阅读说明：本技术 可用作激酶抑制剂的化合物 (Compounds useful as kinase inhibitors ) 是由 N.古伊索特 于 2016-12-16 设计创作，主要内容包括：本发明涉及可用作激酶抑制剂的新型化合物。本发明的化合物是酪氨酸激酶抑制剂。特别地,本发明的化合物可用作布鲁顿酪氨酸激酶(BTK)的抑制剂。本发明还考虑了这些化合物在治疗可通过抑制布鲁顿酪氨酸激酶而治疗的病症例如癌症、淋巴瘤、白血病和免疫疾病中的用途。(The present invention relates to novel compounds useful as kinase inhibitors. The compounds of the present invention are tyrosine kinase inhibitors. In particular, the compounds of the invention are useful as inhibitors of Bruton's Tyrosine Kinase (BTK). The invention also contemplates the use of these compounds in the treatment of conditions treatable by inhibition of bruton's tyrosine kinase, such as cancer, lymphoma, leukemia and immune disorders.)

1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R¹can be selected from:

R²represents a group selected from: halogen, C_1-8Alkyl radical, C_1-8Haloalkyl or-NR^CR^DWherein R is^CAnd R^DIndependently at each occurrence is selected from: h or C_1-4An alkyl group;

R³represents-C (O) NH₂、-C(O)NHMe、-CH₂OH、CH(OH)CH₃、-CF₃or-CHF₂；

R^4aAnd R^4bIs H;

R⁵is H;

R⁶is methoxyphenyl or methoxyphenyl;

a is unsubstituted phenyl or substituted by one or two R⁷Substituted phenyl, optionally wherein R⁷Selected from: fluoro, methyl, methoxy and-CH₂OH; and

m is 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula IXa, IXb, IXc, or IXd:

3. the compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula IXd:

4. a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder modulated by BTK.

6. The use of claim 5, wherein the disorder modulated by BTK is cancer, lymphoma, leukemia, an autoimmune disease, an inflammatory disorder, a heteroimmune disease, or fibrosis.

7. The use of claim 5, wherein the disorder modulated by BTK is selected from the group consisting of B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome, and lupus.

8. The use of claim 5, wherein the disorder modulated by BTK is graft versus host disease.

Technical Field

The present invention relates to compounds. More particularly, the invention relates to compounds useful as kinase inhibitors, as well as methods for preparing and uses of such compounds. In particular, the invention relates to inhibitors of Bruton's Tyrosine Kinase (BTK).

Background

Kinases are a class of enzymes that control the transfer of phosphate groups from phosphate donor groups, such as ATP, to specific substrates. Protein kinases are a large subset of kinases that play a central role in regulating various cell signaling and processes, and BTK is one of such protein kinases.

BTK is a member of the src-associated Tec family of cytoplasmic tyrosine kinases. BTK plays a key role in the B Cell Receptor (BCR) signaling pathway of B cells, which is essential for development, activation, and survival of B cells. BTK inhibitors were therefore developed with the aim of treating B-cell malignancies that rely on BCR signaling, such as Chronic Lymphocytic Leukemia (CLL) and non-hodgkin lymphoma (NHL) (Buggy 2012). BTK is also expressed in specific bone marrow cells, including monocytes/macrophages, neutrophils, and mast cells. In these bone marrow cells, BTK has been implicated in immune complex-mediated fcyr and fcepsilonr activation, which is thought to contribute to the pathogenesis of Rheumatoid Arthritis (RA) (Whang 2014). Furthermore, BTK is essential for osteoclast maturation, so inhibition of BTK can prevent bone erosion associated with RA. The key role of BTK in both B-cells and bone marrow cells has led to BTK being an attractive target for the treatment of not only B-cell malignancies but also autoimmune diseases.

Ibrutinib is an irreversible BTK inhibitor that has been approved for the treatment of CLL, Mantle Cell Lymphoma (MCL) and Waldenstrom's Macroglobulinemia (WM). Since ibrutinib was first disclosed, there are a number of patent applications relating to structures closely related to ibrutinib, see for example WO 2012/158843, WO 2012/158764, WO 2011/153514, WO 2011/046964, US 2010/0254905, US 2010/0144705, US 7718662, WO 2008/054827 and WO 2008/121742.

Other Btk inhibitors are disclosed in WO 2013/010136, US 9090621, WO 2015/127310, WO 2015/095099 and US 2014/221333. Kinase inhibitors are also disclosed in US 6660744, US 2002/0156081, US 2003/0225098 and WO 01/19829.

Ibrutinib also irreversibly binds interleukin-2 Inducible Tyrosine Kinase (ITK) (Dubovsky 2013). ITK plays a key role in the FcR stimulated Natural Killer (NK) cell function required for antibody-dependent NK cell-mediated cytotoxicity (ADCC). ADCC is a mechanism by which anti-CD 20 antibodies, such as rituximab, are thought to activate, while ibrutinib has been shown to antagonize this mechanism in vitro (Kohrt 2014). Since rituximab in combination with chemotherapy is the standard for the treatment of B-cell malignancies today, it is desirable to have a BTK inhibitor that is more selective for BTK than ITK.

In the clinic, adverse events include atrial fibrillation, diarrhea, skin rash, joint pain, and bleeding (imbruvaca package insert 2014). Known BTK inhibitors such as ibrutinib are also believed to have gastrointestinal side effects, which are believed to be due to secondary EGFR inhibitory activity. There is therefore a need for BTK inhibitors with high BTK inhibition and low EGFR inhibition to reduce or avoid gastrointestinal side effects.

Irreversible and covalently reversible BTK inhibitors specifically target cysteine residue C481 within BTK. After treatment with ibrutinib, primary and secondary resistance cases occurred. Mutations in BTKs such as C481S, C481Y, C481R, C481F have been reported in the literature and clearly interfere with drug binding (Woyach 2014; Maddocks 2015). It is predicted that the incidence of observed drug resistance will increase over time when used clinically outside of clinical trials (Zhang, 2015).

It is therefore an object of the present invention to provide BTK inhibitors, more particularly reversible inhibitors, with different binding patterns. Furthermore, the present invention aims to provide BTK inhibitors with high selectivity for BTK inhibition compared to EGFR and ITK inhibition.

Furthermore, it is an object of certain embodiments of the present invention to provide new cancer treatments. In particular, it is an object of certain embodiments of the present invention to provide compounds that have activity comparable to existing cancer treatments but are also effective against mutations. One aspect of the present invention focuses on providing BTK inhibitors that are effective against the C481 mutation.

It is an object of certain embodiments of the present invention to provide compounds that exhibit reduced cytotoxicity relative to prior art compounds and prior therapies.

It is another object of certain embodiments of the present invention to provide compounds having convenient pharmacokinetic profiles and suitable duration of action following administration. It is another object of certain embodiments of the present invention to provide compounds wherein one or more metabolic fragments of the drug after absorption are GRAS (generally regarded as safe).

Certain embodiments of the present invention meet some or all of the above objectives.

Disclosure of Invention

According to the present invention, there is provided a compound disclosed below. Furthermore, the present invention provides compounds capable of inhibiting Bruton's Tyrosine Kinase (BTK) and the use of these compounds in inhibiting BTK. According to the present invention, a method of treating a disorder modulated by BTK is provided. The present invention provides compounds useful for treating disorders modulated by BTK.

In a first aspect of the invention, there is provided a compound according to formula (I):

wherein the content of the first and second substances,

a represents a ring selected from the group consisting of unsubstituted or substituted: phenyl, pyridine, pyridazine, pyrimidine or pyrazine, in which, when substituted A is substituted by 1 to 4R⁷When substituted;

R¹represents a group selected from: c_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C _2-8Alkyl ethers, -C (O) R^A、C_3-10Carbocyclyl, 3-to 10-membered heterocyclyl, substituted by C_3-10C substituted by carbocyclic radicals_1-8Alkyl and C substituted by 3-to 10-membered heterocyclic group_1-8Alkyl, wherein each of the above radicals is unsubstituted orSubstituted with 1 to 5 substituents independently selected from: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-NR^AR^B、-CN、＝O、-OC(O)R^A、-C(O)R^A、-C(O)OR^A、-NR^AC(O)R^B、-C(O)NR^AR^B、-NR^AS(O)₂R^B、-S(O)₂NR^AR^BBenzoyl, 5-OR 6-membered heterocycloaryl, a 3-to 6-membered heterocycloalkyl ring, substituted by-OR^ASubstituted C_1-4Alkyl and is-OR^ASubstituted C_1-4Alkoxy, or R¹Is substituted twice to form a 3-to 6-membered heterocycloalkyl or cycloalkyl ring;

R²represents a group selected from: -OH, halogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-10Cycloalkyl radical, C_6-10Aryl, 3-to 10-membered heterocyclyl, substituted by-OR^CSubstituted alkyl, by C_3-10C substituted by carbocyclic radicals_1-8Alkyl, alkyl substituted with 3 to 10 membered heterocyclyl, and-NR^CR^D；

R³represents-C (O) NR^ER^Fis-OR^GSubstituted C_1-6Alkyl or C_1-6A haloalkyl group;

R^4aand R^4bIndependently at each occurrence is selected from: H. c_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl and quilt-OR^HSubstituted C_1-6An alkyl group;

R⁵is H or C_1-4An alkyl group;

R⁶selected from the following substituted or unsubstituted groups: phenyl or a 5 or 6 membered heteroaryl ring, wherein, when substituted, R ⁶Containing 1 to 5 substituents independently selected at each occurrence from the group consisting of: halogen, -OR^I、-NR^IR^J、-CN、C_1-6Alkyl radical, C_1-6Haloalkyl and substituted aryl^ISubstituted C_1-6An alkyl group;

R⁷selected from: H. halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and is-OR^HSubstituted C_1-6An alkyl group;

m is 1 or 2;

R^Aand R^BIndependently at each occurrence is selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, phenyl, benzyl OR by-OR^HSubstituted C_1-4An alkyl group;

R^C、R^D、R^Eand R^FIndependently at each occurrence is selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, unsubstituted C_3-10Carbocyclyl, unsubstituted C_3-10C substituted by carbocyclic radicals_1-4Alkyl by 1 or 2R^HOR-OR^HSubstituted C_3-10C substituted by carbocyclic radicals_1-4Alkyl, and 3 to 10 membered heterocyclyl;

R^G、R^Iand R^JIndependently at each occurrence is selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy and is-OR^HSubstituted C_1-4An alkyl group; and

R^His selected from H or C_1-4An alkyl group.

In one embodiment, A is unsubstituted phenyl, unsubstituted pyridine, substituted phenyl, substituted pyridyl, unsubstituted pyridyl, substituted pyridyl, unsubstituted pyridyl, or substituted pyridyl⁷Substituted phenyl or substituted by 1 to 4R⁷A substituted pyridine.

Preferably, A is unsubstituted phenyl, unsubstituted pyridine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted pyrazine or substituted by 1 or 2R ⁷A substituted phenyl group.

In one embodiment, A is unsubstituted phenyl, unsubstituted dihydropyridyl, or substituted with 1 to 4R⁷(optionally 1 or 2R⁷) A substituted phenyl group. In one embodiment, A is unsubstituted phenyl or substituted with 1 to 4R⁷A substituted phenyl group.

Such as a knot derived by the skilled person from formula (I)As noted in the formula, the group "A" is substituted with two groups as shown below (which may also optionally be substituted with 1 to 4R⁷Substitution).

These two groups may be para-substituted on a. In other words, both groups may be 1, 4-substituted on A.

In one embodiment, a may be:

wherein A is¹、A²、A⁴And A⁵0, 1 or 2 of (A) are independently selected from N, the remainder are CR⁷。

Thus, the compound according to formula (I) may be a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein A is¹、A²、A⁴And A⁵0, 1 or 2 of (A) are independently selected from N, the remainder are CR⁷。

In an embodiment, A¹、A²，A⁴And A⁵0 or 1 of (A) is N, the remainder is A¹、A²、A⁴And A⁵0 or 1 of (A) is CR⁷And the remainder is CH.

In an embodiment, A¹、A⁴And A⁵Is CH, A²Is CR⁷And R is⁷Selected from fluoro, methyl, methoxy or-CH₂And (5) OH. In an embodiment, A²、A⁴And A⁵Is CH, A¹Is CR⁷And R is⁷Selected from H, fluoro, methyl, methoxy or-CH ₂And (5) OH. In an embodiment, A¹、A⁴And A⁵Is CH, A²Is N. In an embodiment, A²、A⁴And A⁵Is CH, A¹Is N. In an embodiment, A¹And A⁵Is CH, A²And A⁴Is N. In an embodiment, A¹And A⁵Is N, A²And A⁴Is CH. In an embodiment, A¹And A⁴Is CH, A²And A⁵Is N. In an embodiment, A¹And A²Is CH, A⁴And A⁵Is N.

In an embodiment, A¹And A⁵Is CH, A²And A⁴Is CR⁷And R is⁷Selected from fluoro, methyl, methoxy or-CH₂And (5) OH. In an embodiment, A¹And A²Is CH, A⁴And A⁵Is CR⁷And R is⁷Selected from fluoro, methyl, methoxy or-CH₂And (5) OH. In an embodiment, A²And A⁴Is CH, A¹And A⁵Is CR⁷And R is⁷Selected from fluoro, methyl, methoxy or-CH₂And (5) OH. In an embodiment, A¹And A⁴Is CH, A²And A⁵Is CR⁷And R is⁷Selected from fluoro, methyl, methoxy or-CH₂OH。

Optionally, R⁷May be selected from: H. halogen, C_1-6Alkyl radical, C_1-6Alkoxy and is-OR^HSubstituted C_1-6An alkyl group. Preferably, R⁷May be selected from: H. fluoro, methyl, methoxy and-CH₂And (5) OH. Preferably, R⁷Is H.

In embodiments, a may be selected from:

in embodiments, a may be selected from:

in embodiments, a may be selected from:

in a preferred embodiment, a may be selected from:

in an embodiment, R ⁶Selected from the following substituted or unsubstituted groups: phenyl or a 6 membered heteroaryl ring. Preferably, R⁶Selected from the following substituted groups: phenyl or 6-membered heteroaryl ring substituted with 1 or 2 (preferably 1) methoxy (-OMe).

In an embodiment, R⁶Is selected from the following substituted or unsubstituted groups: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl.

Preferably, R⁶Selected from the following substituted groups: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, wherein R is⁶Containing 1, 2, or 3 substituents at each occurrence independently selected from the group consisting of: halogen, -OR^I、-CN、C_1-6Alkyl radical, C_1-6Haloalkyl and substituted aryl^ISubstituted C_1-6Alkyl, optionally R^ISelected from: H. methyl, ethyl, -CF₃、-CH₂-OR^Hand-CH₂CH₂-OR^H. Preferably, R^IIs H or methyl.

As the skilled artisan will appreciate, based on the description of the structural formulae of the compounds of the present invention, R ⁶The remainder of the compounds of the invention are linked through a carbonyl group (-C (═ O) -). When R is⁶When substituted by 1, 2 or 3 substituents, R⁶By carbonyl (will R)⁶Attached to the rest of the compound) and 1, 2 or 3 additional substituents. In a preferred embodiment, one of the substituents is substituted adjacent to-C (═ O) -. In other words, one of the substituents is substituted in the ortho position to the carbonyl group (-C (═ O) -). Preferably, at R⁶The substituent of the above substituted 1, 2 or 3 substituents is methoxy.

In an embodiment, R⁶Is substituted or unsubstituted: phenyl or pyridyl (preferably substituted). In a particularly preferred embodiment, R⁶Is a substituted phenyl group.

Preferably, R⁶Containing 1, 2, or 3 substituents at each occurrence independently selected from the group consisting of: fluorine, chlorine, methoxy, ethoxy, isopropoxy, -CN, methyl, ethyl, trifluoromethyl, trifluoroethyl or-OCF₃. In an embodiment, R⁶Containing 1 or 2 substituents independently at each occurrence selected from the group consisting of: fluoro, methoxy or methyl. Preferably, R⁶Containing 1 methoxy substituent or 2 substituents of fluorine and methoxy.

R⁶A particularly preferred substituent of (a) is methoxy. Thus, in a preferred embodiment, R ⁶Selected from the following methoxy substituted groups: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl. Optionally, R⁶Selected from the following methoxy substituted groups: phenyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl.

R⁶Particularly preferred substituents of (a) are methoxy and fluoro. Thus, in a preferred embodiment, R⁶Selected from the group consisting of fluoro and methoxy substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl,Oxadiazolyl or thiadiazolyl. Optionally, R⁶Selected from the group consisting of fluoro and methoxy substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl.

R⁶It may be a methoxyphenyl or fluoromethoxyphenyl group. R⁶It may be a methoxyphenyl group. As will be appreciated by those skilled in the art, R⁶The remainder of the compounds of the invention are linked through a carbonyl group (-C (═ O) -). When R is⁶When it is methoxyphenyl, R ⁶The phenyl group of (a) is substituted with a carbonyl group (linking the phenyl ring to the rest of the compound) and a methoxy group. In which R is⁶In a preferred embodiment that is methoxyphenyl, the methoxy group is substituted adjacent to — C (═ O) -. In other words, the methoxy group is substituted in the ortho position to the carbonyl group (-C (═ O) -). Thus, in one embodiment, the compound according to formula (I) is a compound of formulae (IIIa) and (IIIb):

thus, in a preferred embodiment, R⁶Is 2-methoxybenzen-1-yl.

