3，15.3Hz，1H)，2.99-2.45(m，3H)，2.24-2.08(m，2H)；ES-LCMS m/z 300.1[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -N- [ (5R) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrido [3, 2-d]Pyrimidin-4-amine (I-252b) and 2- (5-fluoro-3-pyridinyl) -N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrido [3, 2-d]Pyrimidine-4-amine (I-252a)

2-chloro-N- (4, 5, 6, 7-tetrahydro-1H-indol-5-yl) pyrido [3, 2-d]Pyrimidin-4-amine (120mg, 397.52 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (168.04mg, 1.19mmol, 3 eq), Pd (dppf) Cl₂(29.09mg, 39.75. mu. mol, 0.1 equiv.) and Cs₂CO₃(518.08mg, 1.59mmol, 4 equiv.) in 1, 4-dioxane (3mL) and H₂O (1mL) placed in a microwave tube and N₂The atmosphere was purged for 1 minute. The sealed tube was heated at 110 ℃ for 1 hour under microwave. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (pure PE to PE/EtOAc: 1/1, TLC: PE/EtOAc: 2/1, R_f0.40) to yield a residue which was purified by chiral SFC (column: xylonite CHIRALCEL OJ-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂O EtOH](ii) a B%: 40% -40%) to obtainTo the enantiomer (19.36mg, 52.04 μmol, 13.1% yield, 96.9% purity, SFC: Rt 4.040, ee 100%, optical rotation [ α% ] [ α ]]^23.9 _D＝-8.542(CHCl₃，c＝0.075g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.43(s，1H)，8.71(dd，J＝1.5，4.2Hz，1H)，8.56-8.48(m，2H)，8.15(dd，J＝1.5，8.6Hz，1H)，7.76-7.73(m，1H)，6.62(d，J＝2.4Hz，1H)，5.90(d，J＝2.4Hz，1H)，4.84-4.78(m，1H)，3.09(dd，J＝4.9，15.2Hz，1H)，2.85-2.69(m，3H)，2.27(d，J＝12.5Hz，1H)，2.14(d，J＝6.6Hz，1H)；ES-LCMS m/z 361.2[M+H]⁺And the other enantiomer (17.54mg, 47.86 μmol, 12.0% yield, 98.3% purity) as a red solid (SFC: Rt 4.941, ee 100%, optical rotation [ α: []^25.0 _D＝+10.973(CHCl₃，c＝0.054g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.44(s，1H)，8.71(dd，J＝1.2，4.2Hz，1H)，8.57-8.49(m，2H)，8.16(dd，J＝1.2，8.6Hz，1H)，7.75(dd，J＝4.2，8.6Hz，1H)，6.64(s，1H)，5.92(d，J＝2.4Hz，1H)，4.86-4.81(m，1H)，3.11(dd，J＝5.0，15.0Hz，1H)，2.88-2.70(m，3H)，2.28(d，J＝9.8Hz，1H)，2.19-2.11(m，1H)；ES-LCMS m/z 361.2[M+H]⁺。

Example 191

Synthesis I-253

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (2-tetrahydropyran-2-ylpyrazol-3-yl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

Reacting (3R) -N- [ 8-bromo-2- (5-fluoro-3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (100mg, 202.79. mu. mol, 1 eq.), Cs₂CO₃(66.07mg, 202.79. mu. mol, 1 eq.), Pd (dppf) Cl₂(148.39mg, 202.79. mu. mol, 1 eq.) and 1-tetrahydropyran-2-yl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (56.41mg, 202.79. mu. mol, 1 eq.) in 1, 4-dioxane (6mL) and H₂O (2mL) was placed in the microwave tube. The sealed tube was heated under microwave at 110 ℃ for 30 minutes. TLC (PE/EtOAc ═ 1/1, R_f0.4) indicates complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EA ═ 1/0 to 1/1, TLC: PE/EtOAc ═ 1/1, R_f0.4) to yield (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (2-tetrahydropyran-2-ylpyrazol-3-yl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (70mg, 122.27 μmol, 60.3% yield, 96.0% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.82(s，1H)，9.41-9.38(m，2H)，8.73(d，J＝2.7Hz，1H)，8.49-8.47(d，J＝9.0Hz，1H)，8.38(s，1H)，7.64(s，1H)，7.37-7.35(d，J＝7.8Hz，1H)，7.29-7.27(d，J＝7.8Hz，1H)，7.02-6.99(m，1H)，6.95-6.92(m，1H)，6.74(s，1H)，5.66-5.64(d，J＝9.0Hz，1H)，4.89(d，1H)，3.95-3.91(m，2H)，3.59-3.57(m，1H)，3.15-2.88(m，4H)，2.23(brs，2H)，1.64-1.52(m，3H)，1.23(m，1H)，0.85-0.83(d，J＝7.8Hz，1H)；ES-LCMS m/z 550.3[M+H]⁺。

Step 2: (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (1H-pyrazol-5-yl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-253)

Mixing (3R) -N- [2- (5-fluoro-3-pyridyl) -8- (2-tetrahydropyran-2-yl pyrazol-3-yl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]A solution of-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (70mg, 122.27 μmol, 1 eq) in HCl/MeOH (10mL) was stirred at 15 ℃ for 20 min. NaHCO for reaction mixture₃Basified with aqueous until pH 7-8, extracted with EtOAc (50 mL. times.3) over Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 53% -83%, 8min) to give (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (1H-pyrazol-5-yl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (19.45mg, 33.83 μmol, 27.7% yield, 100.0% purity, 3HCl, [ α ]]^26.4 _D＝+13.329(MeOH，c＝0.098g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.82(s，1H)，9.51(s，1H)，9.29-9.27(d，J＝8.6Hz，1H)，8.75(d，J＝2.7Hz，1H)，8.68(d，J＝10.0Hz，1H)，8.64(s，1H)，7.84-7.83(d，J＝2.0Hz，1H)，7.37-7.35(d，J＝7.6Hz，1H)，7.29-7.27(d，J＝8.1Hz，1H)，7.04-7.00(m，2H)，6.95-6.93(m，1H)，4.89-4.87(d，J＝7.6Hz，1H)，3.17-3.12(m，J＝5.5，14.8Hz，1H)，3.04-2.88(m，3H)，2.24-2.23(d，J＝3.7Hz，2H)；ES-LCMS m/z 466.2[M+H]⁺。

Example 192

Synthesis I-254

The synthesis scheme is as follows:

step 1: (3R) -3- [ tert-Butoxycarbonyl- (8-isopropyl-2-morpholinyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Reacting tert-butyl- (3R) -3- [ tert-butoxycarbonyl- (8-isopropyl-2-methylsulfinyl-pyrazolo [1, 5-a ]][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (100mg, 156.06 μmol, 1 equiv.) and morpholine (40.79mg, 468.17 μmol, 41.20 μ L, 3 equiv.) in t-BuOH (4mL) were placed in a microwave tube and N was used₂And purifying for 1 minute. The sealed tube was heated at 120 ℃ for 2 hours under microwave. The reaction mixture was concentrated to give (3R) -3- [ tert-butoxycarbonyl- (8-isopropyl-2-morpholinyl-pyrazolo [1, 5-a) as a yellow oil][1，3，5]Triazin-4-yl) amino]Tert-butyl 1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (100mg, 142.46 μmol, 91.3% yield, 90% purity), which was used in the next step without purification.¹H NMR(400MHz，CDCl₃)δppm 8.10(d，J＝8.0Hz，1H)，7.82(s，1H)，7.35(d，J＝7.5Hz，1H)，7.22(dd，J＝6.7，13.9Hz，2H)，4.74(s，1H)，3.79-3.74(m，8H)，3.23(d，J＝10.8Hz，2H)，3.15-3.07(m，3H)，2.26(d，J＝4.3Hz，2H)，1.65(s，9H)，1.36(s，9H)，1.33(d，J＝7.0Hz，6H)；ES-LCMS m/z 632.3[M+H]⁺。

Step 2: (3R) -N- (8-isopropyl-2-morpholinyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-254)

To (3R) -3- [ tert-butyloxycarbonyl- (8-isopropyl-2-morpholinyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]To a solution of tert-butyl (1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (100mg, 142.46 μmol, 1 eq) in DCM (4mL) was added TFA (1.54g, 13.51mmol, 1mL, 94.81 eq). The reaction mixture was stirred at 20 ℃ for 0.5 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 8min) and then lyophilized to give (3R) -N- (8-isopropyl-2-morpholinyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetraHydrogen-1H-carbazol-3-amine (28.19mg, 59.32 μmol, 41.6% yield, 98.5% purity, HCl, [ α ]]^24.7 _D＝+84.327，MeOH，c＝0.074g/100mL)。¹H NMR(400MHz，CD₃OD)δppm 7.95(s，1H)，7.37(d，J＝7.8Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.08-7.02(m，1H)，7.00-6.94(m，1H)，4.72-4.63(m，1H)，3.93-3.87(m，4H)，3.83-3.78(m，4H)，3.27-3.19(m，2H)，3.03-2.86(m，3H)，2.35-2.18(m，2H)，1.32(d，J＝6.8Hz，6H)；ES-LCMS m/z 432.3[M+H]⁺。

Example 193

Synthesis I-255

The synthesis scheme is as follows:

step 1: (3R) -N- [ 8-isopropyl-2- (3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-255)

The compound containing (3R) -N- (8-isopropyl-2-methylthio-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (100mg, 242.03. mu. mol, 1 eq.), 3-pyridylboronic acid (89.25mg, 726.08. mu. mol, 3 eq.), Pd (PPh)₃)₄1, 4-dioxane (3mL) (27.97mg, 24.20. mu. mol, 0.1 equiv.) and copper thiophene-2-carbonyl oxo (138.46mg, 726.08. mu. mol, 3 equiv.) was placed in a microwave tube and N was used₂And purifying for 1 minute. The sealed tube was heated at 120 ℃ for 2 hours under microwave. The reaction mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 35% -65%, 8min) and then lyophilized to give (3R) as a yellow solid-N- [ 8-isopropyl-2- (3-pyridyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (28.39mg, 56.08 μmol, 23.2% yield, 98.1% purity, 2HCl, [ α%]^25.1 _D＝+34.261(MeOH，c＝0.071g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.69(s，1H)，9.49(d，J＝8.3Hz，1H)，8.89(d，J＝4.5Hz，1H)，8.16-8.10(m，1H)，8.06(s，1H)，7.38(d，J＝7.8Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.08-7.03(m，1H)，7.00-6.94(m，1H)，4.90-4.88(m，1H)，3.37-3.34(m，1H)，3.30(d，J＝7.0Hz，1H)，3.13-2.90(m，3H)，2.44-2.24(m，2H)，1.45(d，J＝7.0Hz，6H)；ES-LCMS m/z 424.3[M+H]⁺。

Example 194

Synthesis I-256

The synthesis scheme is as follows:

step 1: 1-Aminoimidazole-2-carboxylic acid ethyl ester

To a solution of ethyl 1H-imidazole-2-carboxylate (1g, 7.14mmol, 1 eq) in DMF (80mL) cooled to-10 ℃ was added LiHMDS (1M, 7.85mL, 1.1 eq). The mixture was stirred at-10 ℃ for 0.5 h. To the mixture was added N-diphenylphosphorylhydroxylamine (1.83g, 7.85mmol, 1.1 equiv). The mixture was stirred at 15 ℃ for 11.5 hours. The mixture was saturated with NH at-10 deg.C₄Aqueous Cl (50mL) was quenched. The mixture was concentrated and EtOAc (100mL) was added to the residue. After filtration, washing with EtOAc (50mL × 3), the filtrate was concentrated to give ethyl 1-aminoimidazole-2-carboxylate (3g, crude) as a yellow solid, which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 7.10(s，1H)，6.98(s，1H)，5.74(s，2H)，4.33(q，J＝7.2Hz，2H)，1.36-1.33(m，3H)；ES-LCMS m/z 156.0[M+H]⁺。

Step 2: 1- [ bis (ethoxycarbonyl) amino]Imidazole-2-carboxylic acid ethyl ester

To 1-aminoimidazole-2-carboxylic acid ethyl ester (5.3g, 17.08mmol, 1 eq) in THF (80mL) and H₂To a solution in O (80mL) was added Na₂CO₃(12.67g, 119.56mmol, 7 equiv.) and ethyl chloroformate (8.47g, 78.05mmol, 7.43mL, 4.57 equiv.). The mixture was stirred at 15 ℃ for 2 hours. Adding H to the mixture₂O (100mL), extracted with EtOAc (100 mL. times.2). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated. The residue was subjected to silica gel column chromatography (pure PE to PE/EtOAc-3/1, TLC: PE/EtOAc-3/1, R_f0.6) to give 1- [ bis (ethoxycarbonyl) amino group as a yellow solid]Imidazole-2-carboxylic acid ethyl ester (2.69g, 6.29mmol, 36.8% yield, 70% purity).¹H NMR(400MHz，CDCl₃)δppm 7.30(d，J＝1.0Hz，1H)，7.10(s，1H)，4.44-4.33(m，4H)，4.19-4.08(m，2H)，1.39(td，J＝7.3，16.3Hz，6H)，1.08(t，J＝7.2Hz，3H)；ES-LCMS m/z 300.1[M+H]⁺。