R⁶May be a fluoromethoxyphenyl group. As will be appreciated by those skilled in the art, R⁶The remainder of the compounds of the invention are linked through a carbonyl group (-C (═ O) -). When R is⁶When it is fluoromethoxyphenyl, R⁶The phenyl group of (a) is substituted with a carbonyl group (linking the phenyl ring to the rest of the compound), a fluoro group, and a methoxy group. In which R is⁶In a preferred embodiment that is fluoromethoxyphenyl, the methoxy group is substituted adjacent to-C (═ O) -and the fluoro group is substituted opposite the methoxy group. In other words, the methoxy group is substituted in the ortho position to the carbonyl group (-C (═ O) -), and the fluoro group is attached para to the methoxy group. Thus, in one embodiment, the compound according to formula (I) is a compound of formulae (IIIc) and (IIId):

thus, in a preferred embodiment, R ⁶Is 5-fluoro-2-methoxybenzen-1-yl.

In an embodiment, R⁶Is 2-methoxybenzen-1-yl or 5-fluoro-2-methoxybenzen-1-yl.

R⁵May be H or methyl. Preferably, R⁵Is H.

R^4aAnd R^4bCan be independently selected at each occurrence from: H. c_1-6Alkyl radical, C_3-6Cycloalkyl and quilt-OR^HSubstituted C_1-6An alkyl group. Optionally, R^4aAnd R^4bCan be independently selected at each occurrence from: H. methyl, ethyl, cyclopropyl or-CH₂And (5) OH. Optionally, R^4aIs H, R^4bMay be selected from: H. methyl, ethyl, cyclopropyl or-CH₂And (5) OH. Optionally, R^4aIs H, R^4bSelected from: H. methyl or-CH₂And (5) OH. Preferably, R^4aIs H, R^4bIs H.

In an embodiment, m is 1.

In an embodiment, m is 1, R^4aAnd R^4bIs H. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is fluoromethoxyphenyl or methoxyphenyl. In an embodiment, m is 1, R^4aAnd R^4bIs H, and A is unsubstituted phenyl or substituted by one R⁷A substituted phenyl group. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, and A is unsubstituted phenyl or substituted by one R⁷A substituted phenyl group. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is fluoromethoxyphenyl or methoxyphenyl and A is unsubstituted phenyl or substituted by one R ⁷A substituted phenyl group. R⁷May be selected from: fluoro, methyl, methoxy and-CH₂OH。

In an embodiment, m is 1, R^4aAnd R^4bIs H. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is a methoxyphenyl group. In an embodiment, m is 1, R^4aAnd R^4bIs H, and A is unsubstituted phenyl or substituted by one R⁷A substituted phenyl group. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, and A is unsubstituted phenyl or substituted by one R⁷A substituted phenyl group. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is methoxyphenyl and A is unsubstituted phenyl or substituted by one R⁷A substituted phenyl group. R⁷May be selected from: fluoro, methyl, methoxy and-CH₂OH。

In an embodiment, R³represents-C (O) NR^ER^F. Preferably, R³represents-C (O) NHMe or-C (O) NH₂。

In an embodiment, the compound according to formula (I) may be a compound of formula (IV):

in an embodiment, R²Represents a group selected from: halogen, C_1-8Alkyl radical, C_1-8Haloalkyl and-NR^CR^D. Preferably, R²Represents Cl or CHF₂、CF₃、NH₂NHPh, NHMe, NHEt and NH^i-Pr。

In embodiments, the compound according to formula (I) may be a compound of formula (IVa), (IVb), (IVc) or (IVd):

Additionally or alternatively, in embodiments, the compound according to formula (I) may be a compound of formula (IVe) or (IVf):

in one embodiment, R^CAnd R^DIndependently at each occurrence is selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, unsubstituted C_3-10Carbocyclyl (optionally C)_3-6Carbocyclyl or phenyl), 3-to 10-membered heterocyclyl (optionally 3-to 6-membered heterocyclyl). Preferably, R^CAnd R^DIndependently selected from: H. methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl. For example, R^CIs H, R^DSelected from: H. methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

In one embodiment, R^CAnd R^DIndependently at each occurrence is selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, unsubstituted C_3-10Carbocyclyl (optionally C)_3-6Carbocyclyl), 3-to 10-membered heterocyclyl (optionally 3-to 6-membered heterocyclyl). Preferably, R^CAnd R^DIndependently selected from: H. methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl. In a particularly preferred embodiment, R^CAnd R^DIs H.

In an embodiment, R^EAnd R^FIndependently at each occurrence is selected from: H. c _1-4Alkyl radical, C_1-4Haloalkyl, unsubstituted C_3-10Carbocyclyl (optionally C)_3-6Carbocyclyl), 3-to 10-membered heterocyclyl (optionally 3-to 6-membered heterocyclyl). In an embodiment, R^EAnd R^FIndependently at each occurrence is selected from: H. c_1-4Alkyl (preferably R)^EAnd R^FIndependently at each occurrence is selected from: H. methyl and ethyl). In an embodiment, R^EAnd R^FIs H.

In an embodiment, R^C、R^D、R^EAnd R^FIs H.

In embodiments, the compound according to formula (I) may be a compound of formulae (Va) and (Vb):

R²represents a group selected from: -OH, halogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-10Cycloalkyl radical, C_6-10Aryl, 3-to 10-membered heterocyclyl, substituted by-OR^CSubstituted C_1-8Alkyl radical, C_3-10C substituted by carbocyclic radicals_1-8Alkyl, C substituted by 3-to 10-membered heterocyclic group_1-8Alkyl, and-NR^CR^D。

In an embodiment, R²Represents a group selected from: halogen, C_1-8Alkyl or-NR^CR^DWherein R is^CAnd R^DIndependently at each occurrence is selected from: h or C_1-4An alkyl group.

In some embodiments, R²Represents a group selected from: fluoro, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, morpholinyl, -CH₂OH and-NR^CR^DWherein R is^CAnd R^DIndependently at each occurrence is selected from: H. methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

Preferably, R²Is NH₂Or Me.

In an embodiment, R³represents-C (O) NR^ER^Fis-OR^GSubstituted C_1-6Alkyl, or C_1-6Haloalkyl, optionally, wherein R^EAnd R^FIndependently at each occurrence is selected from: h or C_1-4Alkyl (preferably R)^EAnd R^FIndependently at each occurrence is selected from: H. methyl and ethyl, R^GSelected from: h or C_1-4Alkyl groups).

In an embodiment, R^EAnd R^FOne of which is H and the other is selected from

In an embodiment, R³represents-C (O) NH₂、-C(O)NHMe、-CH₂OH、CH(OH)CH₃、-CF₃or-CHF₂。

Preferably, R³represents-C (O) NH₂。

In an embodiment, R²Is NH₂Or Me, R³is-C (O) NH₂. In a particularly preferred embodiment, R²Is NH₂，R³is-C (O) NH₂。

In an embodiment, m is 1, R^4aAnd R^4bIs H, R²Is NH₂，R³is-C (O) NH₂. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R²Is NH₂，R³is-C (O) NH₂. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is fluoromethoxyphenyl or methoxyphenyl, R²Is NH₂，R³is-C (O) NH₂. In an embodiment, m is 1, R^4aAnd R^4bIs H, R⁵Is H, R⁶Is methoxyphenyl radical, R²Is NH₂，R³is-C (O) NH₂。

R¹Represents a group selected from: c_1-8Alkyl radical, C_1-8Haloalkyl, C_2-8Alkyl ethers, -C (O) R^A、C_3-10Carbocyclyl, 3-to 10-membered heterocyclyl, substituted by C_3-10C substituted by carbocyclic radicals _1-8Alkyl and C substituted by 3-to 10-membered heterocyclic group_1-8Alkyl, wherein each of the foregoing groups is unsubstituted or substituted with 1 to 5 substituents selected from: halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-CN、＝O、-C(O)OR^A、-C(O)NR^AR^B3-to 6-membered heterocycloalkyl ring, -OR^Ais-OR^ASubstituted byC_1-4An alkoxy group; wherein R is^AAnd R^BIndependently selected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, benzyl OR by-OR^HSubstituted C_1-4An alkyl group.

R¹Represents a group selected from: c_1-8Alkyl radical, C_1-8Haloalkyl, C_2-8Alkyl ethers, -C (O) R^A、C_3-10Carbocyclyl, 3-to 10-membered heterocyclyl, substituted by C_3-10C substituted by carbocyclic radicals_1-8Alkyl and C substituted by 3-to 10-membered heterocyclic group_1-8Alkyl, wherein each of the foregoing groups is unsubstituted or substituted with 1 to 5 substituents selected from: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-CN、＝O、-C(O)OR^Ais-OR^ASubstituted C_1-4Alkyl, quilt-OR^ASubstituted C_1-4An alkoxy group; wherein R is^ASelected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, benzyl OR by-OR^HSubstituted C_1-4An alkyl group.

R¹Represents a group selected from: c_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkyl ethers, -C (O) R^A、C_3-10Cycloalkyl (preferably C)_3-6Cycloalkyl), C_6-10Aryl (preferably phenyl or indanyl), 3-to 10-membered heterocycloalkyl (optionally 3-to 6-membered), 3-to 10-membered heteroaryl (optionally 3-to 6-membered, e.g. 5-or 6-membered), optionally substituted with C _3-10Cycloalkyl (preferably C)_3-6Cycloalkyl) substituted C_1-6Alkyl radical, C_6-10Aryl (preferably phenyl) substituted C_1-6Alkyl, C substituted by 3-to 10-membered heterocycloalkyl (optionally 3-to 6-membered)_1-6Alkyl and C substituted with 3-to 10-membered heteroaryl (optionally 3-to 6-membered, e.g. 5-or 6-membered)_1-6Alkyl, wherein each of the foregoing groups is unsubstituted or substituted with 1 to 5 substituents selected from: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-CN、＝O、-C(O)OR^A、-C(O)NR^AR^B3-to 6-membered heterocycloalkyl ring, by-OR^ASubstituted C_1-4Alkyl, quilt-OR^ASubstituted C_1-4Alkoxy, wherein R^ASelected from: H. c_1-4Alkyl radical, C_1-4Haloalkyl, benzyl OR by-OR^HSubstituted C_1-4An alkyl group.

In an embodiment, R¹Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, propyl, hexyl, tert-butyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, difluoropropyl, chloropropyl, propyl ether, cyclopropyl, cyclopentenyl, cyclohexyl, indanyl, bicyclo [3.1.0 ]]Hexyl, oxetane, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, phenyl, pyridinyl, thiazolyl, C substituted by oxetane_1-8Alkyl (preferably methyl or ethyl), C substituted by morpholine _1-8Alkyl (preferably methyl or ethyl), C substituted by tetrazole_1-8Alkyl (preferably methyl or ethyl), C substituted by piperidine_1-8Alkyl (preferably methyl or ethyl), C substituted by cyclohexyl_1-8Alkyl (preferably methyl or ethyl), C substituted by cyclopentyl_1-8Alkyl (preferably methyl or ethyl), C substituted by tetrahydropyranyl_1-8Alkyl (preferably methyl or ethyl), C substituted by pyrrolidinyl_1-8Alkyl (preferably methyl or ethyl), C substituted by pyridyl_1-8Alkyl (preferably methyl or ethyl), C substituted by phenyl_1-8Alkyl (preferably methyl or ethyl), C substituted by tetrahydrofuran_1-8Alkyl (preferably methyl or ethyl) and C substituted by cyclopropyl_1-8Alkyl (preferably methyl or ethyl).

In an embodiment, R¹Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, bicyclo [3.1.0 ]]Hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C substituted by oxetane_1-8Alkyl (preferably methyl or ethyl), C substituted by morpholine_1-8Alkyl (preferably methyl or ethyl), quiltTetrazole substituted C_1-8Alkyl (preferably methyl or ethyl), C substituted by piperidine _1-8Alkyl (preferably methyl or ethyl) and C substituted by cyclohexyl_1-8Alkyl (preferably methyl or ethyl).

Preferably, R¹Substituted with 1 to 5 substituents (optionally 1 to 4) selected from: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-CN、＝(O)OR^A、-C(O)NR^AR^B5-OR 6-membered heteroaryl, 3-to 6-membered heterocycloalkyl ring, OR^ASubstituted C_1-4Alkyl, quilt-OR^ASubstituted C_1-4Alkoxy, or R¹Is substituted twice to form a 3 to 6 membered heterocycloalkyl or cycloalkyl ring.

In an embodiment, R¹Substituted with 1 to 4 substituents selected from: -OH, -O, -OMe, -CN, methyl, ethyl, propyl, isopropyl, tert-butyl, CF₃、Cl、F、-OBn、-CO₂H、-CO₂Me、-CO₂Et、-C(O)NH₂、-C(O)NHMe、-C(O)NMe₂-C (O) NHOMe, pyridyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl or tetrahydrofuranyl, or R¹Is substituted twice to form ethylene oxide or oxetane.

Optionally, R¹Substituted with 1 to 5 substituents (optionally 1 to 3) selected from: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_2-4Alkyl ethers, -OR^A、-CN、＝O、-C(O)OR^Ais-OR^ASubstituted C_1-4Alkyl, quilt-OR^ASubstituted C_1-4An alkoxy group. In an embodiment, R¹Substituted with 1 to 3 substituents selected from: -OH, ═ O, -OMe, -CN, methyl, CF ₃Cl, F, -OBn or-CO₂Et。

In an embodiment, R¹Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutylAlkyl, cyclopentyl, cyclohexyl, indanyl, bicyclo [3.1.0]Hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C substituted by oxetane_1-8Alkyl (preferably methyl or ethyl), C substituted by morpholine_1-8Alkyl (preferably methyl or ethyl), C substituted by tetrazole_1-8Alkyl (preferably methyl or ethyl), C substituted by piperidine_1-8Alkyl (preferably methyl or ethyl) and C substituted by cyclohexyl_1-8Alkyl (preferably methyl or ethyl), wherein R¹Substituted with 1 to 5 substituents selected from: -OH, ═ O, -OMe, -CN, methyl, CF₃Cl, F, -OBn or-CO₂Et。

In an embodiment, R¹Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, wherein R¹Substituted with 1 to 5 substituents selected from: -OH, ═ O, -OMe, -CN, methyl, CF₃Cl, F, -OBn or-CO₂Et。

R¹May be selected from:

R¹may be selected from:

in an embodiment, R¹Selected from substituted or unsubstituted: c_3-10Carbocyclyl wherein, when substituted, R ¹When substituted with 1 to 5 substituents selected from: halogen, C_1-4Alkyl OR-OR^AWherein R is^AIs selected from H or C_1-4An alkyl group.

In some embodiments, R¹Selected from substituted or unsubstituted: c_3-6Cycloalkyl or phenyl, wherein, when substituted, R¹When substituted with 1 to 5 substituents selected from: halogen, C_1-4Alkyl OR-OR^AWherein R is^AIs selected from H or C_1-4An alkyl group.

In a preferred embodiment, R¹Selected from substituted or unsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl, bicyclo [3.1.0]Hexyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl) ethyl, or (tetrahydropyranyl) ethyl. Thus, R¹May be selected from:

in a preferred embodiment, R¹Selected from substituted or unsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl or bicyclo [3.1.0]And hexyl. Preferably, R¹May be selected from:

in a preferred embodiment, R¹Selected from substituted or unsubstituted: piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl) ethyl, or (tetrahydropyranyl) ethyl. Thus, R¹May be selected from:

in one embodiment, the compound according to formula (I) may be a compound of formulae (VIa) and (VIb) or a pharmaceutically acceptable salt thereof:

Alternatively, the compound according to formula (I) may be a compound of formulae (VIc) and (VId) or a pharmaceutically acceptable salt thereof:

in one embodiment, the compound according to formula (I) may be a compound of formulae (VIIa) and (VIIb):

alternatively, the compound according to formula (I) may be a compound of formulae (VIIc) and (VIId):

in one embodiment, the compound according to formula (I) may be a compound of formulae (VIIIa) and (VIIIb):

alternatively, the compound according to formula (I) may be a compound of formulae (VIIIc) and (VIIId):

in one embodiment, the compound according to formula (I) may be a compound of formulae (IXa) and (IXb):

alternatively, the compound according to formula (I) may be a compound of formulae (IXc) and (IXd):

for compounds of formula (VIa), (VIIa), (VIIIa), (IXa), (VIc), (VIIc), (VIIIic) and (IXc), R⁷May be as defined elsewhere herein, preferably R⁷May be selected from: H. fluoro, methyl, methoxy and-CH₂OH。

In a particularly preferred embodiment of the invention, R ¹Is thatThus, the compound according to formula (I) may be a compound of formula (X) or a pharmaceutically acceptable salt thereof:

wherein R is^1AIs selected from C_1-2Alkyl or C_1-2Haloalkyl, R^1BSelected from unsubstituted C_1-4Alkyl radical, C_1-4Haloalkyl, C substituted by OH_1-4Alkyl, C substituted by OMe_1-4Alkyl, 5 or 6 membered heteroaryl, 3 to 6 membered heterocycloalkyl ring, phenyl or C_3-10Carbocyclyl (e.g., 3-to 10-membered cycloalkyl ring). With the proviso that when R^1AIs C_1-2When alkyl, then R^1BNot being unsubstituted C_1-4An alkyl group.