Step 3: 1H-imidazo [2, 1-f)][1，2，4]Triazine-2, 4-diones

1- [ bis (ethoxycarbonyl) amino]Imidazole-2-carboxylic acid ethyl ester (2.1g, 4.91mmol, 1 eq.) and NH₃·H₂A solution of O (97.50g, 778.99mmol, 107.14mL, 158.59 equivalents) in i-PrOH (20mL) was stirred in a sealed tube at 120 ℃ for 16 h. The mixture was concentrated. To the residue was added PE/MeOH (10/1, 50mL) and stirred at room temperature for 10 min. After filtration, the filter cake was washed with PE/MeOH (10/1, 15mL) and dried in vacuo. Crude product (1)g) Column chromatography over silica gel (DCM/MeOH-10/1 to 1/2, TLC: DCM/MeOH 10/1, R_f0.3) to yield 1H-imidazo [2, 1-f)][1，2，4]Triazine-2, 4-dione (0.9g, 96.4% yield, 80.0% purity).¹H NMR(400MHz，DMSO-d₆)δppm 10.02(br s，1H)，7.24(s，1H)，7.13(br s，1H)，7.07(s，1H)。

Step 4: 2, 4-dichloroimidazo [2, 1-f)][1，2，4]Triazine

1H-imidazo [2, 1-f ] in a sealed tube][1，2，4]Triazine-2, 4-dione (500mg, 2.63mmol, 1 eq.), N-diethylethanamine hydrochloride (723.95mg, 5.26mmol, 2 eq.) and POCl₃(87.18g, 568.57mmol, 52.84mL, 216.21 equiv.) the mixture was stirred at 120 ℃ for 24 h. The mixture was concentrated and DCM (30mL) was added to the residue. The mixture was poured into ice-cold water (50mL) and extracted with DCM (30mL × 2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtering and concentrating to obtain 2, 4-dichloroimidazo [2, 1-f ] as a yellow solid][1，2，4]Triazine (400mg, 1.27mmol, 48.3% yield, 60% purity).¹H NMR(400MHz，CDCl₃)δppm 8.09(s，1H)，8.02(s，1H)；ES-LCMS m/z 189.2，191.1[M+H]⁺。

Step 5: (3R) -N- (2-chloroimidazo [2, 1-f)][1，2，4]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

2, 4-dichloroimidazo [2, 1-f)][1，2，4]Triazine (400mg, 1.27mmol, 1 equiv.), DIEA (492.34mg, 3.81mmol, 663.53. mu.L, 3 equiv.), and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (236.51mg, 1.27mmol, 1 equiv.) in CH₃The mixture in CN (15mL) was stirred at 70 ℃ for 6 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc ═ 5/1 to 1/2, TLC:PE/EtOAc＝1/1，R_fpurification No. 0.4) to give (3R) -N- (2-chloroimidazo [2, 1-f) as a yellow solid][1，2，4]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (220mg, 636.38 μmol, 50.1% yield, 98.0% purity).¹H NMR(400MHz，CDCl₃)δppm 7.83(br s，1H)，7.67(s，1H)，7.48-7.36(m，2H)，7.30(d，J＝7.8Hz，1H)，7.18-7.12(m，1H)，7.11-7.04(m，1H)，6.84(d，J＝7.3Hz，1H)，4.86-4.84(m，1H)，3.27(dd，J＝4.9，15.7Hz，1H)，2.98-2.80(m，3H)，2.29-2.17(m，2H)；ES-LCMS m/z 339.1[M+H]⁺。

Step 6: (3R) -N- [2- (5-fluoro-3-pyridinyl) imidazo [2, 1-f)][1，2，4]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-256)

Reacting (3R) -N- (2-chloroimidazo [2, 1-f)][1，2，4]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (100mg, 289.26 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (81.52mg, 578.52 μmol, 2 eq), Cs₂CO₃(282.74mg, 867.78. mu. mol, 3 equiv.) and Pd (dppf) Cl₂(21.17mg, 28.93. mu. mol, 0.1 equiv.) in 1, 4-dioxane (2mL) and H₂Mixture in O (0.5mL) in N₂Stirred under an atmosphere at 110 ℃ for 2 hours. After filtration, the filtrate was concentrated. The residue was purified by preparative TLC (PE/EtOAc ═ 1/1, R)_f0.3) to yield (3R) -N- [2- (5-fluoro-3-pyridinyl) imidazo [2, 1-f) as a yellow solid][1，2，4]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60.97mg, 152.65 μmol, 52.8% yield, 100% purity, [ α ]]^26.9 _D＝+9.272(MeOH，c＝0.101g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.30(s，1H)，8.54(d，J＝2.7Hz，1H)，8.42(td，J＝2.1，9.8Hz，1H)，7.96(d，J＝1.0Hz，1H)，7.55(s，1H)，7.36(d，J＝7.6Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.05-6.97(m，1H)，6.96-6.89(m，1H)，4.98-4.90(m，1H)，3.26(br s，1H)，2.97(t，J＝5.7Hz，2H)，2.90(dd，J＝7.2，15.3Hz，1H)，2.40-2.32(m，1H)，2.31-2.21(m，1H)；ES-LCMS m/z 399.9[M+H]⁺。

Example 195

Synthesis I-257

The synthesis scheme is as follows:

step 1: 2-chloro-N- [2- (1H-indol-3-yl) ethyl]Pyrido [3, 2-d]Pyrimidin-4-amines

To 2, 4-dichloropyrido [3, 2-d ]]To a solution of pyrimidine (100mg, 499.94. mu. mol, 1 eq) in THF (3mL) was added DIEA (193.84mg, 1.50mmol, 261.24. mu.L, 3 eq.) and 2- (1H-indol-3-yl) ethylamine (88.11mg, 549.93. mu. mol, 1.1 eq.). The mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.2) to yield 2-chloro-N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrido [3, 2-d]Pyrimidin-4-amine (90mg, 271.57 μmol, 54.3% yield, 97.7% purity).¹H NMR(400MHz，CDCl₃)δppm 8.61(dd，J＝1.3，4.3Hz，1H)，8.07(s，1H)，8.01(dd，J＝1.3，8.4Hz，1H)，7.71(d，J＝7.8Hz，1H)，7.63(dd，J＝4.3，8.4Hz，1H)，7.47(s，1H)，7.41(d，J＝8.1Hz，1H)，7.24(t，J＝7.5Hz，1H)，7.18-7.12(m，2H)，4.03(q，J＝6.7Hz，2H)，3.22(t，J＝6.8Hz，2H)；ES-LCMS m/z 324.1[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl]Pyrido [3, 2-d]Pyrimidine-4-amine (I-257)

2-chloro-N- [2- (1H-indol-3-yl) ethyl]Pyrido [3, 2-d]Pyrimidin-4-amine (50mg, 150.87 μmol, 1 eq), (5-fluoro-3-pyridinyl) boronic acid (25.51mg, 181.05 μmol, 1.2 eq), Pd (dppf) Cl₂(11.04mg, 15.09. mu. mol, 0.1 equiv.) and Cs₂CO₃(147.47mg, 452.62. mu. mol, 3 equiv.) in 1, 4-dioxane (2mL) and H₂O (1mL) was placed in a microwave tube. The sealed tube was heated at 110 ℃ for 0.5 hour under microwave. The reaction mixture was diluted with water (5mL) and extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: Xtimate C18150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 8min) and then lyophilized to give 2- (5-fluoro-3-pyridinyl) -N- [2- (1H-indol-3-yl) ethyl as a yellow solid]Pyrido [3, 2-d]Pyrimidin-4-amine (24.02mg, 51.42 μmol, 34.1% yield, 97.9% purity, 2 HCl).¹H NMR(400MHz，CD₃OD)δppm 9.03(s，1H)，9.01(dd，J＝1.3，4.3Hz，1H)，8.82(d，J＝2.7Hz，1H)，8.20(dd，J＝1.5，8.6Hz，1H)，8.10-8.05(m，1H)，8.01(dd，J＝4.3，8.7Hz，1H)，7.56(d，J＝7.8Hz，1H)，7.14(d，J＝8.1Hz，1H)，7.05(s，1H)，6.92(t，J＝7.2Hz，1H)，6.85-6.71(m，1H)，4.26(t，J＝6.6Hz，2H)，3.26(t，J＝6.6Hz，2H)；ES-LCMS m/z 385.2[M+H]⁺。

Example 196

Synthesis I-258

The synthesis scheme is as follows:

step 1: (3R) -N- [2- (3, 6-dihydro-2H-pyran-4-yl) -8-isopropyl-pyrazoleAnd [1, 5-a ]][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

Stirring (3R) -N- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]A solution of triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (300mg, 703.15 μmol, 1 eq) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (443.15mg, 2.11mmol, 3 eq) in 1, 4-dioxane (15mL) was degassed and degassed with N₂Purging was followed by addition of thiophene-2-carbonyl copper oxo (268.17mg, 1.41mmol, 2 equiv.) and Pd2(dba)3(64.39mg, 70.31. mu. mol, 0.1 equiv.). The reaction mixture is stirred under N₂Stirring was carried out at 130 ℃ for 12 hours under an atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc: 100/1 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.55) to yield (3R) -N- [2- (3, 6-dihydro-2H-pyran-4-yl) -8-isopropyl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (60mg, 127.97 μmol, 18.2% yield, 91.4% purity).¹H NMR(400MHz，CD₃OD)δppm 7.87(s，1H)，7.37(d，J＝7.6Hz，1H)，7.29-7.20(m，2H)，7.03(t，J＝7.1Hz，1H)，6.98-6.92(m，1H)，4.73(s，1H)，4.34(d，J＝2.7Hz，2H)，3.89(t，J＝5.5Hz，2H)，3.29-3.15(m，2H)，3.00-2.91(m，2H)，2.86(dd，J＝8.9，15.0Hz，1H)，2.69(d，J＝1.7Hz，2H)，2.32(s，1H)，2.26-2.17(m，1H)，1.35(d，J＝7.1Hz，6H)；ES-LCMS m/z 429.3[M+H]⁺。

Step 2: (3R) -N- (8-isopropyl-2-tetrahydropyran-4-yl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-258)

To the stirred (3R) -N- [2- (3, 6-bishydro-2H-pyran-4-yl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]A solution of-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (55mg, 117.31 μmol, 1 eq) in MeOH (20mL) was added Pd/C (0.1g, 10% wt). The reaction mixture is reacted in H₂Stirring was carried out at 20 ℃ for 5 hours under an atmosphere (15 psi). The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 55% -85%, 8 min). Lyophilizing the desired fractions to obtain (3R) -N- (8-isopropyl-2-tetrahydropyran-4-yl-pyrazolo [1, 5-a) as a white solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (16.60mg, 36.74. mu. mol, 31.3% yield, 95.3% purity, [ α ]]^25.0 _D＝+9.739(MeOH，c＝0.098g/100mL))。¹H NMR(400MHz，CD₃OD)δppm8.08(s，1H)，7.37(d，J＝7.8Hz，1H)，7.27(d，J＝8.0Hz，1H)，7.07-7.01(m，1H)，6.99-6.93(m，1H)，4.86-4.77(m，1H)，4.05(dd，J＝2.0，11.5Hz，2H)，3.61-3.50(m，2H)，3.28-3.17(m，2H)，3.10-2.88(m，4H)，2.39-2.20(m，2H)，2.11-1.98(m，2H)，1.96-1.87(m，2H)，1.35(d，J＝6.8Hz，6H)；ES-LCMS m/z 431.3[M+H]⁺。

Example 197

Synthesis of I-259a, I-259b and I-259c

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -8-methyl-N- [ (5R) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazin-4-amine (I-259b) and 2- (5-fluoro-3-pyridyl) -8-methyl-N- [ (5S) -4, 5, 6, 7-tetrahydro-1H-indol-5-yl]Pyrazolo [1, 5-a][1，3，5]Triazine-4-amine (I-259a)

Reacting 4-chloro-2- (5-fluoro-3-pyridyl) -8-methyl-pyrazolo [1, 5-a][1，3，5]A mixture of triazine (100mg, 379.28. mu. mol, 1 eq), 4, 5, 6, 7-tetrahydro-1H-indol-5-amine (56.82mg, 417.21. mu. mol, 1.1 eq) and DIEA (147.06mg, 1.14mmol, 198.19. mu.L, 3 eq) in i-PrOH (3mL) was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica chromatography (PE/EtOAc: 1/0 to 2/1, TLC: PE/EtOAc: 1/1, R_fPurification at 0.60) afforded the crude product, which was purified by chiral SFC (column: xylonite CHIRALPAKAD (250 mm. times.50 mm, 10 μm); mobile phase: [ 0.1% NH ]₃H₂O/IPA](ii) a B%: 40% -40%) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to give a residue which was dissolved in MeCN (20mL) and H₂O (40mL) and lyophilized to give the enantiomer as an off-white solid (20.50mg, 56.41 μmol, 14.9% yield, 100.0% purity, SFC: R_t＝1.488，ee＝100％，[α]^26.1 _D＝-32.731(CHCl₃，c＝0.108g/100mL))。¹H NMR(400MHz，CDCl₃)δppm 9.51(s，1H)，8.56(d，J＝2.8Hz，1H)，8.50-8.41(m，1H)，7.94-7.87(m，1H)，7.85(s，1H)，6.72(t，J＝2.4Hz，1H)，6.66(d，J＝8.0Hz，1H)，6.05(t，J＝2.4Hz，1H)，4.88-4.77(m，1H)，3.17(dd，J＝4.8，15.2Hz，1H)，2.88-2.71(m，3H)，2.35(s，3H)，2.28(dq，J＝2.4，6.0Hz，1H)，2.23-2.12(m，1H)；ES-LCMS m/z 364.2[M+H]⁺. Peak 2 was concentrated under reduced pressure to give a residue which was dissolved in MeCN (20mL) and H₂O (40mL) and lyophilized to give the other enantiomer as an off-white solid (19.32mg, 53.17. mu. mol, 14.0% yield, 100.0% purity, SFC: R_t＝1.691，ee＝100％，[α]^26.0 _D＝+10.595(CHCl₃，c＝0.102g/100mL))。¹H NMR(400MHz，CDCl₃)δppm 9.51(br s，1H)，8.56(br s，1H)，8.46(d，J＝9.2Hz，1H)，7.90(s，1H)，7.85(s，1H)，6.72(s，1H)，6.66(d，J＝8.4Hz，1H)，6.05(s，1H)，4.90-4.80(m，1H)，3.16(d，J＝10.8Hz，1H)，2.87-2.73(m，3H)，2.35(s，3H)，2.30-2.22(m，1H)，2.20-2.10(m，1H)；ES-LCMS m/z 364.2[M+H]⁺。