Preferably, R^1ASelected from methyl, difluoromethyl or trifluoromethyl, R^1BSelected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH₂OH、-CH₂CH₂OH、-CH₂OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; with the proviso that when R^1AWhen not methyl, then R^1BNot methyl, ethyl or propyl. In an embodiment, R^1AIs trifluoromethyl.

Preferably R^1ASelected from methyl or trifluoromethyl, R^1BSelected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH₂OH、-CH₂OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclobutyl, cyclopentyl, or cyclohexyl; with the proviso that when R ^1AWhen not methyl, then R^1BNot methyl, ethyl or propyl. In an embodiment, R^1AIs trifluoromethyl.

The compound according to formula (I) may be a compound of formula (II):

wherein A is¹、A²、A⁴And A⁵0, 1 or 2 of (A) are independently selected from N, the remainder are CR⁷。

In one embodiment, the compound according to formula (I) is a compound of formulae (XIIa), (XIIb), (XIIc), and (XIId):

in an embodiment, the compound according to formula (I) is a compound of formulae (XIIIa), (XIIIb), (XIIIc), (XIIId), (XIIIe), and (XIIIf):

in one embodiment, the compound according to formula (I) may be a compound of formulae (XIVa), (XIVb), (XIVc), and (XIVd), or a pharmaceutically acceptable salt thereof:

in one embodiment, the compound according to formula (I) may be a compound of formulae (XVa), (XVb), (XVc) and (XVd) or a pharmaceutically acceptable salt thereof:

in the compounds of formulae (XVa), (XVb), (XVC) and (XVd), R^CAnd R^DMay be H. In the compounds of formulae (XVa), (XVb), (XVc) and (XVd), R^EAnd R^FMay be H. In the compounds of formulae (XVa), (XVb), (XVc) and (XVd), R^CAnd R^DCan be H, R^EAnd R^FMay be H.

In one embodiment, the compound according to formula (I) may be a compound of formulae (XVa), (XVb), (XVc) and (XVd) or a pharmaceutically acceptable salt thereof:

in an embodiment of the compounds of formulae (XVIa), (XVIb), (XVIc) and (XVId), A¹、A²、A⁴And A⁵Is CH, or A¹、A⁴And A⁵Is CH, A²Is CH, or A²、A⁴And A⁵Is CH, A¹Is CF.

In an embodiment of the compounds of formulae (XVIa), (XVIb), (XVIc) and (XVId), R²represents-NR^CR^D，R³represents-C (O) NR^ER^F. Alternatively, R^CAnd R^DIs H, R^EAnd R^FIs H.

A compound represented by the formula (X) (i.e., wherein R is¹is-CHR^1AR^1B) Is an active species.

Preferred compounds of the invention include:

the compound according to formula (I) may be a compound selected from:

the compound according to formula (I) may also be selected from:

some of the above compounds have one or more chiral centers, for example one or two chiral centers. All enantiomers and diastereomers of the above compounds are contemplated by the present invention. Some chiral centers are indicated by a symbol on the above compounds. The compounds may have chiral centers in addition to those indicated by x. In one embodiment, the compounds of the invention have the (R) -configuration at the stereocenter. In another embodiment, the compounds of the present invention have the (S) -configuration at the stereocenter. When the compound has two stereocenters, the stereocenter may have (R), (R) configuration, (S), (R) configuration, (R), (S) configuration or (S), (S) configuration. Racemic mixtures of these compounds are also contemplated by the present invention.

The compound of formula (I) may be a compound selected from:

any of the compounds described in the examples also form part of the present invention. This includes compounds falling within the scope of formula (I) and, on the other hand, any and all novel intermediates in the synthesis of compounds of formula (I).

Less preferred compounds of formula (I) are given below. In certain embodiments, the compounds shown below do not form part of the present invention.

In another aspect of the invention, there is provided a compound of any of the formulae disclosed herein for use as a medicament.

In another aspect, compounds of any formula herein are used to treat a disorder modulated by Bruton's Tyrosine Kinase (BTK). BTK-modulated disorders are generally disorders that can be treated by inhibiting BTK using the compounds of the present invention. Compounds of any of the formulae disclosed herein are useful for treating disorders treatable by inhibition of Bruton's Tyrosine Kinase (BTK).

BTK inhibition is a novel approach for the treatment of many different human diseases associated with inappropriate activation of B cells, including B cell proliferative disorders, B cell malignancies, immune diseases such as autoimmune diseases, heteroimmune diseases and inflammatory disorders or fibrosis. In particular, BTK inhibition is a novel approach for the treatment of a number of different human diseases associated with inappropriate activation of B cells, including B cell malignancies, immune diseases such as autoimmune diseases and inflammatory conditions.

In embodiments, the disorder treatable by inhibition of BTK may be selected from: cancer, lymphoma, leukemia, autoimmune disease, inflammatory disorder, heteroimmune disease, or fibrosis. The specific disorder treatable by inhibition of BTK may be selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, Lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's thyroiditis Alder syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, multiple sclerosis, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Retle's syndrome, Gaoan's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behcet's disease, chronic fatigue, autonomic nerve abnormality, endometriosis, interstitial cystitis, scleroderma, vulvodynia, graft-versus-host disease, blood transfusions, transplants, allergies, allergic disorders, chronic sclerosis, multiple sclerosis, idiopathic thrombocytopenic purpura, multiple sclerosis, scleroderma, primary biliary cirrhosis, idiopathic hemorrhagic septicemia, multiple sclerosis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, conjunctivitis, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, oophoritis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, lung disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vasculitis, vulvitis, pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, crypto-fibrotic-alveolitis (CFA), and the like, Obliterative bronchiolitis, bronchiectasis, fatty liver, steatosis (e.g. non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g. Primary Biliary Cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile fibrosis, cholestasis or cholangiopathy. In some embodiments, liver fibrosis or fibrosis includes, but is not limited to, liver fibrosis associated with alcoholism, viral infection, such as hepatitis (e.g., hepatitis c, B, or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), kidney fibrosis (e.g., chronic kidney fibrosis), kidney disease associated with injury/fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA kidney fibrosis associated with human Chronic Kidney Disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, liver fibrosis, kidney fibrosis, and the like, kidney fibrosis, and the like, Glomerulosclerosis, Progressive Glomerulonephritis (PGN), endothelial/thrombotic microangiopathy injury, HIV-related renal disease, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory disorders such as barrett's esophagus and chronic gastritis and/or fibrosis associated with postinflammatory bowel disease such as Inflammatory Bowel Disease (IBD), ulcerative colitis and crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma.

B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastases, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, cellular lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis are examples of cancers, lymphomas, and leukemias that are treatable by BTK inhibition.

B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-hodgkin lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer and bone metastasis are examples of cancers, lymphomas and leukemias that can be treated by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Alder's thyroiditis, Graves ' disease, Sjogren's syndrome, Guilin-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Lauter's syndrome, Gauss's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, Lupus's disease, rheumatoid arthritis, psoriasis, still's disease, osteoarthritis, inflammatory bowel disease, rheumatoid arthritis, diabetes mellitus, rheumatoid arthritis, diabetes, AIDS, rheumatoid arthritis, diabetes, AIDS, rheumatoid arthritis, and other arthritis, rheumatoid arthritis, and other arthritis, rheumatoid arthritis, and other arthritis, rheumatoid arthritis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic abnormalities, endometriosis, interstitial cystitis, neuromuscular sclerosis, scleroderma and vulvodynia, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, colitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, inflammatory enteritis, suppurative inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pneumopathy, pneumonitis, and vulvitis, Proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis are examples of immune diseases treatable by BTK inhibition.

Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pulmonary disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis are examples of inflammatory disorders treatable by BTK inhibition.

Lupus and sjogren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's thyroiditis, alder's thyroiditis, graves 'disease, sjogren's syndrome, guillain-barre syndrome, acute disseminated encephalomyelitis, addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, hemolytic anemia, wegener's granulomatosis, psoriasis, alopecia universalis, behcet's disease, chronic fatigue, autonomic abnormalities, chronic fatigue, Endometriosis, interstitial cystitis, neuromuscular rigidity, scleroderma and vulvodynia are examples of autoimmune diseases treatable by BTK inhibition.

Graft versus host disease, transplantation, blood transfusion, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis are examples of heteroimmune diseases that can be treated by BTK inhibition.

Pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, Cryptogenic Fibrotic Alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g. non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g. Primary Biliary Cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, biliary fibrosis, cholestasis or cholangiopathy. In some embodiments, liver fibrosis or fibrosis includes, but is not limited to, liver fibrosis associated with alcoholism, viral infection, such as hepatitis (e.g., hepatitis c, b, or c), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), kidney fibrosis (e.g., chronic kidney fibrosis), kidney disease associated with injury/fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy renal fibrosis associated with human Chronic Kidney Disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, obstruction, chronic uremia, chronic interstitial nephritis, chronic kidney fibrosis, chronic kidney inflammation associated with human chronic kidney disease, chronic kidney disease (e.g., chronic kidney disease, liver fibrosis, liver disease associated with alcohol, liver disease, liver fibrosis, kidney, Radiation nephropathy, glomerulosclerosis, Progressive Glomerulonephritis (PGN), endothelial/thrombotic microangiopathy injury, HIV-related nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory disorders such as barrett's esophagus and chronic gastritis and/or fibrosis associated with postinflammatory bowel disease such as Inflammatory Bowel Disease (IBD), ulcerative colitis and crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma are examples of fibrosis treatable by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, and lupus are examples of immune diseases treatable by BTK inhibition. Arthritis is an example of an inflammatory disease treatable by BTK inhibition. Lupus and sjogren's syndrome are examples of autoimmune diseases that can be treated by BTK inhibition.

Any of the conditions disclosed above that are treatable by BTK inhibition can be treated by a compound of the invention, or can be treated in a method that includes administration of a compound of the invention, or can be treated by a medicament made via use of a compound of the invention.

In an embodiment, the compounds of the invention may be used for the treatment of: cancer, lymphoma, leukemia, immune diseases, autoimmune diseases, and inflammatory disorders. The compounds of the invention are useful for treating a particular condition selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-hodgkin lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, sjogren's syndrome, and lupus. The compounds may also be used to treat conditions associated with kidney transplantation.

In one embodiment, the compounds of the invention may be used to treat a particular condition selected from: such as B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus and arthritis.

In one aspect of the invention, there is provided a method of treating a condition modulated by bruton's tyrosine kinase, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the invention.

The method of treatment may be a method of treating a condition treatable by inhibition of bruton's tyrosine kinase.

The invention also provides methods of treating a condition selected from the group consisting of: cancer, lymphoma, leukemia, immune diseases, autoimmune diseases, and inflammatory conditions, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the invention. The present invention also provides a method of treating a particular condition selected from: a B cell malignancy, a B cell lymphoma, a diffuse large B cell lymphoma, chronic lymphocytic leukemia, a non-hodgkin's lymphoma such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, a B cell non-hodgkin's lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, sjogren's syndrome, and lupus, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of any of the formulae disclosed herein. The method can also treat conditions associated with kidney transplantation.

In one embodiment, the method may be used to treat a particular condition selected from the group consisting of: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-hodgkin's lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, arthritis and lupus.

In another aspect of the invention, there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition may be a combination product comprising additional pharmaceutically active agents. The additional pharmaceutically active agent may be an antineoplastic agent as described below.

Detailed Description

The following gives definitions of terms used in the present application. Any terms not defined herein have their normal meaning as will be understood by the skilled person.

The term "halo" refers to one of the halogens of group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C _1-8Alkyl "or" C_1-6Alkyl "means a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms or 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Alkylene groups can likewise be straight-chain or branched and can have two positions of attachment to the rest of the molecule. Furthermore, the alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. The substituents of alkyl may be halogen, for example fluorine, chlorine, bromine and iodine, OH, ═ O or C_1-6An alkoxy group.

The term "alkoxy" refers to an alkyl group attached to a molecule through an oxygen. This includes moieties in which the alkyl moiety may be straight or branched. For example, the term "C_1-6Alkoxy "means an alkyl group attached to the molecule through an oxygen containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Thus, alkoxy can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl portion of an alkoxy group can be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Alkane (I) and its preparation method The substituents of the radicals may be halogens, e.g. fluorine, chlorine, bromine and iodine, OH, C_1-6An alkoxy group.

The term "alkyl ether" refers to a straight or branched alkyl chain interrupted by a single oxygen atom to provide an ether. For example, the term "C_2-6Alkyl ether "or" C_2-4Alkyl ether "means a straight or branched hydrocarbon chain containing 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms with a single oxygen atom in the chain, for example-CH₂OCH₃、-(CH₂)₂OCH₃、-(CH₂)₃OCH₃、-CH₂OCH₂CH₃、-CH₂O(CH₂)₂CH₃Or- (CH)₂)₂O(CH₂)₂CH₃。

The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently selected at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, "C_1-6Haloalkyl "means a hydrocarbon chain containing 1,2, 3, 4, 5 or 6 carbon atoms substituted by at least one halogen atom, such as chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2, 2-trichloroethyl, 2,2, 2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2, 2-trifluoroethyl and 2,2, 2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C _2-6Alkenyl "means a branched or straight hydrocarbon chain containing at least one double bond having 2, 3, 4, 5, or 6 carbon atoms. The double bond may exist as an E or Z isomer. The double bond may be located at any possible position of the hydrocarbon chain. For example, "C_2-6Alkenyl "may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl.

The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, the term "C_2-6Alkynyl radicals "Refers to a branched or straight hydrocarbon chain containing at least one triple bond having 2, 3, 4, 5, or 6 carbon atoms. The triple bond may be located at any possible position of the hydrocarbon chain. For example, "C_2-6Alkynyl "may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

The term "heteroalkyl" refers to a branched or straight hydrocarbon chain wherein at least one heteroatom selected from N, O and S is located between any carbons in the chain or at the end of the chain. For example, the term "C_1-6Heteroalkyl "refers to a branched or straight hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, and at least one heteroatom selected from N, O and S is located between any carbons in the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. C _1-6The heteroalkyl group may be bonded to the remainder of the molecule through a carbon or heteroatom. For example, "C_1-6Heteroalkyl "may be C_1-6N-alkyl, C_1-6N, N-alkyl or C_1-6An O-alkyl group.

The term "carbocycle" refers to a saturated or unsaturated carbocyclic ring-containing system. The "carbocyclic" system may be a monocyclic or fused polycyclic system, such as bicyclic or tricyclic. The "carbocyclic" moiety may contain 3 to 14 carbon atoms, for example 3 to 8 carbon atoms in a monocyclic ring system and 7 to 14 carbon atoms in a polycyclic ring system. "carbocycle" includes cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems that include an aromatic moiety.

The term "heterocycle" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1, 2, 3 or 4 heteroatoms, for example 1 or 2. The "heterocyclic" system may be a monocyclic or fused polycyclic ring system, for example a bicyclic or tricyclic ring system. The "heterocyclic" moiety may contain 3 to 14 carbon atoms, for example 3 to 8 carbon atoms in a monocyclic ring system and 7 to 14 carbon atoms in a polycyclic ring system. "heterocycle" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties, and heteroaromatic moieties. For example, a heterocyclyl group can be ethylene oxide, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

The term "cycloalkyl" refers to a saturated hydrocarbon ring system. A "cycloalkyl" group can be represented as a "C" group containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms_3-10Cycloalkyl groups ". The ring system may be a monocyclic or bicyclic or tricyclic ring system. For example, "cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclohexyl, cycloheptyl, and cyclooctyl.

The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. "cycloalkenyl" can be represented by "C_3-10Cycloalkenyl groups ". "C_3-10Cycloalkenyl "is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring may contain more than one double bond, provided that the ring system is not aromatic. The ring system may be a monocyclic or bicyclic or tricyclic ring system. For example, "cycloalkenyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl, and cyclohexadienyl.

The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system having at least one heteroatom selected from N, O and S in the ring. "Heterocycloalkyl" may be represented by "C_3-10Heterocycloalkyl "is used herein. "C_3-10Heterocycloalkyl "is a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. A "heterocycloalkyl" group can also be represented as a "3-to 10-membered heterocycloalkyl," which is also a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. The ring system may be a monocyclic or bicyclic or tricyclic ring system. When the ring system is bicyclic, one of the rings may be aromatic, for example in indane. "heterocycloalkyl" can be bonded to the rest of the molecule through any carbon or heteroatom. "heterocycloalkyl" may have one or more, e.g., one or two, linkages to the rest of the molecule: these linkages may be through any atom in the ring. For example, "heterocycloalkyl" may be ethylene oxide, aziridine, nitrogen Azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and indane.