Example 198

Synthesis I-262

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid esters

2- (5-fluoro-3-pyridyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]A solution of triazine-8-carbonitrile (200mg, 335.51. mu. mol, 1 eq.) in HCl/MeOH (4M, 10mL) was stirred in a sealed tube at 70 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was quenched by addition of water (50mL), by NaHCO₃The pH was adjusted to 9 with aqueous solution and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue which is purified by preparative TLC (PE/EtOAc: 1/2, TLC: PE/EtOAc: 1/2, R_fPurification (0.53) to give 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as a yellow solid]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid methyl ester (50mg, 96.84 μmol, 28.8% yield, 88.6% purity).¹H NMR(400MHz，CDCl₃)δppm 9.57(br s，1H)，8.67-8.48(m，2H)，8.41(s，1H)，7.98(s，1H)，7.55-7.42(m，1H)，7.36(d，J＝8.1Hz，1H)，7.19(t，J＝7.7Hz，1H)，7.15-7.10(m，1H)，6.96(d，J＝8.1Hz，1H)，4.99(s，1H)，3.98(s，3H)，3.39(dd，J＝4.8，15.3Hz，1H)，3.09-2.97(m，3H)，2.43-2.32(m，2H)；ES-LCMS m/z458.2[M+H]⁺。

Step 2: 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid

To 2- (5-fluoro-3-pyridyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid methyl ester (140mg, 306.04. mu. mol, 1 eq.) in THF (2mL), MeOH (2mL), and H₂LiOH (73.29mg, 3.06mmol, 10 equiv.) was added to a solution in O (1mL) and stirred at 50 ℃ for 12 hours. The solution was adjusted to pH 6 with 2N HCl aqueous solution and concentrated to give 2- (5-fluoro-3-pyridyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid (120mg, 187.00 μmol, 61.1% yield, 69.1% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm9.69(s，1H)，9.21(d，J＝6.6Hz，1H)，8.93(s，1H)，8.49(s，1H)，7.36(d，J＝7.8Hz，1H)，7.29-7.17(m，1H)，7.08-6.89(m，2H)，4.93(d，J＝4.2Hz，1H)，3.30-3.20(m，1H)，3.19-2.88(m，3H)，2.53-2.08(m，2H)；ES-LCMS m/z 444.1[M+H]⁺。

Step 3: [2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazin-8-yl radical]Morpholinyl-methanones (I-262)

To 2- (5-fluoro-3-pyridyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl group]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxylic acid (50mg, 77.91. mu. mol, 1 eq.), morpholine (20.36mg, 233.74. mu. mol, 20.57 μ L, 3 equiv.) to a solution in DMF (2mL) was added HATU (35.55mg, 93.50 μmol, 1.2 equiv.) and TEA (23.65mg, 233.74 μmol, 32.53 μ L, 3 equiv.). The mixture was stirred at 15 ℃ for 12 hours. The reaction mixture was quenched by addition of water (50mL) and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (10mL) and Na ₂SO₄Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC (column: DuraShell 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN)](ii) a B%: 32% -62%, 7min) and subsequent lyophilization to give [2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl ] as a yellow solid]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazin-8-yl radical]Morpholinyl-methanone (15.18mg, 25.93 μmol, 33.2% yield, 100% purity, 2HCl, [ α ]]^24.3 _D＝+20.863(MeOH，c＝0.059g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.52(s，1H)，8.90(dd，J＝1.5，9.0Hz，1H)，8.85(s，1H)，8.35(s，1H)，7.37(d，J＝7.6Hz，1H)，7.28(d，J＝8.1Hz，1H)，7.04(t，J＝7.0Hz，1H)，6.99-6.93(m，1H)，4.99-4.92(m，1H)，3.81(s，8H)，3.29(d，J＝5.6Hz，1H)，3.17-2.91(m，3H)，2.46-2.23(m，2H)；ES-LCMS m/z 513.3[M+H]⁺。

Example 199

Synthesis of I-263a, I-263b and I-263c

The synthesis scheme is as follows:

step 1: (2S) -N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-1, 2, 3, 4-tetrahydrocyclopenta [ b ]]Indol-2-amine (I-263a) and (2R) -N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]-1, 2, 3, 4-tetrahydrocyclopenta [ b ]]Indole-2-amine (I-263b)

To 4-chloro-2- (5-fluoro-3-pyridyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazine (120mg, 391.62. mu. mol, 1 eq.) and 1, 2, 3, 4-tetrahydrocyclopenta [ b ]]To a solution of indol-2-amine (67.45mg, 391.62. mu. mol, 1 eq) in i-PrOH (10mL) was added DIEA (404.91mg, 3.13mmol, 545.71. mu.L, 8 eq). The mixture was stirred at 50 ℃ for 2 hours and concentrated to give N- [2- (5-fluoro-3-pyridinyl) -8-isopropyl-pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-1, 2, 3, 4-tetrahydrocyclopenta [ b ]]Indol-2-amine (120mg, 274.65. mu. mol, 70.1% yield, 97.8% purity) was passed over chiral SFC (column: xylonite CHIRALCEL OJ-H (250 mm. times.30 mm, 5 μm); mobile phase: [ 0.1% NH ]₃H₂OEtOH](ii) a B%: 40% -40%) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 68% -98%, 8 min). The desired fractions were lyophilized to give the enantiomer as a yellow solid (31.51mg, 62.97 μmol, 16.1% yield, 100.0% purity, 2HCl, SFC: R_t＝5.092，ee＝99.41％，[α]^24.5 _D＝+37.706(MeOH，c＝0.093g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.94(s，1H)，9.43-9.40(m，2H)，8.71(d，J＝2.9Hz，1H)，8.45-8.41(m，1H)，8.15(s，1H)，7.35-7.31(m，2H)，7.00-6.95(m，2H)，5.65-5.60(m，1H)，3.43-3.34(m，2H)，3.24-3.19(m，2H)，3.03(dd，J＝6.6，13.9Hz，1H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z 428.2[M+H]⁺. Peak 2 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 68% -98%, 8 min). The desired fractions were lyophilized to give the other enantiomer as a yellow solid (24.54mg, 49.04 μmol, 12.5% yield, 100.0% purity, 2HCl, SFC: R_t＝6.749，ee＝99.76％，[α]^24.6 _D＝-41.018(MeOH，c＝0.087g/100mL))。¹H NMR(400MHz，DMSO-d₆)δppm 10.93(s，1H)，9.43-9.40(m，2H)，8.71(d，J＝2.7Hz，1H)，8.45-8.41(m，1H)，8.15(s，1H)，7.35-7.31(m，2H)，7.02-6.95(m，J＝7.0，15.1Hz，2H)，5.67-5.60(m，1H)，3.41-3.34(m，2H)，3.24-3.21(m，J＝7.2，14.1Hz，2H)，3.04-2.99(dd，J＝6.4，13.9Hz，1H)，1.37(d，J＝6.8Hz，6H)；ES-LCMS m/z428.2[M+H]⁺。

Example 200

Synthesis I-264

The synthesis scheme is as follows:

step 1: (3R) -3- [ tert-Butoxycarbonyl- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

To (3R) -N- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]To a solution of triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (300mg, 726.08 μmol, 1 eq) in 1, 4-dioxane (30mL) was added DMAP (266.12mg, 2.18mmol, 3 eq) and Boc₂O (950.78mg, 4.36mmol, 1.00mL, 6 equiv.). The mixture was stirred at 110 ℃ for 10 hours. Adding Boc to the mixture₂O (950.78mg, 4.36mmol, 1.00mL, 6 equiv.). The mixture was stirred at 110 ℃ for a further 16 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc: 3/1, TLC: PE/EtOAc: 5/1, R_f0.7) to give (3R) -3- [ tert-butoxycarbonyl- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (420mg, 637.7)1 μmol, 87.8% yield, 90.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.10-8.04(m，1H)，7.93(s，1H)，7.33(d，J＝7.3Hz，1H)，7.23-7.13(m，2H)，4.76-4.74(m，1H)，3.33-2.97(m，5H)，2.59-2.51(m，3H)，2.37-2.27(m，1H)，2.24-2.26(m，1H)，1.63(s，9H)，1.54(s，9H)，1.36(d，J＝6.8Hz，6H)；ES-LCMS m/z 593.3[M+H]⁺。

Step 2: (3R) -3- [ tert-Butoxycarbonyl- (8-isopropyl-2-methylsulfinyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

To (3R) -3- [ tert-butoxycarbonyl- (8-isopropyl-2-methylsulfanyl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) amino]To a solution of tert-butyl (1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (400mg, 607.34 μmol, 1 eq) in MeOH (20mL) was added oxone (373.37mg, 607.34 μmol, 1 eq). The mixture was stirred at 15 ℃ for 3 hours. After filtration, EtOAc (80mL) was added to the filtrate and saturated Na was added₂SO₃The solution (50mL) was quenched. The aqueous layer was extracted with EtOAc (30 mL. times.3) and the combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (PE/EtOAc: 10/1 to 2/1, TLC: PE/EtOAc: 5/1, R_f0.2) to give (3R) -3- [ tert-butoxycarbonyl- (8-isopropyl-2-methylsulfinyl-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl) amino]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (250mg, 403.70 μmol, 66.5% yield, 98.3% purity).¹H NMR(400MHz，CDCl₃)δppm 8.16(s，1H)，8.07(d，J＝8.1Hz，1H)，7.32(d，J＝7.6Hz，1H)，7.24-7.14(m，2H)，4.85-4.83(m，1H)，3.40(td，J＝6.8，13.8Hz，1H)，3.34-3.01(m，4H)，2.94(d，J＝2.7Hz，3H)，2.43(d，J＝12.0Hz，1H)，2.27(d，J＝8.1Hz，1H)，1.64(s，9H)，1.45-1.29(m，15H)；ES-LCMS m/z 631.3[M+Na]⁺.

Step 3: (3R) -3- [ [ 8-isopropyl-2- (1-piperidinyl) pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]Amino group]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester

Irradiation of (3R) -3- [ tert-Butoxycarbonyl- (8-isopropyl-2-methylsulfinyl-pyrazolo [1, 5-a ] under microwave][1，3，5]Triazin-4-yl) amino]A solution of tert-butyl-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (100mg, 161.48 μmol, 1 eq) and piperidine (172.44mg, 2.03mmol, 0.2mL, 12.54 eq) in t-BuOH (1mL) and stirred at 120 ℃ for 2 h. Concentrating the mixture to obtain (3R) -3- [ [ 8-isopropyl-2- (1-piperidinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]Amino group]-1, 2, 3, 4-tetrahydrocarbazole-9-carboxylic acid tert-butyl ester (80mg, 137.44 μmol, 85.1% yield, 91.0% purity).¹H NMR(400MHz，CDCl₃)δppm 8.11(d，J＝8.3Hz，1H)，7.57(s，1H)，7.35(d，J＝7.1Hz，1H)，7.27(br s，1H)，7.23-7.17(m，1H)，6.26(d，J＝7.8Hz，1H)，4.60-4.59(m，1H)，3.79(d，J＝4.6Hz，4H)，3.35(d，J＝5.1Hz，3H)，3.27-3.14(m，3H)，3.02(td，J＝6.8，13.8Hz，1H)，2.72(dd，J＝7.7，14.6Hz，1H)，2.25(br s，1H)，2.12(d，J＝8.3Hz，1H)，1.54-1.39(m，12H)，1.28(d，J＝6.8Hz，6H)；ES-LCMS m/z 530.4[M+H]⁺。

Step 4: (3R) -N- [ 8-isopropyl-2- (1-piperidinyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-264)