The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic and has at least one heteroatom selected from N, O and S in the ring. "Heterocycloalkenyl" may be represented by "C_3-10A heterocycloalkenyl group. "C_3-10Heterocycloalkenyl "is a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "heterocycloalkenyl" can also be represented as "3-to 10-membered heterocycloalkenyl" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. The ring system may be a monocyclic or bicyclic or tricyclic ring system. When the ring system is bicyclic, one of the rings may be aromatic, for example in indoline and dihydrobenzofuran. "heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon or heteroatom. "heterocycloalkenyl" may have one or more, for example one or two, linkages to the rest of the molecule: these linkages may be through any atom in the ring. For example, "C _3-8Heterocycloalkenyl "can be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene, and indoline.

The term "aromatic" when applied as a whole to a substituent refers to a monocyclic or polycyclic ring system having 4n +2 electrons in a conjugated pi system within the ring or ring system, wherein all atoms contributing to the conjugated pi system are in the same plane.

The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in the conjugated pi system within the ring, with all atoms contributing to the conjugated pi system being in the same plane. The ring system may be a monocyclic or bicyclic or tricyclic ring system. For example, "aryl" may be phenyl and naphthyl. The aryl system may itself be substituted with other groups.

The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N and S, either within a single ring or within a fused ring system. The ring or ring system has 4n +2 electrons in the conjugated pi system, with all atoms contributing to the conjugated pi system being in the same plane. The ring system may be a monocyclic or bicyclic or tricyclic ring system. For example, "heteroaryl" can be imidazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

The term "alkaryl" refers to a bond with C_1-4An alkyl-bonded aryl group as defined above, wherein C_1-4The alkyl group provides a link to the rest of the molecule.

The term "alkylheteroaryl" refers to a group with C_1-4An alkyl-bonded heteroaryl group as defined above, wherein the alkyl group provides a link to the rest of the molecule.

The term "halogen" herein includes indications of F, Cl, Br and I. The halogen may be Cl. The halogen may be F.

To be provided withThe bond at the end indicates that the bond is attached to another atom not shown in the structure. A bond that terminates within a cyclic structure and does not terminate at a ring structure atom means that the bond may be attached to any atom in the cyclic structure that the valence state allows.

When a moiety is substituted, it may be substituted at any point on the moiety where it is chemically possible and meets the requirements for atomic valence. The moiety may be substituted with one or more substituents, for example 1, 2, 3 or 4 substituents; optionally with 1 or 2 substituents on the group. When there are two or more substituents, the substituents may be the same or different. The substituents may be selected from: OH, NHR⁹Amidino, guanidino, hydroxyguanidino, amidino, isothioureido, ureido, mercapto, C (O) H, acyl, acyloxy, carboxyl, sulfo, sulfamoyl, carbamoyl, cyano, nitro, halogen, C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl, heteroaryl or alkaryl. When the group to be substituted is an alkyl group, the substituent may be ═ O. When a moiety is substituted with two or more substituents and the two substituents are adjacent, the adjacent substituents may form C together with the atom of the moiety substituted by the substituent_4-8Ring of which C_4-8The ring is a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7 or 8 carbon atoms and 1, 2 or 3 heteroatoms.

If chemically possible, cyclic substituents may be substituted on the groups to form spiro rings.

Substituents are present only at their chemically possible positions and the skilled person is able to determine (experimentally or theoretically) which substitutions are chemically feasible and which are not without undue effort.

Ortho, meta and para substitution are well understood terms in the art. For the avoidance of doubt, an "ortho" substitution is a substitution pattern in which adjacent carbons have a substituent, whether simple or not, such as a fluoro group in the examples below, or other parts of the molecule, such as The keys at the end indicate.

"meta" substitution is a substitution pattern in which two substituents are on carbons one carbon away from the other, i.e., having a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom of the atom having another substituent. For example, the following groups are meta-substituted.

"para" substitution is a substitution pattern in which two substituents are on carbons two carbons away from each other, i.e., having two carbon atoms between the substituted carbons. In other words, there is one substituent on the third atom of the atom having another substituent. For example, the following groups are para-substituted.

"acyl" refers to an organic radical derived from an organic acid, for example, by removal of a hydroxyl group, such as a radical having the formula R-C (O) -, where R may be selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, phenyl, benzyl or phenethyl, e.g. R is H or C_1-3An alkyl group. In one embodiment, the acyl group is an alkyl-carbonyl group. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, and butyryl. A particular acyl group is acetyl.

In embodiments where a single enantiomer of a compound of the invention is present, the compound of the invention may have an enantiomeric purity of at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), at least about 99% enantiomeric excess (ee), or 100% enantiomeric excess (ee). In embodiments where a mixture of enantiomers of a compound of the invention is present, the compound of the invention may be a racemic mixture of enantiomers or any other mixture, for example, a compound of the invention may have an enantiomeric purity of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), or at least about 95% enantiomeric excess (ee).

Throughout the specification, the disclosure of the compounds also includes pharmaceutically acceptable salts, solvates, and stereoisomers thereof. When the compound has a stereocenter, the present invention contemplates both the (R) and (S) stereoisomers, and the present application contemplates an equivalent or racemic mixture of the stereoisomers. When the compounds of the present invention have two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of the (R) and (S) stereoisomers may result in a mixture of diastereomers or a single diastereomer. The compounds of the present invention may exist as a single stereoisomer, or may be mixtures of stereoisomers, such as racemic and other enantiomeric mixtures, as well as diastereomeric mixtures. Where the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those disclosed above. When the compounds are single stereoisomers, the compounds may still contain other diastereomers or enantiomers as impurities. Thus, a single stereoisomer need not have 100% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), but may have about at least 85% e.e. or d.e.

The present invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include acid addition and base salts of the compounds. These may be acid addition salts and base salts of the compounds. In addition, solvates of these compounds are contemplated by the present invention. These may be hydrates or other solvated forms of the compounds.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyacinate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 1, 5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, gluconate, stearate, dihydrogenphosphate, Succinate, tartrate, tosylate and trifluoroacetate.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, Selection, and Use "(Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of the following three methods:

(i) by reacting a compound of formula (I) with the desired acid or base;

(ii) by removal of acid or base labile protecting groups from suitable precursors of compounds of formula (I), or by ring opening of suitable cyclic precursors (e.g. lactones or lactams) using the desired acid or base; or

(iii) By converting one salt of a compound of formula (I) into another by reaction with a suitable acid or base or by means of a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can range from complete ionization to little ionization.

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term 'hydrate' is used.

Complexes such as clathrates, drug-host inclusion complexes are included within the scope of the invention, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Also included are pharmaceutical complexes containing two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of such complexes see J Pharm Sci, 64(8), 1269-.

Hereinafter, all references to compounds of any formula include references to salts, solvates and complexes thereof, and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of the various formulae defined herein, including all polymorphs and crystal habits thereof, as defined hereinafter, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers), as well as isotopic labels of the invention.

Prior to purification, the compounds of the invention may exist as a mixture of enantiomers depending on the synthetic procedure used. Enantiomers may be separated by conventional techniques known in the art. Thus, the present invention encompasses the individual enantiomers and mixtures thereof.

For some steps of the process for preparing compounds of formula (I), it may be desirable to protect potentially reactive functional groups that are not desired to react, and to subsequently cleave the protecting group. In this case, any compatible protecting radical may be used. In particular, protection and deprotection methods such as those described in T.W.GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or P.J.Kocienski (Protective Groups, Georg Thieme Verlag, 1994) can be used. The preparation of all the novel starting materials used in the above-mentioned reactions and the processes described above is conventional and the reagents and reaction conditions suitable for their performance or preparation and the methods of isolating the desired products are well known to the person skilled in the art under the precedent of the references and the examples and preparations in this respect.

In addition, the compounds of the present invention and intermediates used in their preparation may be purified according to various well-known methods such as crystallization or chromatography.

The method of treatment or the compound for the treatment of cancer, lymphoma, leukemia or immune diseases as defined above may be applied as a sole therapy or in combination therapy with another active agent.

The method of treatment or the compounds for the treatment of cancer, lymphoma or leukaemia may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Such chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, phenobarbital, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytarabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as paclitaxel and taxotere, and polo kinase inhibitors); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin);

(ii) Inhibitors of cell growth that are translationally mis-productive such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodixan), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5 α -reductase inhibitors such as finasteride;

(iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;

(iv) growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB 2 antibody trastuzumab [ herceptin ]^TM]anti-EGFR antibody panitumumananti-erbB 1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-yl) amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; protein modulators that modulate apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and/or nilotinib (AMN 107); serine/threonine kinase inhibitors (e.g., Ras/Raf signal transduction inhibitors such as farnesyl transferase inhibitors, e.g., sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptors, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors, such as CDK2 and/or CDK4 inhibitors;

(v) Anti-angiogenic agents, e.g., those that inhibit the action of vascular endothelial growth factor [ e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin)^TM) (ii) a Thalidomide; lenalidomide; and for example VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

(vi) gene therapy methods, including, for example, methods of replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA 2;

(vii) immunotherapeutic approaches, including, for example, antibody therapy, such as alemtuzumab, rituximab, ibritumomab tiuxetanAnd ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines including prophylactic and therapeutic vaccines such as HPV vaccines, e.g. Gardasil, Cervarix, Oncophage and Sipuleucel-t (provenge);and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and

(viii) cytotoxic agents, e.g. fludarabine (fludara), cladribine, pentostatin (Nipent)^TM)；

(ix) Steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, e.g., alclometasone, clomethasone dipropionate, aldosterone, amcinonide, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone butyrate, clobetasone propionate, prednisolone, cortisone acetate, cortisol, deoxycorticosterone, desoximetasone, dexamethasone sodium phosphate, dexamethasone sodium isononate, difluorocorticosterone, fluorochlordosisone, flunisolone, fluocinolone, fluocinonide, fluocortexolone, fluocortolone acetate, hydrocortisone butyrate, hydrocortisone acetate, Hydrocortisone butyrate, hydrocortisone ketobutyrate, hydrocortisone acephate, hydrocortisone valerate, beclomethasone, acexamethasone, prednisone, methylprednisolone, mometasone pametasone, mometasone furoate monohydrate, prednisone ester, prednisolone, prednisone, ticortisone, tixocortol, triamcinolone acetonide, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, for example combinations of two or more steroids mentioned in this paragraph;

(x) Targeted therapies, such as PI3Kd inhibitors, such as idellaris and piperacillin.

The therapeutic methods or compounds for treating immune disorders may include other active agents in addition to the compounds of the present invention. The additional active agent may be one or more active agents for the treatment of a condition treatable by a compound of formula (I) and the additional active agent. The additional active agent may include one or more of the following active agents:

(i) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, such as alclometasone, clomethasone dipropionate, aldosterone, amcinonide, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone butyrate, clobetasone propionate, prednolone, cortisone acetate, cortisol, deoxycorticosterone, desoximetasone, dexamethasone sodium phosphate, dexamethasone sodium isonicotinate, difluorocorticosterone, fluorochlordosisone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortebufenolone acetate, fluocortexine, fluocortolone acetate, hydrocortisone butyrate, hydrocortisone acetate, Hydrocortisone butyrate, hydrocortisone ketobutyrate, hydrocortisone acephate, hydrocortisone valerate, beclomethasone, acexamethasone, prednisone, methylprednisolone, mometasone pametasone, mometasone furoate monohydrate, prednisone ester, prednisolone, prednisone, ticortisone, tixocortol, triamcinolone acetonide, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, for example combinations of two or more steroids mentioned in this paragraph;

(ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), semuzumab (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2A agonists (e.g., 2, 5-dimethoxy-4-iodophenylpropylamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylacridine);

(iii) anti-inflammatory agents, such as non-steroidal anti-inflammatory agents;

(iv) dihydrofolate reductase inhibitors/antifolates such as methotrexate, trimethoprim, ipratropium bromide, tetraoxyproline, elargoline, pemetrexed, raltitrexed and pralatrexate; and

(v) immunosuppressants such as cyclosporin, tacrolimus, sirolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors such as thiol-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g., fosinopril).

Such combination therapy may be achieved by administering the individual components of the therapy simultaneously, sequentially or separately. Such combination products employ the compounds of the present invention within the therapeutically effective dosage ranges described above, and the other pharmaceutically active agents are within their approved dosage ranges.

According to another aspect of the present invention there is provided a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a further active agent. The additional active agent may be an anti-neoplastic agent as defined above for the combined treatment of a disorder modulated by BTK.

According to another aspect of the present invention there is provided a method of treating a BTK-modulated disorder comprising administering to a patient in need thereof simultaneously, sequentially or separately a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent as defined above.

According to another aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a BTK modulated disorder, simultaneously, sequentially or separately with a further antineoplastic agent as defined above.

According to another aspect of the invention there is provided the use of a compound of formula (I) in combination with an anti-tumour agent as described above. The compounds of formula (I) may be used simultaneously, sequentially or separately with another antineoplastic agent. The use may be in a single combination comprising a compound of formula (I) and an antineoplastic agent.

According to a further aspect, there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumour agent as defined above. The method may comprise combining the compound of formula (I) and the antineoplastic agent in a single dosage form. Alternatively, the method may comprise providing the antineoplastic agent as a separate dosage form.

According to a further aspect, there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumour agent as defined above. The method may comprise combining the compound of formula (I) and the antineoplastic agent in a single dosage form. Alternatively, the method may comprise providing the antineoplastic agent as a separate dosage form.

The BTK-mediated disorder described above may be cancer, leukemia or cancer. More specifically, disorders modulated by BTK may be selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-hodgkin's lymphoma, waldenstrom's macroglobulinemia, and multiple myeloma.

The compounds of the invention may be present in single crystal form or in the form of a crystalline mixture, or they may be amorphous. Thus, the compounds of the invention for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained in the form of solid fillers, powders or films by processes such as precipitation, crystallization, freeze drying or spray drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

For the above compounds of the invention, the dosage administered will, of course, vary with the compound used, the mode of administration, the treatment desired and the disease state indicated. For example, if a compound of the invention is administered orally, the daily dose of the compound of the invention may range from 0.01 micrograms per kilogram of body weight (μ g/kg) to 100 milligrams per kilogram of body weight (mg/kg).

The compounds of the present invention or pharmaceutically acceptable salts thereof may be used alone, but are generally administered in the form of a pharmaceutical composition in which the compound of the present invention or pharmaceutically acceptable salt thereof is combined with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", m.e. aulton, churchlill Livingstone, 1988.

Depending on the mode of administration of the compounds of the invention, the pharmaceutical compositions for administering the compounds of the invention will preferably comprise from 0.05 to 99% by weight (by weight) of the compounds of the invention, more preferably from 0.05 to 80% by weight of the compounds of the invention, still more preferably from 0.10 to 70% by weight of the compounds of the invention, even more preferably from 0.10 to 50% by weight of the compounds of the invention, all percentages by weight being based on the total composition.

The pharmaceutical composition may be administered topically (e.g. to the skin) in the form of, for example, a cream, gel, lotion, solution, suspension or systemically, for example by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of sterile solutions, suspensions or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); rectal administration by suppository form; or inhaled by aerosol form.

For oral administration, the compounds of the invention may be mixed with adjuvants or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; a cellulose derivative; binders, such as gelatin or polyvinylpyrrolidone; and/or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, and paraffins, etc., and then compressed into tablets. If a coated tablet is desired, the core prepared as described above may be coated with a concentrated sugar solution which may comprise, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a volatile organic solvent.

For the preparation of soft gelatin capsules, the compounds of the invention may be mixed with, for example, vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of the compound using the above-mentioned tablet excipients. Liquid or semisolid formulations of the compounds of the present invention may also be filled into hard gelatin capsules. Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing the compounds of the invention, the remainder being a mixture of sugar and ethanol, water, glycerol and propylene glycol. Optionally, such liquid formulations may contain coloring agents, flavoring agents, sweetening agents (e.g., saccharin), preservatives, and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.

For intravenous (parenteral) administration, the compounds of the invention may be administered as a sterile aqueous or oily solution.

The size of the dose of the compound of the present invention for therapeutic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

It is expected that the dosage level, frequency of dosage and duration of treatment of the compounds of the invention will depend on the formulation and clinical indication, age and comorbidity of the patient. For most clinical indications, the standard duration of treatment with the compounds of the invention is expected to vary between 1 and 7 days. In the case of recurrent infections or infections associated with poorly blood-supplied tissues or implanted materials (including bone/joint, respiratory, endocardial and dental tissues), it may be necessary to extend the duration of the treatment beyond 7 days.

Examples and syntheses

As used herein, the following terms have the meanings given: "Boc" refers to tert-butoxycarbonyl; "DCM" means dichloromethane; "DIPEA" refers to N, N-diisopropylethylamine; "EtOAc" refers to ethyl acetate; "LCMS" refers to liquid chromatography/mass spectrometry; "MIM" refers to monoisotopic masses; "min" means minutes; "DMF" refers to N, N-dimethylformamide; ether "refers to petroleum ether; "TLC" refers to thin layer chromatography; "Rf" refers to a retention factor; "RT" means RT; "SCX" refers to strong cation exchange; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TBME" means t-butyl methyl ether.

Solvents, reagents and starting materials were purchased from commercial suppliers and used as received unless otherwise indicated. All reactions were carried out at room temperature unless otherwise indicated.