Reacting (3R) -3- [ [ 8-isopropyl-2- (1-piperidinyl) pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl]Amino group]A solution of tert-butyl (1, 2, 3, 4-tetrahydrocarbazole-9-carboxylate (80mg, 137.44. mu. mol, 1 eq.) and TFA (1.12g, 9.83mmol, 728.00. mu.L, 71.54 eq.) in DCM (5mL) was stirred at 20 ℃ for 2 h. Concentrating the mixture. The residue was purified by preparative HPLC (column: Aigerl ASB 150X 25mm X5 μm; mobile phase: [ water (0.05% HCl) -ACN](ii) a B%: 50% -80%, 8min) and then lyophilized to give (3R) -N- [ 8-isopropyl-2- (1-piperidinyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (34.59mg, 71.55. mu. mol, 52.1% yield, 96.4% purity, HCl; optical rotation [ α ]]^22.2 _D＝+82.409，(MeOH，c＝0.096g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 7.89(s，1H)，7.37(d，J＝7.8Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.04(t，J＝7.5Hz，1H)，7.00-6.93(m，1H)，4.69-4.57(m，1H)，3.87(br s，4H)，3.28-3.16(m，2H)，2.97(br s，2H)，2.93-2.82(m，1H)，2.37-2.15(m，2H)，1.74(br s，6H)，1.31(d，J＝6.8Hz，6H)；ES-LCMS m/z 430.3[M+H]⁺。

Example 201

Synthesis I-265

The synthesis scheme is as follows:

step 1: 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxamide (I-265)

2- (5-fluoro-3-pyridyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl]Amino group]Pyrazolo [1, 5-a][1，3，5]A solution of triazine-8-carbonitrile (170mg, 396.53. mu. mol, 1 eq.) in HCl/MeOH (4M MeOH solution, 30mL) was stirred at 80 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by addition of saturated NaHCO₃Aqueous (50mL) was quenched and extracted with EtOAc (30 mL. times.3). Combination of Chinese herbsThe organic layer was washed with brine (10mL) and Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (PE/EtOAc: 1/0 to 0/1, TLC: PE/EtOAc: 1/1, R_fPurification (0.11) to give 2- (5-fluoro-3-pyridinyl) -4- [ [ (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-yl) as a yellow solid]Amino group]Pyrazolo [1, 5-a][1，3，5]Triazine-8-carboxamide (60mg, 135.61. mu. mol, 34.2% yield, 100% purity, [ α ]]^23.7 _D＝+21.368(MeOH，c＝0.088g/100mL))。¹HNMR(400MHz，DMSO-d₆)δppm 10.79(s，1H)，9.56-9.41(m，2H)，8.78-8.67(m，2H)，8.50(s，1H)，7.52(s，1H)，7.45(s，1H)，7.34(d，J＝7.8Hz，1H)，7.28(d，J＝7.8Hz，1H)，7.05-6.98(m，1H)，6.97-6.89(m，1H)，4.86(s，1H)，3.23-2.77(m，4H)，2.22(s，2H)；ES-LCMS m/z443.1[M+H]⁺。

Example 202

Synthesis I-267

The synthesis scheme is as follows:

step 1: n- [ [4- (trifluoromethyl) -1H-pyrazol-5-yl ] amino acids]Thiocarbamoyl radical]Urethane composition

A solution of 4- (trifluoromethyl) -1H-pyrazol-5-amine hydrochloride (1g, 4.46mmol, 1 eq, HCl) and ethyl N- (thiolmethylene) carbamate (585.47mg, 4.46mmol, 1 eq) in DCM (10mL) and DMF (10mL) was stirred at 20 ℃ for 2.5H. The reaction mixture was concentrated under reduced pressure to give N- [ [4- (trifluoromethyl) -1H-pyrazol-5-yl ] residue as a yellow solid]Thiocarbamoyl radical]Ethyl carbamate (1.1g, 3.90mmol, 87.3% yieldYield, crude material purity) which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 11.52(s，1H)，11.06(s，1H)，8.34(s，1H)，4.21(q，J＝7.0Hz，2H)，1.25(t，J＝7.0Hz，3H)；ES-LCMS m/z283.0[M+H]⁺。

Step 2: 2-thione-8- (trifluoromethyl) -1H-pyrazolo [1, 5-a][1，3，5]Triazin-4-ones

To N- [ [4- (trifluoromethyl) -1H-pyrazol-5-yl group]Thiocarbamoyl radical]Ethyl carbamate (1.1g, 3.90mmol, 1 eq.) in CH₃CN (5mL) solution to which K was added₂CO₃(1.62g, 11.69mmol, 3.0 equiv.). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was quenched by AcOH solution (6mL) with H₂O (50mL) was diluted and extracted with EtOAc (50 mL. times.3). The combined organic layers were passed over anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure to give a residue. The residue was diluted with EtOAc/PE (2mL/10mL), filtered and the solid collected to give 2-thione-8- (trifluoromethyl) -1H-pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-one (900mg, 3.33mmol, 85.4% yield, 87.3% purity), which was used in the next step without further purification.¹H NMR(400MHz，DMSO-d₆)δppm 12.65(br s，1H)，8.16(s，1H)；ES-LCMS m/z 237.0[M+H]⁺。

Step 3: 2-methylthio-8- (trifluoromethyl) -3H-pyrazolo [1, 5-a][1，3，5]Triazin-4-ones

To 2-thione-8- (trifluoromethyl) -1H-pyrazolo [1, 5-a][1，3，5]To a solution of triazin-4-one (900mg, 3.33mmol, 1 equiv.) in EtOH (15mL) was added NaOH (266.12mg, 6.65mmol, 2 equiv.) in H₂A solution in O (6mL) and then MeI (472.20mg, 3.33mmol, 207.11 μ L, 1 eq) was added dropwise.The mixture was stirred at 20 ℃ for 1 hour. The reaction mixture was acidified with 1n hcl solution (10mL) and concentrated under reduced pressure to remove EtOH, form a solid, filter and collect the solid to give 2-methylsulfanyl-8- (trifluoromethyl) -3H-pyrazolo [1, 5-a ] as a yellow solid][1，3，5]Triazin-4-one (800mg, 3.00mmol, 90.2% yield, 93.8% purity), which was used in the next step without further purification.¹H NMR(400MHz，CD₃OD)δppm 8.16(s，1H)，2.64(s，3H)；ES-LCMS m/z 251.1[M+H]⁺。

Step 4: 4-chloro-2-methylthio-8- (trifluoromethyl) pyrazolo [1, 5-a][1，3，5]Triazine

Reacting 2-methylsulfanyl-8- (trifluoromethyl) -3H-pyrazolo [1, 5-a][1，3，5]Triazin-4-one (200mg, 749.80. mu. mol, 1 eq.) and DIEA (290.72mg, 2.25mmol, 391.80. mu.L, 3.0 eq.) in POCl₃(34.43g, 224.55mmol, 20.87mL, 299.47 equiv.) in N₂Stirring was carried out at 130 ℃ for 12 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to give 4-chloro-2-methylsulfanyl-8- (trifluoromethyl) pyrazolo [1, 5-a) as a dark brown oil][1，3，5]Triazine (200mg, 744.47 μmol, 99.3% yield, crude purity), which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)δppm 8.29(s，1H)，2.66-2.64(m，3H).

Step 5: (3R) -N- [ 2-methylsulfanyl-8- (trifluoromethyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine

To 4-chloro-2-methylsulfanyl-8- (trifluoromethyl) pyrazolo [1, 5-a][1，3，5]To a solution of triazine (200mg, 744.47 μmol, 1 eq.) and (3R) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (166.39mg, 893.37 μmol, 1.2 eq.) in ACN (10mL) was added DIEA (962.18mg, 7.44mmol, 1.30mL,10 equivalents). The mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.32) to yield the product (3R) -N- [ 2-methylsulfanyl-8- (trifluoromethyl) pyrazolo [1, 5-a) as a brown oil][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (150mg, 353.10 μmol, 47.4% yield, 98.5% purity).¹H NMR(400MHz，CDCl₃)δppm 7.99(s，1H)，7.84(brs，1H)，7.47(d，J＝7.5Hz，1H)，7.34(d，J＝7.8Hz，1H)，7.24-7.08(m，2H)，6.65(d，J＝9.3Hz，1H)，4.82(m，1H)，3.31(dd，J＝5.4，15.4Hz，1H)，3.03-2.84(m，3H)，2.60(s，3H)，2.31-2.21(m，2H)；ES-LCMS m/z 419.1[M+H]⁺。

Step 6: (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (trifluoromethyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-267)

To (3R) -N- [ 2-methylsulfanyl-8- (trifluoromethyl) pyrazolo [1, 5-a][1，3，5]Triazin-4-yl]To a solution of (E) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (100mg, 235.40. mu. mol, 1 equiv.) and (5-fluoro-3-pyridinyl) boronic acid (99.51mg, 706.20. mu. mol, 3.0 equiv.) in 1, 4-dioxane (6mL) was added Pd (PPh)₃)₄(27.20mg, 23.54. mu. mol, 0.1 equiv.) and thiophene-2-carbonyl copper oxo (89.78mg, 470.80. mu. mol, 2.0 equiv.). N for the mixture₂Purge for 1 min and stir at 120 ℃ for 5 h under microwave. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 10/3, TLC: PE/EtOAc: 3/1, R_f0.38) and preparative HPLC (column: durashell 150X 25mm X5 μm; mobile phase: [ Water (0.05% HCl) -ACN](ii) a B%: 45% -75%, 8min) and then lyophilized to give the product (3R) -N- [2- (5-fluoro-3-pyridinyl) -8- (trifluoromethyl) pyrazolo [1, 5-a) as a yellow solid][1，3，5]Triazin-4-yl]-2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine(36.04mg, 66.30. mu. mol, 28.2% yield, 99.4% purity, 2HCl, optical rotation: ([ α ]]^24.3 _D＝+51.474，(MeOH，c＝0.048g/100mL))。¹H NMR(400MHz，CD₃OD)δppm 9.48(br s，1H)，8.71(d，J＝8.8Hz，2H)，8.35(s，1H)，7.36(d，J＝7.8Hz，1H)，7.26(d，J＝8.3Hz，1H)，7.06-6.99(m，1H)，6.97-6.88(m，1H)，4.91(d，J＝3.8Hz，1H)，3.29(d，J＝5.5Hz，1H)，3.10-2.90(m，3H)，2.45-2.35(m，1H)，2.33-2.21(m，1H)；ES-LCMS m/z 468.2[M+H]⁺。

Example 203

Synthesis I-270

The synthesis scheme is as follows:

step 1: 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine

5-bromopyrimidine (1g, 6.29mmol, 1 eq.), 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolan (1.76g, 6.93mmol, 1.10 eq.), Pd (dppf) Cl₂·CH₂Cl₂Mixture of (513.66mg, 628.99 μmol, 0.1 equiv.), KOAc (1.85g, 18.87mmol, 3 equiv.) in 1, 4-dioxane (40mL) and DMF (10mL) in N₂Stirring was carried out at 100 ℃ for 2 hours under an atmosphere. The mixture was concentrated. The residue was subjected to silica gel column chromatography (PE/EtOAc: 1/0 to 3/1, TLC: PE/EtOAc: 3/1, R_f0.23) to yield 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine as a red oil (1.5g, 5.82mmol, 92.6% yield, 80% purity).¹HNMR(400MHz，CDCl₃)δppm 9.25(s，1H)，9.00(br s，2H)，1.33(s，12H)。

Step 2: (3R) -N- (8-isopropyl-2-pyrimidin-5-yl-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (I-270)

Reacting (3R) -N- (8-isopropyl-2-methylthio-pyrazolo [1, 5-a)][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (150mg, 351.57. mu. mol, 1 eq.), 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (271.66mg, 1.05mmol, 3 eq.), Pd₂(dba)₃Mixture of (32.19mg, 35.16 μmol, 0.1 equiv.) and thiophene-2-carbonyl copper (I) oxo (134.08mg, 703.15 μmol, 2 equiv.) in 1, 4-dioxane (4mL) in N₂Stirring was carried out at 110 ℃ for 12 hours under an atmosphere. The mixture was concentrated to give a crude material which was purified by silica gel column chromatography (PE/EtOAc: 1/0 to 2/1, TLC: PE/EtOAc: 3/1, R_f0.25) to give a grey solid, which was purified with MeCN/H₂O/DMF (3/1/0.5, 10mL) formed a slurry. After filtration, the filter cake was washed with MeCN (10mL × 3) and dried under vacuum to give (3R) -N- (8-isopropyl-2-pyrimidin-5-yl-pyrazolo [1, 5-a) as a gray solid][1，3，5]Triazin-4-yl) -2, 3, 4, 9-tetrahydro-1H-carbazol-3-amine (42.34mg, 99.74. mu. mol, 28.4% yield, 100% purity, [ α%]^24.5 _D＝+83.175(DMSO，c＝0.102g/100mL))。¹H NMR(400MHz，DMSO)δppm 10.75(s，1H)，9.57(s，2H)，9.26(s，1H)，9.01(br s，1H)，8.12(s，1H)，7.31(d，J＝7.6Hz，1H)，7.24(d，J＝8.1Hz，1H)，7.01-6.94(m，1H)，6.93-6.86(m，1H)，4.80-4.77(m，1H)，3.11-3.00(m，2H)，2.99-2.81(m，3H)，2.18(m，2H)，1.34(d，J＝6.8Hz，6H)；ES-LCMS m/z 425.2[M+H]⁺。

While various embodiments of the invention have been described, it will be apparent that the basic examples may be varied to provide other embodiments which utilize the compounds and methods of the invention. It is, therefore, to be understood that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments shown by way of example.

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