Confirmation of compound identity and purity was performed by LCMS UV using Waters Acquity SQ detector 2(ACQ-SQD2# LCA 081). The diode array detector wavelength was 254nM, and the MS was in positive and negative electrospray modes (m/z: 150-. A2 μ L aliquot was injected sequentially onto a guard column (0.2 μm. times.2 mm filter) and a UPLC column (C18, 50X 2.1mm, <2 μm) and held at 40 ℃. The samples were eluted with a mobile phase system consisting of A (0.1% (v/v) aqueous formic acid) and B (0.1% (v/v) acetonitrile formic acid) at a flow rate of 0.6mL/min according to the gradient listed in Table 1 below. Retention time RT is reported in minutes.

TABLE 1

Compound identity was also confirmed by LCMS UV using Waters alliance 2695 micro mass ZQ (K98SM 4512M-LAA 434). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray modes (m/z: 150-. A10 μ L aliquot was injected onto an HPLC column (C18, 75X 4.6mm, 2.5 μm) at RT controlled at 19 ℃. The sample was eluted at a flow rate of 0.9mL/min using a mobile phase system consisting of A (95: 5(v/v) water with 0.1% (v/v) formic acid: acetonitrile) and B (95: 5(v/v) acetonitrile with 0.1% (v/v) formic acid: water) according to the gradient listed in Table 2 below. Retention time RT is reported in minutes.

TABLE 2

Compound identity confirmation was also performed by analytical Supercritical Fluid Chromatography (SFC) using Agilent 1260 analytical SFC (SFC-a). A10 μ L aliquot was injected onto an HPLC column (C18, 75X 4.6mm, 2.5 μm) at RT controlled at 19 ℃. The method uses the following components of A: CO 2₂And B: a mobile phase system of methanol (0.05% DEA, V/V) eluted the sample at a flow rate of 3mL/min to dilute the B phase gradient from 5% to 40% within 3.6 min.

NMR was also used to characterize the final compound. NMR spectra were obtained on Bruker avim 400 Nanobay with 5mm bbfo probe. Optionally, compound Rf values were measured on silica Thin Layer Chromatography (TLC) plates.

Compound purification was performed by silica gel flash column chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass spectrometer detector in positive and negative electrospray modes (m/z: 150-800) with a Waters 2489UV/Vis detector. A mobile phase system consisting of A (0.1% (v/v) formic acid in water) and B (0.1% (v/v) formic acid in acetonitrile) was used according to the gradient listed in Table 3 below, in Xbridge^TMPreparation of C185. mu.M OBD 19X100mm column the sample was eluted at a flow rate of 20 mL/min.

TABLE 3

Time (minutes)	％A	％B
			0	90	10
1.5	90	10
			11.7	5	95
13.7	5	95
			14	90	90
15	90	90

Compound purification was also performed by preparative Supercritical Fluid Chromatography (SFC). SFC purification was performed using Waters 80Q preparative SFC (SFC-B). The method uses the following components of A: CO2, and B: methanol (0.1% NH)₃H₂O) mobile phase system samples of 5 μm particle size were eluted under isocratic elution (25% phase B) on a ChiralPak OJ-H column, 250 x 30mm i.d. at a flow rate of 50 g/min.

The chemical Name in this document was generated using mol2 nm-Structure to Name Conversion by OpenEye Scientific Software. The starting materials were purchased from commercial sources or synthesized according to literature procedures.

General scheme

The compounds of the invention may be prepared by following general scheme 1 or general scheme 2, one of the general schemes shown below.

General scheme 1

In one aspect of the invention, there is provided a compound of formula (a):

wherein R is⁶As defined elsewhere herein, optionally wherein R⁶Is a substituted phenyl or a substituted or unsubstituted 5 or 6 membered heteroaryl ring, wherein, when substituted, R⁶Containing 1 to 5 substituents independently at each occurrence selected from the group consisting of: halogen, -OR^I、-NR^IR^J、-CN、C_1-6Alkyl radical, C_1-6Haloalkyl and substituted aryl^ISubstituted C_1-6An alkyl group;

y is a halogen group, such as fluorine; and

z is a metal ion, for example a group 1 metal such as potassium or sodium.

In the above aspect of the present invention, R⁶Preferably by methoxy and 0 to 4 additional substituents independently selected at each occurrence from: halogen, -OR^I、-NR^IR^J、-CN、C_1-6Alkyl radical, C_1-6Haloalkyl and substituted aryl^ISubstituted C_1-6An alkyl group.

In a preferred embodiment, the compound according to formula (a) is a compound according to formula (B) or (C):

general scheme 2

General scheme 3

General procedure

General procedure A

To a suspension of [4- (aminomethyl) phenyl ] boronic acid hydrochloride (1.1 eq) and the corresponding benzoic acid (1.0 eq) in anhydrous THF (0.49M) under a nitrogen atmosphere were added N, N-diisopropylethylamine (5.0 eq) and a solution of propylphosphonic anhydride (50 wt% in EtOAc) (1.5 eq) in that order. The reaction mixture was heated at 70 ℃ under reflux for 14h and stirred. The mixture was diluted with water and DCM and then separated into layers. The aqueous layer was extracted with DCM (. times.2). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the desired boronic acid. No further purification was attempted and the product was used directly in the next step.

General procedure B

To [4- (aminomethyl) phenyl group under nitrogen atmosphere]To a suspension of boronic acid hydrochloride (1.0 equivalent) and DIPEA (3.0 equivalents) in anhydrous THF (0.2M) was added a solution of the corresponding benzoyl chloride derivative (1.1 equivalent) in anhydrous THF (0.2M). The reaction mixture was stirred at room temperature for 16h, quenched with saturated aqueous ammonium chloride solution, and then extracted into ethyl acetate (× 3). The combined organics were washed with brine, washed with Na₂SO₄Dried, filtered and then concentrated under reduced pressure to give the desired boronic acid derivative. No further purification was attempted and the product was used directly in the next step.

General procedure C

A mixture of halogen (1.0 equivalent), boric acid or pinacol ester (1.5 equivalents), and potassium carbonate (2.0 equivalents) in 1, 4-dioxane and water (3: 1, 0.1M) was degassed by bubbling nitrogen gas therethrough for 25 minutes. 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.05 eq) was added and the mixture was degassed again by bubbling nitrogen gas through it for 30 minutes. The mixture was then heated at 120 ℃ for 14 h. Warp beamThe reaction mixture was filtered. The filter cake was washed with DCM. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (. times.2). The combined organic extracts are passed through a phase separator Filtered and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography on silica gel afforded the desired compound.

General procedure D

A mixture of halogen (1.0 equivalent), boric acid or pinacol ester (1.5 equivalents), and potassium carbonate (2.0 equivalents) in 1, 4-dioxane and water (3: 1, 0.1M) was degassed by bubbling nitrogen gas through it for 15 minutes. 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.05 eq) was added and the mixture was degassed again by bubbling nitrogen gas through it for 15 minutes. The mixture was then heated under microwave irradiation at 120-140 ℃ for 60-90 minutes. The reaction mixture was purified by SCX SPE column and used as such, or purified using the following procedure, unless the crude product was stated to be used. By passingThe pad filters the mixture. The filter cake was washed with DCM. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (. times.2). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography gave the desired compound.

General procedure E

To a solution of ketone (1.0 eq) in MeOH (0.2M) was added the corresponding hydrazine (1.05 eq) and the reaction was stirred at room temperature for 15 h. Volatiles were removed under reduced pressure to afford crude Boc-hydrazone derivatives.

General procedure F

A solution of Boc-hydrazone derivative (1.00 eq) in methanol was treated with 10% palladium on carbon (0.02 eq), acetic acid (0.01 eq) and H₂And (5) purifying. The solution is added in H₂(1atm) overnight, then by stirringAnd (5) filtering. The filtrate was concentrated under reduced pressure to give the corresponding Boc-protected hydrazine.

General procedure G

To a solution containing Boc-protected hydrazine (1.0 eq) in MeOH (0.5M) was added 4N HCl in 1, 4-dioxane (8.0 eq) and the reaction was stirred at room temperature for 5 h. Diethyl ether was added to form a precipitate, which was collected by filtration to give the desired hydrazine intermediate. Alternatively, the mixture was concentrated under reduced pressure and used as such.

General procedure H

To a solution of 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (1.0 eq) and TEA (3.0 eq) in EtOH (0.6M) was added the corresponding hydrazine derivative (1.2 eq) and stirred at 100 ℃ for 2-14 h. Volatiles were removed under reduced pressure. To the residue were added saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel afforded the desired compound.

General procedure I

To a stirred solution of alcohol (1.0 eq) in DCM (0.9M) cooled at 0 ℃ under a nitrogen atmosphere was added triethylamine (1.1 eq). The resulting solution was stirred for 10 minutes, then methanesulfonyl chloride (1.1 eq) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1h, quenched with water, and extracted with DCM (× 2). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the desired mesylated product.

General procedure J

Hydrochloric acid (1M, 3.0 equiv.) is added to a suspension of 1, 3-dioxolane derivative (1.0 equiv.) in THF (1M) cooled at 0 deg.C. The reaction mixture was allowed to come to room temperature and stirred for 14 h. The mixture was then carefully basified with saturated sodium carbonate solution and the aqueous layer was extracted with DCM (× 3). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give crude carbonyl groups.

General procedure K

A mixture of halogen derivative (1.0 equivalent), Molander salt (1.0 equivalent), cesium carbonate (3.0 equivalents) and XPhos (0.1 equivalent) in THF and water (10: 1, 0.06M) was degassed by bubbling nitrogen through it for 15 minutes. Then addPalladium acetate (0.05 eq) was added and the mixture was degassed again by bubbling nitrogen through it for 5 minutes. The mixture was then heated to 85 ℃ for 16h, overAnd (5) filtering. The filter cake was washed with DCM. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (. times.2). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure. Further purification by flash column chromatography on silica gel afforded the desired compound.

General procedure L

To a solution of nitrile derivative (1.0 equiv) in EtOH/water (2: 1, 0.8M) was added hydrogenated (dimethylphosphonous acid kP) [ Hydrobis (dimethylphosphino-kP) ] platinum (II) (0.07g, 0.163 mmol). The mixture was heated at 80 ℃ overnight and then concentrated under reduced pressure. The residue was then partitioned between DCM and water. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure to give the desired crude amide.

General procedure M

To the nitrile derivative (1 eq) was added a solution of sulfuric acid (10 eq) and trifluoroacetic acid (40 eq) and the reaction mixture was heated to 55 ℃ for 5 h. Once cooled, the mixture was poured into an ice-water mixture, carefully neutralized with sodium bicarbonate, and then extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel afforded the desired amide.

General procedure N

Cesium carbonate (1.5 equivalents) was added to a mixture of 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1H-pyrazole-4-carboxamide (1 equivalent) and halide derivative (1.2 equivalents) in DMF (0.1M). The reaction mixture was heated to 80 ℃ for 1.5h and then concentrated under reduced pressure. Further purification by flash column chromatography on silica gel or by mass directed semi-preparative HPLC gave the desired product.

General procedure O

To a solution of hydrazone (1 equivalent) in THF (0.5M) at 0 deg.C under nitrogen was added a solution of borane tetrahydrofuran complex (BH)₃THF, 1.0M in THF, 2 equivalents). The reaction mixture was returned to RT, stirred for 14h, then quenched with methanol (1mL) and water. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Hydrogen chloride-containing dioxane (4M, 10 equivalents) was added to the residue and the mixture was stirred at room temperature for 14 h. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethanol (0.2M). Adding 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.5-1.0 equiv) and TEA (5 equiv), and the reaction was stirred at room temperature for 14 h. Volatiles were removed under reduced pressure. Water and DCM were added to the residue and the layers were separated. The aqueous layer was extracted with DCM (. times.2). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel gave the desired product.

General procedure P

Under nitrogen, 1M borane THF complex (5.0 equivalents) was added dropwise to a stirred solution of the nitrile derivative (1.0 equivalent) in anhydrous THF (0.10M). The reaction mixture was then heated at reflux for 4h before cooling to room temperature. Methanol was carefully added dropwise until the evolution of gas ceased. The solvent was removed under reduced pressure, the residue was dissolved in methanol and treated with concentrated aqueous HCl. The resulting mixture was heated to reflux for 10 minutes and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was carefully treated with an excess of aqueous sodium bicarbonate. The resulting suspension was extracted with ethyl acetate, the organic layer was dried, filtered and evaporated under reduced pressure to give the corresponding amine.

General procedure Q

A solution of 1-hydroxybenzotriazole hydrate (1.1 equiv.) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.1 equiv.) in DMF (0.5M) containing acid (1.1 equiv.) and 1-hydroxybenzotriazole hydrate (1.1 equiv.) was stirred at room temperature for 30 minutes, then treated with the corresponding amine (1.0 equiv.) followed by triethylamine (5.0 equiv.). The reaction mixture was then stirred at room temperature for 18h, poured into brine and extracted with ethyl acetate. The organic layer was washed with 0.2M aqueous HCl and brine. The organic layer was then dried, filtered and the solvent evaporated under reduced pressure to give the desired crude amide.

General procedure R

To a degassed solution of 1, 4-dioxane (0.12M) containing potassium acetate (3.0 equivalents), bis (pinacolato) diboron (1.5 equivalents) and halide derivative (1.0 equivalents) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.05 equivalents). The reaction mixture was then degassed with nitrogen for an additional 5 minutes and then stirred at 90 ℃ until the reaction was complete. Once cooled, the mixture is passed throughAnd (5) filtering. Water was added to the filtrate and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (× 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure. The resulting residue was used as crude product or further purified by flash column chromatography on silica gel to give the desired pinacol ester.

General procedure S

To a solution of benzoyl hydrazine (1 eq) in toluene (0.5M) was added ketone (1.5 eq). The reaction mixture was heated to 110 ℃ for 10-18h and then cooled to room temperature. The reaction mixture was poured into water and then filtered. The solid was washed with water and further dried to give the desired crude hydrazone.

General procedure T

To a cooled solution of hydrazone (1 equivalent) in THF (0.2-0.4M) at 0 deg.C was added borane-THF (1M, 2 equivalents). The reaction was allowed to come to room temperature and stirred for 3-14 h. The mixture was then cooled to 0 ℃, quenched with MeOH and allowed to return to room temperature. The mixture is then concentrated under reduced pressure and the residue is taken up in a suitable solvent (pet. ether, Et) ₂O or EtOAc) to give the desired hydrazine or purification by flash column chromatography on silica gel.

General procedure U

To a solution of benzoyl hydrazine (1 eq) in MeOH (0.7M) was added 37% aqueous hydrogen chloride (16 eq). The mixture was heated at 80 ℃ for 16h, cooled to room temperature and concentrated under reduced pressure. EtOAc was added, the precipitate was filtered and washed twice with EtOAc to give the crude hydrazonium salt.

General procedure W

To a solution of malononitrile (1 equivalent) in toluene (0.5M) and THF (0.5M) was added the corresponding benzoyl chloride (1 equivalent). The reaction mixture was cooled to-10 ℃ and then N, N-diisopropylethylamine (2 eq) was added dropwise while maintaining the internal temperature below-10 ℃. Once the addition was complete, the reaction mixture was stirred at room temperature for 14h and diluted with EtOAc. The layers were layered. The organic layer was washed successively with 1M HCl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound.

General procedure X

To a solution of 1, 4-dioxane (0.5M) containing dinitrile (1 equivalent) was added sodium carbonate (2 equivalents) at room temperature. The reaction was stirred for 10 minutes, then dimethyl sulfate (1.25 equivalents) was added dropwise. Once the addition was complete, the reaction was heated to reflux for 14h, cooled and concentrated under reduced pressure. Water was added to the crude residue, and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the desired compound.

General procedure Y

Allyltrimethylsilane (1.5 equiv.) and boron trifluoride diethyl etherate (1.5 equiv.) were added to a stirred solution of olefin (1.0 equiv.) containing DCE (0.5M). The resulting solution was heated to reflux for 5 minutes. The solvent was then removed under reduced pressure and the mixture was dissolved in DMF (0.5M). Trimethyl (trifluoromethyl) silane (2.0 equiv.) and sodium acetate (4.0 equiv.) are then added sequentially. The reaction mixture was stirred at room temperature for 2 hours and saturated Na was added₂CO₃The solution was quenched and diluted with water. The aqueous solution was then extracted with ether (× 2), dried over a hydrophobic frit and concentrated under reduced pressure to give the desired derivative.

[4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Boric acid

Following general procedure a, using 2-methoxybenzoic acid (13.32mL, 89.45mmol) and [4- (aminomethyl) phenyl ] boronic acid hydrochloride (15.24g, 81.32mmol) gave the title compound (20.70g, 72.61mmol, 89% yield) as an off-white solid.

UPLC-MS(ES⁺Short acidic): 1.31 min, M/z 286.1[ M + H]⁺

N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

Following general procedure C, 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (6.04g, 32.32mmol) and [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] boronic acid (after purification by flash column chromatography, eluting with 0-10% MeOH in DCM) gave N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) phenyl ] methyl ] -2-methoxy-benzamide (6.45g, 18.57mmol, 57% yield) as a light brown solid.

UPLC-MS(ES⁺Short acidic): 1.42 min, M/z 348.2[ M + H]⁺

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoroacetyl) Pyrazole-4-carboxamides

To a degassed solution of N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) phenyl ] methyl ] -2-methoxy-benzamide (6.25g, 17.99mmol) was added sulfuric acid (9.59mL, 179.92mmol) and trifluoroacetic acid (55.3mL, 719.68 mmol). The reaction mixture was heated to 55 ℃ for 5 hours. The reaction mixture was poured into an ice-water mixture, carefully neutralized with sodium bicarbonate, and then extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM gave 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1H-pyrazole-4-carboxamide (5.00g, 13.68mmol, 76% yield) and 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroacetyl) pyrazole-4-carboxamide (0.37g, 0.80mmol, 4% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.26 min, M/z 366.2[ M + H ]]⁺

UPLC-MS(ES⁺Is short and shortAcidic): 1.63 min, M/z 462.1[ M + H ]]⁺

UPLC-MS(ES⁺Long acidic): 3.31 min, M/z 462.2[ M + H ] ]⁺

Trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Borane potassium

A toluene solution of potassium bis (trimethylsilyl) amide (0.5M, 23.8mL, 11.9mmol) was added dropwise to a solution of 2- (bromomethyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (2.5g, 11.3mmol) in anhydrous THF (25 mL). After stirring at-78 ℃ for 25 min, the mixture was allowed to warm to room temperature and anhydrous methanol (1.3mL, 32.1mmol) was added. After 1 h, 2-methoxybenzoyl chloride (3.4mL, 22.6mmol) was added slowly and the mixture was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The obtained residue was diluted with methanol (25mL), and then saturated aqueous potassium hydrogen fluoride solution (3.5g, 45.3mmol) was added. After stirring overnight, the mixture was concentrated under reduced pressure. The resulting residue was washed with hot acetone (× 4). The acetone phase was filtered and the filtrate was concentrated under reduced pressure until almost all of the acetone disappeared. Et was then added₂And O, precipitating and collecting the product. To obtain trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (1.50g, 5.53mmol, 49% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.03 min, M/z 232.1[ M-K]⁺

2- [ (4-bromophenyl) -hydroxy-methylene]Malononitrile

To a solution of 4-bromobenzoyl chloride (7.00g, 31.9mmol) and malononitrile (2.32g, 35.1mmol) in toluene (40mL) and THF (8.6mL) cooled to-10 deg.C under a nitrogen atmosphere was added dropwise a solution of N, N-diisopropylethylamine (11.11mL, 63.8mmol) in toluene (30mL) while maintaining the internal temperature at-10 deg.C. Once the addition was complete, the reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 18 hours. Hydrochloric acid (1M) was added and the reaction mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with HCl (1M), brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give 2- [ (4-bromophenyl) -hydroxy-methylene ] malononitrile (7.72g, 31.0mmol, 97% yield) as a light brown solid.

¹H NMR(400MHz,DMSO-d₆,δ):7.58(dt,J＝8.7,2.1Hz,2H),7.52(dt,J＝8.8,2.1Hz,2H)。

2- [ (4-bromophenyl) -hydroxy-methylene]Malononitrile

A2L reactor equipped with a thermometer was charged under nitrogen with 4-bromobenzoyl chloride (200g, 911mmol), toluene (1000mL), and THF (200mL) and malononitrile (63mL, 1003 mmol). The reaction mixture was cooled to-10 ℃ and then N, N-diisopropylethylamine (318mL, 1823mmol) was added dropwise to the reaction mixture, maintaining the internal temperature below-10 ℃ (coolant at-20 ℃) for over 45 minutes. Once the addition was complete, the jacket was adjusted to 0 ℃ for 2 hours, then 25 ℃ for 2 hours. The reaction mixture was transferred to a 7L separatory funnel, and the reactor was washed sequentially with 1M aqueous HCl (1.5L) and EtOAc (1.5L), each transferred to a separatory funnel. The layers were separated and the organic layer was washed with 1M aqueous HCl (250mL) and brine (250 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a slurry under reduced pressure. Then slurried with petroleum ether (500mL) and filtered. The solid was washed with cold petroleum ether (100mL) to give the product, crude 2- [ (4-bromophenyl) -hydroxy-methylene ] malononitrile (232g) after air drying. The material was slurried with a minimum amount of cold ethyl acetate and filtered, washed with a minimum amount of ethyl acetate and diethyl ether to give 2- [ (4-bromophenyl) -hydroxy-methylene ] malononitrile (210g, 843mmol, 93% yield) as a light yellow solid.

2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile

A solution of 2- [ (4-bromophenyl) -hydroxy-methylene ] malononitrile (7.00g, 28.11mmol) in THF (17mL) was added dropwise to a suspension of sodium hydride (1.24g, 30.92mmol) in THF (20mL) and cooled to 0 ℃. After stirring at 0 ℃ for 30 min, dimethyl sulfate (7.98mL, 84.32mmol) was added and the reaction mixture was heated to 80 ℃ and stirred for 14 h. The mixture was cooled to RT, quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Further purification by flash column chromatography on silica eluting with 20-80% DCM in heptane afforded 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (3.58g, 13.61mmol, 48% yield) as a white crystalline solid.

UPLC-MS(ES⁺Short acidic): 1.76 min, M/z 263.4[ M ]]⁺

2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile

To a solution of 2- [ (4-bromophenyl) -hydroxy-methylene ] malononitrile (210g, 843mmol) in 1, 4-dioxane (1500mL) was added sodium carbonate (179g, 1686mmol) at room temperature. The mixture was stirred for 10 minutes, then dimethyl sulfate (100mL, 1054mmol) was added dropwise over 10 minutes. The reaction mixture was then heated to reflux for 2 hours, cooled and partitioned between water (1.5L) and DCM (1.5L). The aqueous layer was then extracted with DCM (1L), and the combined organic extracts were washed with water (500mL) and brine (500mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an orange solid. Further purification by flash column chromatography on silica gel eluting with 50-100% DCM in petroleum ether and then 25% ethyl acetate in DCM gave a pale orange solid which was then slurried with petroleum ether (500mL) and filtered to give 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (153g, 582mmol, 69% yield) as an off-white solid.

5-fluoro-2-methoxy-benzoyl chloride

Oxalyl chloride (124mL, 1469mmol) was added to a stirred suspension of 5-fluoro-2-methoxybenzoic acid (125g, 735mmol) and DMF (2.7g, 37mmol) in DCM (1750mL) at RT. The reaction mixture was then stirred at room temperature for 16 h and concentrated under reduced pressure to give crude 5-fluoro-2-methoxy-benzoyl chloride (138g, 732mmol, assuming quantitative yield) as a yellow oil which crystallized rapidly.

UPLC-MS(ES⁺Short acidic): 1.46 minutes, m/z: 1.46 min [ M + H]⁺(methyl ester adduct)

Trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Borane potassium

A0.7M solution of potassium bis (trimethylsilyl) amide in toluene (174mL, 770mmol) was added dropwise to a solution of 2- (bromomethyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (170g, 770mmol) in anhydrous THF (1200 mL). After stirring at-78 ℃ for 25 minutes, the mixture was stirred at 0 ℃ for another 10 minutes and then at room temperature for 30 minutes. Anhydrous methanol (99g, 3078mmol) was added at RT and a precipitate formed. The mixture was stirred at RT for a further 1 hour, then the reaction mixture was concentrated under reduced pressure while maintaining the water bath at 30 ℃. The mixture was co-evaporated with THF (2X 250 mL). The residue was dissolved in anhydrous THF (750mL) and a solution of 5-fluoro-2-methoxy-benzoyl chloride (138g, 731mol) in THF (250mL) was added slowly. The reaction mixture was then stirred at room temperature for 14 hours and then concentrated under reduced pressure. The resulting residue was dissolved with ice-cold MeOH (1000mL), then the mixture was cooled to 0 ℃, and then a saturated potassium hydrogen fluoride solution (264g, 3386mmol in water (600 mL)) was added. The reaction mixture was warmed to room temperature and stirred for 15 hours, then concentrated under reduced pressure. The residue was azeotroped twice with toluene (3X 500mL) to remove water. The residue was then washed with cold TBME and filtered. The white solid was washed with cold acetone (750mL) and then with a hot acetone solution containing 25% MeOH (3X 2000 mL). The filtrate was concentrated under reduced pressure. Once most of the solvent was removed, TBME (500mL) was added and the resulting white solid was filtered off and washed with cold TBME to give potassium trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] borane (198g, 411mmol, 53% yield).

¹H NMR(400MHz,DMSO-d₆,):7.80-7.71(m,1H),7.64(dd,J＝9.8,3.4Hz,1H),7.31-7.25(m,1H),7.16(dd,J＝9.2,4.4Hz,1H),3.88(s,3H),2.17-2.09(m,2H)。

4-bromo-2, 6-difluoro-benzoyl chloride

To a suspension of 4-bromo-2, 6-difluorobenzoic acid (2g, 8.44mmol) in DCM (30mL) at 0 deg.C was added oxalyl chloride (0.80mL, 9.28mmol) and DMF (0.1mL, 1.30 mmol). The reaction mixture was stirred at room temperature for 4 hours and cooled to 0 ℃. More oxalyl chloride (0.79mL, 9.28mmol) was added and the reaction mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure to give 4-bromo-2, 6-difluoro-benzoyl chloride (1.58g, 6.19mmol, 73% yield).

UPLC-MS：(ES⁺Short acidic): 1.74 min, M/z 250.9[ M]⁺(methyl ester adduct)

2- [ (4-bromo-2, 6-difluoro-phenyl) -hydroxy-methylene]Malononitrile

Following general procedure W, using malononitrile (450mg, 6.80mmol) and 4-bromo-2, 6-difluoro-benzoyl chloride (1.58g, 6.19mmol) gave 2- [ (4-bromo-2, 6-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2g, 7.05mmol, assuming quantitative yield) as a thick yellow oil.

UPLC-MS：(ES⁺Short acidic): 1.13 min, M/z 286.7[ M +2 ]]⁺

2- [ (4-bromo-2, 6-difluoro-phenyl) -methoxy-methylene]Malononitrile

Following general procedure X, purification by flash column chromatography on silica gel eluting with 20-80% DCM in heptane afforded 2- [ (4-bromo-2, 6-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.01g, 7.05mmol) as a white solid (1.48g, 4.95mmol, 70% yield).

UPLC-MS：(ES⁺Short acidic): 1.69 min, M/z 300.9[ M +2 ]]⁺

2- [ (4-chloro-3, 5-difluoro-phenyl) -hydroxy-methylene]Malononitrile

Following general procedure W, using 4-chloro-3, 5-difluorobenzoyl chloride (2.00g, 9.48mmol) gave 2- [ (4-chloro-3, 5-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.48g, 10.31mmol, assuming quantitative yield) as a brown thick oil.

UPLC-MS：(ES^-Short acidic): 1.34 min, M/z 238.8[ M-H]^-

2- [ (4-chloro-3, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile

Following general procedure X, purification by flash column chromatography on silica gel eluting with 20-80% DCM in heptane afforded 2- [ (4-chloro-3, 5-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.48g, 10.31mmol) as a pale yellow solid (1.68g, 6.60mmol, 64% yield).

UPLC-MS：(ES⁺Short acidic): 1.70 min, M/z 254.9[ M + H ]]⁺

2- [ (4-chloro-2, 5-difluoro-phenyl) -hydroxy-methylene]Malononitrile

Following general procedure W, using 4-chloro-2, 5-difluorobenzoyl chloride (2.00g, 9.48mmol) gave 2- [ (4-chloro-2, 5-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.66g, 11.06mmol, assuming quantitative yield) as an off-white solid.

UPLC-MS：(ES^-Short acidic): 1.11 min, M/z 238.8[ M-H ]^-

2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile

Following general procedure X, purification by flash column chromatography on silica gel eluting with 20-80% DCM in heptane afforded 2- [ (4-chloro-2, 5-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.66g, 11.06mmol) as a pale yellow oil (1.64g, 6.44mmol, 58% yield).

UPLC-MS：(ES⁺Short acidic): 1.67 min, M/z 254.9[ M + H ]]⁺

4-chloro-2, 3-difluoro-benzoyl chloride

To a suspension of 4-bromo-2, 6-difluorobenzoic acid (2.00g, 8.44mmol) in DCM (30mL) was added oxalyl chloride (0.80mL, 9.28mmol) and DMF (0.1mL, 1.30mmol) at 0 deg.C. The reaction mixture was stirred at room temperature for 4 hours and cooled again to 0 ℃. More oxalyl chloride (0.80mL, 9.28mmol) was added and the reaction mixture was stirred at RT for 16h, then concentrated under reduced pressure to give 4-chloro-2, 3-difluoro-benzoyl chloride (2.19g, 10.38mmol, assuming quantitative yield).

UPLC-MS：(ES⁺Short acidic): 1.74 min, M/z 206.8[ M ]]⁺(methyl ester adduct)

2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene]Malononitrile

Following general procedure W, malononitrile (750mg, 11.42mmol) and 4-chloro-2, 3-difluoro-benzoyl chloride (2.19g, 10.38mmol) gave crude 2- [ (4-chloro-2, 3-difluoro-phenyl) -hydroxy-methylene ] malononitrile (2.61g, 10.85mmol, assuming quantitative yield) as a brown solid. Purification by flash column chromatography on silica gel eluting with 20-80% DCM in heptane according to general procedure X gave 2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene ] malononitrile (1.6g, 6.40mmol, 59% yield) as an off-white solid.

UPLC-MS：(ES⁺Short acidic): 1.70 min, M/z 254.9[ M + H ]]⁺

Example 1: 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

General procedure H, reaction of 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and cyclopentylhydrazine hydrochloride (0.91mmol) were reacted to give the title compound (0.83 mmol). UPLC-MS (ES)⁺Short acidic): 2.17 min, M/z 333.2[ M +2 ]]⁺

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.45mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.45mmol) was reacted to give the title compound (0.36mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.87 min, M/z 416.2[ M + H]⁺

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure M, oxidation of N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.36mmol) to give the title compoundThe title compound (0.23mmol) was an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.58 min, M/z 434.2[ M + H]⁺UPLC-MS(ES⁺Long acidic): 3.59 min, M/z 434.2[ M + H]⁺

¹H NMR(400MHz,DMSO-d₆δ is 8.73(t, J ═ 6.1Hz,1H),7.75(dd, J ═ 7.7,1.8Hz,1H),7.51-7.37(m,5H),7.17-7.13(m,1H),7.03(td, J ═ 7.5,1.0Hz,1H),6.31(s,2H),4.60 (quintuple, J ═ 7.3Hz,1H),4.54(d, J ═ 6.1Hz,2H),3.90(s,3H),2.02-1.86(m,4H),1.83-1.72(m,2H),1.65-1.51(m, 2H).

The compound of example 1 can also be prepared by the following method.

5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

A solution of 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (72.2mmol), cyclopentylhydrazine dihydrochloride (72.2mmol) and trimethylamine (288.9mmol) in EtOH (400mL) was refluxed for 1.5 h. The reaction mixture was heated to reflux for 1.5 h, cooled and concentrated under reduced pressure. Work up and purify to give the title compound (51.9mmol) as a pale yellow solid.

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

Reacting trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (36.2mmol), palladium (II) acetate (1.27mmol), cesium carbonate (108.7mmol) and 5-amino-3- (4-bromophenyl) -cyclopentyl-pyrazole-4-carbonitrile (36.2mmol) were suspended in THF (250mL) and water (75 mL). The orange reaction mixture was degassed under vacuum and flushed with nitrogen three times. 2-Dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (2.54mmol) was added, and the mixture was heated under reflux for 4 hours. By passing Filtration, treatment and concentration gave the title compound (32.01mmol) as a pale orange solid.

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

After heating to 55 ℃ for 3 hours, a mixture of N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl ] methyl ] -2-methoxy-benzamide (32.0mmol), sulfuric acid (320.1mmol) and trifluoroacetic acid (800.3mmol) was cooled and then added carefully to an ice-cold solution of sodium bicarbonate (1921mmol) in water (750mL) with vigorous stirring. A mixture of heptane/EtOAc (100mL, 1: 1) was added and the mixture was filtered. The solid was suspended in 10% MeOH/DCM (750mL) and water (100 mL). After work-up and crystallization from EtOAc and MeOH (200mL), the title product (13.15mmol) was obtained as an off-white solid.

Example 2: 5-amino-1- [ (1R, 2R) -2-hydroxycyclopentyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- [ (1R, 2R) -2-hydroxycyclopentyl]Pyrazole-4-carbonitriles

General procedure H, reaction of 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and (1R, 2R) -2-hydrazinocyclopentanol (0.38mmol) reacted to give the title compound (0.38mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.82 min, M/z 349.1[ M +2 ]]⁺

N- [ [4- [ 5-amino-4-cyano-1- [ (1R, 2R) -2-hydroxycyclopentyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

Following general procedure C, 5-amino-3- (4-bromophenyl) -1- [ (1R, 2R) -2-hydroxycyclopentyl group was used]Pyrazole-4-carbonitrile (0.12mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.13mmol) gave the title compound (0.11mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 432.2[ M + H]⁺

5-amino-1- [ (1R, 2R) -2-hydroxycyclopentyl radical]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

Following general procedure L, using N- [ [4- [ 5-amino-4-cyano-1- [ (1R, 2R) -2-hydroxycyclopentyl group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.10mmol) gave the title compound (0.05mmol, 49% yield) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.44 min, M/z 450.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.16 min, M/z 450.3[ M + H]⁺

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝5.9Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.52-7.38(m,5H),7.18-7.14(m,1H),7.04(td,J＝7.5,1.0Hz,1H),6.26(s,2H),5.03(d,J＝4.6Hz,1H),4.55(d,J＝6.1Hz,2H),4.36-4.24(m,2H),3.90(s,3H),2.11-2.00(m,1H),2.00-1.85(m,2H),1.79-1.67(m,2H),1.60-1.48(m,1H)。

Example 3: 5-amino-1-tert-butyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-tert-butyl-pyrazole-4-carbonitrile

General procedure H, after purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was used to purify 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.57mmol) and tert-butylhydrazine hydrochloride (0.86mmol) gave the title compound (0.52mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 2.21 min, M/z 321.0[ M +2 ]]⁺

N- [ [4- (5-amino-1-tert-butyl-4-cyano-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was followed by reaction of 5-amino-3- (4-bromophenyl) -1-tert-butyl-pyrazole-4-carbonitrile (0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.24mmol) gave the title compound (0.21mmol, 98% yield) as a yellow solid. UPLC-MS (ES)⁺Is short and shortAcidic): 1.90 min, M/z 404.2[ M + H]⁺

5-amino-1-tert-butyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

After purification by flash column chromatography on silica gel according to general procedure L, using N- [ [4- (5-amino-1-tert-butyl-4-cyano-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.74mmol) gave the title compound (0.03mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.61 min, M/z 422.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.57 min, M/z 422.3[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.50-7.37(m,5H),7.17-7.13(m,1H),7.03(td,J＝7.5,1.1Hz,1H),6.28(s,2H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),1.56(s,9H)。

Example 4: 5-amino-1- (3-bicyclo [3.1.0] hexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

Bicyclo [3.1.0]Hex-3-one

To a solution of pyridine (1.68mmol) and pyridinium chlorochromate (7.64mmol) in DCM (6mL) cooled to 0 deg.C was added cis-bicyclo [3.1.0] dropwise]Hex-3-ol (5.09 mmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ether and the black residue was washed with more ether (× 3). The combined organics were then passed through a pad of Frorisil and the solvent removed under reduced pressure to give the title compound as a crude yellow oil.¹H NMR(400MHz,CDCl₃,δ):2.64-2.54(m,2H),2.20-2.12(m,2H),1.57-1.50(m,2H),0.94-0.86(m,1H),-0.03--0.08(m,1H)。

N- (3-bicyclo [ 3.1.0)]Hexylidene amino) carbamic acid tert-butyl ester

Will bicyclo [3.1.0]Hex-3-one (5)58mmol) and tert-butyl carbazate (5.58mmol) in methanol (20mL) were stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was quenched with water (20mL) and extracted with DCM (3X 20 mL). The combined organic extracts were filtered through a hydrophobic frit and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica eluting with 0-100% EtOAc in heptane to give the title compound (2.84mmol) as a clear oil.¹H NMR(400MHz,CDCl₃,δ):2.85-2.77(m,1H),2.63-2.56(m,1H),2.39-2.35(m,2H),1.52-1.35(m,12H),0.74-0.66(m,1H),-0.13--0.18(m,1H)。

3-bicyclo [3.1.0]Hexylhydrazine; 2,2, 2-trifluoroacetic acid

Sodium cyanoborohydride (4.71mmol) was added portionwise to a stirred solution of tert-butyl N- (3-bicyclo [3.1.0] hexylidene amino) carbamate (4.76mmol) in acetic acid (7mL) and water (7 mL). The resulting mixture was stirred at room temperature for 2 hours, neutralized by addition of 1m naoh (aq), and then extracted with DCM (× 2). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to dryness to give crude tert-butyl N- (3-bicyclo [3.1.0] hexylamino) carbamate (4.71mmol) as a clear oil. The crude product was dissolved in DCM (4.5 mL). To trifluoroacetic acid (58.77mmol) was added dropwise a stirred solution of tert-butyl N- (3-bicyclo [3.1.0] hexanylamino) carbamate (4.71mmol) in DCM (4.5 mL). The resulting solution was stirred for 2 hours, then concentrated under reduced pressure to give the crude title compound (4.42mmol) as a clear oil.

¹H NMR(400MHz,CDCl₃,δ):3.88-3.78(m,1H),2.43-2.31(m,2H),1.74(dd,J＝14.9,4.9Hz,2H),1.40-1.24(m,2H),0.83-0.75(m,1H),0.17-0.11(m,1H)。

5-amino-1- (3-bicyclo [3.1.0 ]]Hexyl) -3- (4-bromophenyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.78mmol) and 3-bicyclo [3.1.0]A hexylhydrazine; 2,2, 2-trifluoroacetic acid (1.17 mmo)l) the title compound (0.21mmol) was obtained as a colorless oil. UPLC-MS (ES)⁺Short acidic): 2.15 min, M/z 345.1[ M +2 ]]⁺

N- [ [4- [ 5-amino-1- (3-bicyclo [3.1.0 ]]Hexyl) -4-cyano-pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, using 5-amino-1- (3-bicyclo [3.1.0 ]]Hexane) -3- (4-bromophenyl) pyrazole-4-carbonitrile (0.21mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.21mmol) gave the title compound (0.23 mmol). UPLC-MS (ES)⁺Short acidic): 1.86 min, M/z 428.2[ M + H]⁺

5-amino-1- (3-bicyclo [3.1.0 ]]Hexyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical] Pyrazole-4-carboxamides

General procedure L, after purification by mass directed semi-preparative HPLC, N- [ [4- [ 5-amino-1- (3-bicyclo [3.1.0 ]]Hexyl) -4-cyano-pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.21mmol) gave the title compound (0.04 mmol). UPLC-MS (ES) ⁺Short acidic): 1.68 min, M/z 446.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.72 min, M/z 446.3[ M + H]⁺

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.2Hz,1H),7.77(dd,J＝7.7,1.8Hz,1H),7.54-7.38(m,5H),7.16(dd,J＝8.4,0.7Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.29(s,2H),5.01-4.83(m,1H),4.55(d,J＝6.1Hz,2H),3.91(s,3H),2.46-2.36(m,2H),1.92(dd,J＝13.8,4.8Hz,2H),1.35-1.27(m,2H),0.81(q,J＝4.1Hz,1H),0.66-0.54(m,1H)。

Example 5: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-methylcyclopentyl) pyrazole-4-carboxamide

N- [ (3-methylcyclopent-2-en-1-ylidene) amino]Carbamic acid tert-butyl esterButyl ester

To a solution of 3-methyl-2-cyclopenten-1-one (10.40mmol) in methanol (59.4mL) was added tert-butyl carbazate (10.92mmol), and the reaction was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give the title compound (12.18 mmol).¹H NMR(400MHz,DMSO-d₆,δ):5.98-5.93(m,1H),3.26-3.05(br s,1H),2.62-2.57(m,2H),2.44-2.41(m,2H),2.15(s,3H),1.47(s,9H)。

(3-methylcyclopentyl) hydrazine

To the N- [ - (3-methylcyclopent-2-en-1-ylidene) amino group]To a solution of tert-butyl carbamate (10.40mmol) in THF/MeOH (21mL, 1: 1) was added sodium cyanoborohydride (12.50mmol) in portions. The reaction was heated to reflux for 10 minutes under nitrogen and then cooled to room temperature. Hydrogen chloride (30.00mmol) was added and the reaction mixture was heated under reflux for 3 h, cooled to room temperature and stirred for 16 h. The reaction was filtered to remove inorganic insolubles and the filtrate was concentrated under reduced pressure and azeotroped with toluene (. times.3). The residue was dissolved in hot isopropanol, cooled to RT, diluted with ether and then cooled to 0 ℃. The precipitate was filtered and the filtrate was concentrated in vacuo to give the title compound (6.50 mmol). ¹H NMR(400MHz,DMSO-d₆δ diastereomer mixtures) 3.83-3.62 and 3.56-3.38(m,1H),3.10-2.99 and 2.78-2.68(m,2H),2.26-2.01(m,2H),2.00-1.57(m,5H),1.40-1.02(m,1H),0.99 and 0.93(d, J ═ 6.5Hz, 3H).

5-amino-3- (4-bromophenyl) -1- (3-methylcyclopentyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica gel eluting with 0-2% MeOH in DCM, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and (3-methylcyclopentyl) hydrazine (0.38mmol) gave the title compound. UPLC-MS (ES)⁺Short acidic): 2.26 min, M/z 345.1[ M]⁺

N- [ [4- [ 5-amino-4-cyano-1- (3-methylcyclopentyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, purification by flash column chromatography on silica gel, 0-10%After elution with MeOH in DCM, 5-amino-3- (4-bromophenyl) -1- (3-methylcyclopentyl) pyrazole-4-carbonitrile (0.08mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.08mmol) gave the title compound (0.05 mmol). UPLC-MS (ES)⁺Short acidic): 2.03 min, M/z 430.2[ M + H]⁺

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (3-methylcyclopentyl) pyrazole- 4-carboxamides

General procedure L, after purification by mass directed semi-preparative HPLC, N- [ [4- [ 5-amino-4-cyano-1- (3-methylcyclopentyl) pyrazol-3-yl) ]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.08mmol) gave the title compound (0.01 mmol). UPLC-MS (ES)⁺Short acidic): 1.73 min, M/z 448.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.86 min, M/z 448.3[ M + H ]]⁺

¹H NMR(400MHz,DMSO-d₆δ) (mixture of diastereomers): 8.74(t, J ═ 6.0Hz,1H),7.76(dd, J ═ 7.6,1.8Hz,1H),7.53-7.38(m,5H),7.16(d, J ═ 7.8Hz,1H),7.04(td, J ═ 7.5,0.9Hz,1H),6.31(s,2H),4.79-4.58(m,1H),4.55(d, J ═ 6.0Hz,2H),3.91(s,3H),2.30-2.21(m,0.5H),2.17-2.05(m,1.5H),2.01-1.92(m,2.5H),1.85-1.75(m,0.5H),1.64-1.51(m, 1.51, 1.5H), 1.11-1.02 (d, J ═ 6.8 Hz,1H), 1.5H).

Example 6: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [5- (trifluoromethyl) -2-pyridinyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- [5- (trifluoromethyl) -2-pyridinyl]Pyrazole-4-carbonitriles

Following general procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (80mg, 0.30mmol) and 5- (trifluoromethyl) pyridin-2-ylhydrazine (0.30mmol) gave the title compound as an off-white solid. UPLC-MS (ES)⁺Is short and shortAcidic): 2.27 min, M/z 408.1[ M]⁺

N- [ [4- [ 5-amino-4-cyano-1- [5- (trifluoromethyl) -2-pyridinyl)]Pyrazol-3-yl ]Phenyl radical]Methyl radical]-2- Methoxy-benzamides

General procedure K, using 5-amino-3- (4-bromophenyl) -1- [5- (trifluoromethyl) -2-pyridinyl]Pyrazole-4-carbonitrile (0.10mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.12mmol) gave the title compound (0.06mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 2.03 min, M/z 493.3[ M + H]⁺

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [5- (trifluoromethyl) -2-pyri-dine Pyridyl radical]Pyrazole-4-carboxamides

General procedure L, using N- [ [4- [ 5-amino-4-cyano-1- [5- (trifluoromethyl) -2-pyridinyl)]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.06mmol) gave the title compound (0.03mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 511.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.19 min, M/z 511.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.90-8.86(m,1H),8.79(t,J＝6.1Hz,1H),8.38(dd,J＝8.9,2.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.83-7.74(m,3H),7.60(d,J＝8.1Hz,2H),7.53-7.45(m,3H),7.17(d,J＝8.3Hz,1H),7.09-7.02(m,1H),4.59(d,J＝6.0Hz,2H),3.92(s,3H)。

Example 7: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [2- (methoxymethoxy) ethyl ] pyrazole-4-carboxamide

General procedure N, after purification by mass directed semi-preparative HPLC (intermediate method), 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.26mmol) and 1-bromo-2- (methoxymethoxy) ethane (0.39mmol) were obtained as the titled compound Compound (0.03 mmol). UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 454.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.10 min, M/z 454.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.38(m,5H),7.18-7.13(m,1H),7.04(td,J＝7.5,1.0Hz,1H),6.30(s,2H),4.57-4.52(m,4H),4.10(t,J＝5.7Hz,2H),3.90(s,3H),3.77(t,J＝5.7Hz,2H),3.19(s,3H)。

Example 8: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ (3-methyloxetan-3-yl) methyl ] pyrazole-4-carboxamide

General procedure N, purification by mass directed semi-preparative HPLC, of 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.25mmol) and 3- (chloromethyl) methyloxetane (0.38mmol) gave the title compound (0.07 mmol). UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 450.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.11 min, M/z 450.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.38(m,5H),7.17-7.13(m,1H),7.04(td,J＝7.5,1.5Hz,1H),6.41(s,2H),4.63(d,J＝5.9Hz,2H),4.54(d,J＝6.1Hz,2H),4.20(d,J＝5.9Hz,2H),4.09(s,2H),3.90(s,3H),1.24(s,3H)。

Example 9: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2-morpholinoethyl) pyrazole-4-carboxamide

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2-morpholinoethyl) pyrazole- 4-carboxamides

General procedure N, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed using 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.27mmol) and N-chloroethylmorpholine hydrochloride (0.41mmol) gave the title compound (0.04 mmol). UPLC-MS (ES) ⁺Short acidic): 1.20 min, M/z 479.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.51 min, M/z 479.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.0Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.53-7.37(m,5H),7.16(d,J＝8.2Hz,1H),7.05(td,J＝7.5,1.0Hz,1H),6.40(s,2H),4.55(d,J＝6.1Hz,2H),4.04(t,J＝6.7Hz,2H),3.90(s,3H),3.60-3.56(m,4H),2.69-2.65(m,2H),2.47-2.44(m,4H)。

Example 10: 5-amino-1- (3, 3-dimethyl-2-oxo-butyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (3, 3-dimethyl-2-oxo-butyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

General procedure N, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed using 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.24mmol) and 1-bromo-3, 3-dimethylbut-2-one (0.36mmol) gave the title compound (0.03 mmol). UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 464.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.49 min, M/z 464.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.53-7.37(m,5H),7.17(d,J＝8.2Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.27(s,2H),5.12(s,2H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),1.18(s,9H)。

Example 11: 5-amino-1- (2-cyanoethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (2-cyanoethyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure N, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, gave 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1H-pyrazole-4-carboxamide (0.25mmol) and 3-bromopropionitrile (0.37mmol) as the title compound (0.07 mmol).

UPLC-MS(ES⁺Short acidic): 1.37 min, M/z 419.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.02 min, M/z 419.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.53-7.37(m,5H),7.16(d,J＝7.7Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.49(s,2H),4.56(d,J＝6.1Hz,2H),4.22(t,J＝6.7Hz,2H),3.90(s,3H),2.97(t,J＝6.7Hz,2H)。

Example 12: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-oxocyclohexyl) pyrazole-4-carboxamide

1, 8-diazabicyclo [5.4.0 ]]A solution of undec-7-ene (0.82mmol) in MeCN (0.5mL) was added slowly to 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.27mmol) in MeCN (2 mL). The reaction was stirred at room temperature for 15 min, then cyclohex-2-enone (0.55mmol) was added. The reaction mixture was stirred for 16 hours. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography on silica eluting with 0-5% MeOH in DCM gave the title compound (0.15mmol) as a light brown solidAnd (3) a solid. UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 462.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.00 min, M/z 462.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.2Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.45(m,3H),7.42-7.37(m,2H),7.17-7.13(m,1H),7.04(td,J＝7.6,1.0Hz,1H),6.38(d,J＝1.8Hz,1H),6.09(s,1H),4.54(d,J＝6.2Hz,2H),4.53-4.49(m,1H),3.89(s,3H),2.13-2.05(m,1H),2.01-1.95(m,1H),1.89-1.79(m,2H),1.78-1.68(m,1H),1.67-1.54(m,2H)1.29-1.06(m,1H)。

Example 13: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-oxocyclopentyl) pyrazole-4-carboxamide

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical ]-1- (3-oxocyclopentyl) pyrazole- 4-carboxamides

To 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]To a mixture of-1H-indol-7-ol (0.27mmol) and 2-cyclopentenone (0.33mmol) in MeCN (0.54mL) was added 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (0.14 mmol). The reaction mixture was stirred at RT for 2 days and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica eluting with 0-3.5% MeOH in DCM followed by reverse phase chromatography eluting with 20-40% MeCN in 0.1% formic acid additive in water to give the title compound (0.04mmol, 14% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.44 min, M/z 448.2[ M + H ]]⁺。

UPLC-MS(ES⁺Long acidic): 3.09 min, M/z 448.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.76-8.69(m,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.52-7.37(m,5H),7.16(d,J＝8.2Hz,1H),7.07-7.00(m,1H),6.42(s,2H),5.05-4.95(m,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),2.73-2.61(m,1H),2.60-2.30(m,3H),2.27-2.11(m,2H)。

Example 14: 5-amino-1- (2-hydroxy-3, 3-dimethyl-butyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (2-hydroxy-3, 3-dimethyl-butyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

At 0 deg.C, 5-amino-1- (3, 3-dimethyl-2-oxobutyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]A solution of pyrazole-4-carboxamide (0.07mmol) in MeOH (1mL) was added dropwise to a solution of sodium borohydride (0.07mmol) in MeOH (1 mL). The reaction mixture was stirred for 30 minutes and then diluted with DCM. Then adding saturated Na ₂CO₃Aqueous solution, and the mixture was extracted with DCM (× 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica eluting with 0-5% MeOH in DCM to give the title compound (0.03 mmol). UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 466.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.49 min, M/z 466.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.38-7.54(m,5H),7.16(d,J＝8.1Hz,1H),7.05(td,J＝7.5,0.9Hz,1H),6.10(s,2H),5.10(d,J＝5.9Hz,1H),4.56(d,J＝6.1Hz,2H),3.99(dd,J＝14.3,1.7Hz,1H),3.91(s,3H),3.78(dd,J＝14.2,9.5Hz,1H),3.47-3.59(m,1H),0.92(s,9H)。

Example 15: 5-amino-1- (2, 4-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2, 4-difluorophenyl) pyrazole-4-carbonitrile

General procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.30mmol) and 2, 4-difluorophenylhydrazine hydrochloride (0.30mmol) gave the title compound (0.22mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 375.1[ M ]]⁺

N- [ [4- [ 5-amino-4-cyano-1- (2, 4-difluorophenyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, starting from 5-amino-3- (4-bromophenyl) -1- (2, 4-difluorophenyl) pyrazole-4-carbonitrile (0.11mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.19mmol) gave the title compound (0.10mmol) as a white powder. UPLC-MS (ES) ⁺Short acidic): 1.73 min, M/z 460.2[ M + H ]]⁺

5-amino-1- (2, 4-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure L using N- [ [4- [ 5-amino-4-cyano-1- (2, 4-difluorophenyl) pyrazol-3-yl ] phenyl ] methyl ] -2-methoxy-benzamide (0.10mmol) gave the title compound (0.05mmol) as an off-white powder.

UPLC-MS(ES⁺Short acidic): 1.57 min, M/z 478.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.58 min, M/z 478.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.69-7.60(m,1H),7.60-7.40(m,6H),7.32-7.23(m,1H),7.16(d,J＝8.3Hz,1H),7.08-7.01(m,1H),6.46(s,2H),4.57(d,J＝6.1Hz,2H),3.90(s,3H)。

Example 16: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [3- (trifluoromethyl) phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- [3- (trifluoromethyl) phenyl]Pyrazole-4-carbonitriles

General procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and [3- (trifluoromethyl) phenyl ]]Hydrazine hydrochloride (0.38mmol) gave the title compound (0.31mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.18 min, M/z 407.1[ M]⁺

5-amino-3- (4-bromophenyl) -1- [3- (trifluoromethyl) phenyl]Pyrazole-4-carboxamides

General procedure nitrile hydrolysis with 5-amino-3- (4-bromophenyl) -1- [3- (trifluoromethyl) phenyl]Pyrazole-4-carbonitrile (0.12mmol) gave the crude title compound (0.12mmol) as a clear oil. UPLC-MS (ES) ⁺Short acidic): 1.93 min, M/z 425.0[ M]⁺

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [3- (trifluoromethyl) phenyl] Pyrazole-4-carboxamides

General procedure K, 5-amino-3- (4-bromophenyl) -1- [3- (trifluoromethyl) phenyl]Pyrazole-4-carboxamide (0.12mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Sodium borohydride (0.18mmol) gave the title compound (0.08mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.79 min, M/z 510.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.06 min, M/z 510.6[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.1Hz,1H),8.02-7.92(m,2H),7.83-7.73(m,3H),7.57(d,J＝8.1Hz,2H),7.53-7.43(m,3H),7.16(d,J＝7.2Hz,1H),7.08-7.02(m,1H),6.65(s,2H),4.58(d,J＝6.1Hz,2H),3.91(s,3H)。

Example 17: 5-amino-1- (cyclohexylmethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

General procedure N, purification by mass directed semi-preparative HPLC, of 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.26mmol) and (bromomethyl) cyclohexane (0.39mmol) gave the title compound (0.04 mmol). UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 462.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.88 min, M/z 462.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.51-7.38(m,5H),7.18-7.14(m,1H),7.04(td,J＝7.5,1.0Hz,1H),6.31(s,2H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.75(d,J＝7.2Hz,2H),1.88-1.75(m,1H),1.73-1.53(m,5H),1.27-1.09(m,3H),1.06-0.91(m,2H)。

Example 18: 5-amino-1-cyclohexyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-cyclohexyl-pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and cyclohexyl hydrazine hydrochloride (0.91mmol) gave the title compound (0.65mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.11 min, M/z 347.1[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclohexyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was followed by reaction of 5-amino-3- (4-bromophenyl) -1-cyclohexyl-pyrazole-4-carbonitrile (0.64mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.70mmol) gave the title compound (0.59mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.81 min, M/z 430.3[ M + H]⁺。

5-amino-1-cyclohexyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure M, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed with N- [ [4- (5-amino-4-cyano-1-cyclohexyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.58mmol) gave the title compound (0.32mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.59 min, M/z 448.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.63 min, M/z 448.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.52-7.38(m,5H),7.19-7.14(m,1H),7.04(td,J＝7.6,0.9Hz,1H),6.32(s,2H),4.55(d,J＝6.1Hz,2H),4.12-4.03(m,1H),3.90(s,3H),1.76-1.60(m,8H),1.45-1.29(m,2H)。

Example 19: 5-amino-1-isopropyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-isopropylpyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica gel eluting with 0-2% MeOH in DCM, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and isopropylhydrazine (0.46mmol) gave the title compound (0.27mmol) as a pale yellow solid. UPLC-MS (ES +, short acidic): 1.96 min, M/z 307.1[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-isopropyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed using 5-amino-3- (4-bromophenyl) -1-isopropyl-pyrazole-4-carbonitrile (0.27mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.19mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.73 min, M/z 390.2[ M + H]⁺。

5-amino-1-isopropyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure M, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed with N- [ [4- (5-amino-4-cyano-1-isopropyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.19mmol) gave the title compound (0.10mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 408.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.23 min, M/z 408.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆δ is 8.73(t, J ═ 6.1Hz,1H),7.75(dd, J ═ 7.7,1.8Hz,1H),7.50-7.38(m,5H),7.18-7.13(m,1H),7.04(td, J ═ 7.5,0.9Hz,1H),6.31(s,2H),4.54(d, J ═ 6.1Hz,2H),4.47 (quintuple, J ═ 6.6Hz,1H),3.90(s,3H),1.33(d, J ═ 6.6Hz, 6H).

Example 20: 5-amino-1- [ (1S, 3R) -3-hydroxycyclopentyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- [ (1S, 3R) -3-hydroxycyclopentyl radical]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

Sodium borohydride (0.20mmol) was added to 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (3-oxocyclopentyl) pyrazole-4-carboxamide (0.18mmol) in methanol (1mL) and cooled to 0 ℃. The reaction mixture was then stirred at room temperature for 30 minutes, quenched with saturated ammonium chloride solution and the layers separated. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification is carried out by means of reverse phase chromatography, Elution with 20-40% MeCN in 0.1% formic acid additive in water afforded the title compound (0.08mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.38 min, M/z 450.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆δ 8.74(t, J ═ 6.1Hz,1H),7.76(dd, J ═ 7.5,1.8Hz,1H),7.55-7.38(m,5H),7.16(d, J ═ 8.3Hz,1H),7.07-7.01(m,1H),6.40(s,2H),5.07(d, J ═ 5.7Hz,1H),4.65 (quintuple, J ═ 7.7Hz,1H),4.55(d, J ═ 6.1Hz,2H),4.18-4.09(m,1H),3.91(s,3H),2.32-2.21(m,1H),2.08-1.92(m,2H),1.92-1.83(m,1H), 1.82-1.82 (m, 2H).

Example 21: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile

Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM according to general procedure H gave 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and 2,2, 2-trifluoroethylhydrazine (70 wt% in water, 0.46mmol) gave the title compound (0.27mmol) as a pale yellow solid. LC-MS (ES)⁺Method 1): 5.80 min, M/z 345.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]Phenyl radical ]Methyl radical]-2-methoxy- Benzamide derivatives

Further purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane according to general procedure K gave 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (0.29mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.38mmol) gave the title compound (0.17mmol) as an off-white solid. LC-MS (ES)⁺Method 1): 5.01 min, M/z 430.2[ M + H]⁺。

5-amino-3- [4-[ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoroethyl) pyri Azole-4-carboxamides

General procedure L, further purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane, afforded N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.16mmol) gave the title compound (0.08mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 448.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.22 min, M/z 448.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.0Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.52-7.40(m,5H),7.16(d,J＝8.1Hz,1H),7.07-7.02(m,1H),6.68(s,2H),4.95(q,J＝9.0Hz,2H),4.56(d,J＝6.1Hz,2H),3.91(s,3H)。

Example 22: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-phenyl-pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-phenyl-pyrazole-4-carbonitrile

General procedure H, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.35mmol) and phenylhydrazine (0.42mmol) gave 5-amino-3- (4-bromophenyl) -1-phenyl-pyrazole-4-carbonitrile (0.28mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.04 min, M/z 339.1[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-phenyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

Further purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane according to general procedure K gave 5-amino-3- (4-bromophenyl) -1-phenyl-pyrazole-4-carbonitrile (0.12mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Borane potassium(0.19mmol) to give the title compound (0.09mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 424.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-phenyl-pyrazole-4-carboxamide

General procedure L, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- (5-amino-4-cyano-1-phenyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.07mmol) gave the title compound (0.05mmol) as a white solid. LC-MS (ES)⁺Method 1): 4.53 min, M/z 442.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.39 min, M/z 442.2[ M + H ] ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,2.0Hz,1H),7.65-7.60(m,2H),7.59-7.38(m,8H),7.16(d,J＝8.1Hz,1H),7.08-7.02(m,1H),6.49(s,2H),4.58(d,J＝6.1Hz,2H),3.91(s,3H)。

Example 23: 5-amino-1- [ (1R) -indan-1-yl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- [ (1R) -indan-1-yl ] radical]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy- Benzamide derivatives

Reacting N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) phenyl]Methyl radical]A suspension of-2-methoxy-benzamide (100mg, 0.29mmol), (S) - (+) -1-indanol (0.49mmol) and triphenylphosphine (0.49mmol) in dry THF (2mL) was cooled to 0 ℃. Diisopropyl azodicarboxylate (0.49mmol) was added dropwise over 5 minutes and the reaction mixture was allowed to return to room temperature over 30 minutes and then stirred for 16 hours. The reaction mixture was concentrated in vacuo. Further purification by SPE SCX cartridge eluting with MeOH afforded the title compound (0.17 mmol). UPLC-MS (ES)⁺Short acidic): 1.90 pointsClock, M/z 464.3[ M + H ]]⁺。

5-amino-1- [ (1R) -indan-1-yl radical]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

General procedure L, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, gave N- [ [4- [ 5-amino-4-cyano-1- [ (1R) -indan-1-yl ] ester]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.27mmol) gave the title compound (0.03 mmol). UPLC-MS (ES) ⁺Short acidic): 1.74 min, M/z 482.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.77 min, M/z 482.3[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.70(t,J＝6.1Hz,1H),7.74(dd,J＝7.6,1.7Hz,1H),7.52-7.43(m,1H),7.41-7.34(m,4H),7.30(d,J＝7.4Hz,1H),7.24(t,J＝7.1Hz,1H),7.20-7.11(m,2H),7.09-6.98(m,2H),6.56(s,2H),5.91(t,J＝7.5Hz,1H),4.52(d,J＝6.0Hz,2H),3.88(s,3H),3.21-3.06(m,1H),2.97-2.84(m,1H),2.49-2.38(m,2H)。

Example 24: 1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5-methyl-pyrazole-4-carboxamide

2- (4-Bromobenzoyl) -3-oxo-butyric acid methyl ester

In N₂Next, a solution of methylmagnesium bromide (2.2M in THF, 9.27mmol) was added to a solution of methyl acetoacetate (9.27mmol) in THF (44mL) at 0 deg.C, then stirred at 0 deg.C for 30 minutes. 4-bromobenzoyl chloride (9.27mmol) was then added and stirred at RT for 16 h. After that, it was quenched with a saturated ammonium chloride solution. The aqueous layer was then extracted with DCM (× 3), the organics combined, filtered through a hydrophobic frit and all volatiles removed under reduced pressure. Purification by flash column chromatography on silica eluting with 0-15% EtOAc in heptane afforded the title compound (4.99mmol) as a clear oil. UPLC-MS (ES)⁺Is short and shortAcidic): 1.88 min, M/z 299.0[ M]⁺。

3- (4-bromophenyl) -5-methyl-1H-pyrazole-4-carboxylic acid methyl ester

Hydrazine hydrate solution (55-60% aqueous solution, 3.99mmol) was added to a solution of 2- (4-bromobenzoyl) -3-oxo-butyric acid methyl ester (4.99mmol) in acetic acid (20 mL). After this time, it was stirred at RT for 72 hours, then all volatiles were removed under reduced pressure. After that, the residue was basified with saturated sodium carbonate solution. The aqueous layer was then extracted with DCM (× 3), the extracts combined and filtered through a hydrophobic frit. Thereafter, purification by flash column chromatography on silica eluting with 0-6% MeOH in DCM gave the title compound (4.21mmol) as a clear oil. UPLC-MS (ES) ⁺Short acidic): 1.60 min, M/z 296.9[ M +2 ]]⁺。

3- (4-bromophenyl) -1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid methyl ester

Cesium carbonate (3.00mmol) was added to a solution of bromocyclopentane (2.40mmol) and methyl 3- (4-bromophenyl) -5-methyl-pyrazole-4-carboxylate (1.20mmol) in DMF (2.5 mL). After this time, it was stirred at 75 ℃ for 45 minutes, and then all volatiles were removed under reduced pressure. The residue was then suspended in EtOAc (50 mL). After that, the organic layer was washed with water (× 2) and a saturated saline solution (× 1). The organic layer was then dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica eluting with 0-40% EtOAc in heptane afforded the title compound (0.87mmol) as a clear oil. UPLC-MS (ES)⁺Short acidic): 2.27 min, M/z 365.1[ M +2 ]]⁺。

3- (4-bromophenyl) -1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid

Lithium hydroxide (2.75mmol) was added to a solution of 3- (4-bromophenyl) -1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid methyl ester (0.28mmol) in 1, 4-dioxane (0.75mL) and water (0.75 mL). Thereafter, stirring was carried out at 80 ℃ for 16 hours and then at 100 ℃ for 16 hours. After cooling the reaction mixture back to RT, the reaction mixture was acidified to pH3 with hydrochloric acid (1M). Then extracted with DCM (. times.3), filtered through a hydrophobic frit, and reduced All volatiles were removed under pressure. Purification by flash column chromatography on silica eluting with 0-20% EtOAc in heptane afforded the title compound (0.28mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.00 min, M/z 351.1[ M +2 ]]⁺。

3- (4-bromophenyl) -1-cyclopentyl-N- [ (2, 4-dimethoxyphenyl) methyl group]-5-methyl-pyrazole-4-carboxamide

In N₂Next, 3- (4-bromophenyl) -1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid (0.28mmol), 2, 4-dimethoxybenzylamine (0.33mmol) and triethylamine (0.41mmol) were suspended in THF (1.4 mL). After stirring the reaction mixture at room temperature for 5 min, a solution of propylphosphonic anhydride (50 wt% in EtOAc, 0.41mmol) was added and the reaction stirred at room temperature for 72 h. Then 2, 4-dimethoxybenzylamine (0.33mmol), triethylamine (0.41mmol) and a solution of propylphosphonic anhydride (50 wt% in EtOAc, 0.41mmol) were added. The reaction was then stirred at room temperature for 16 hours. Saturated ammonium chloride solution (10mL) and water (10mL) were then added. After that, DCM (× 3) was used to extract the aqueous layer. The organic extracts were combined, filtered through a hydrophobic frit, and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica eluting with 0-50% EtOAc in heptane followed by reverse phase chromatography eluting with 30-70% MeCN in 0.1% formic acid in water afforded the title compound (0.07mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 2.18 min, M/z 500.2[ M +2 ]]⁺。

1-cyclopentyl-N- [ (2, 4-dimethoxyphenyl) methyl group]-3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical]-5-methyl-pyrazole-4-carboxamide

Purification by flash column chromatography on silica gel eluting with 0-2.5% MeOH in DCM and then by reverse phase chromatography using 20-70% MeCN in 0.1% formic acid in water followed by 3- (4-bromophenyl) -1-cyclopentyl-N- [ (2, 4-dimethoxyphenyl) methyl]-5-methyl-pyrazole-4-carboxamide (0.07mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borate gave the title compound (0.05mmol) as a white solid. UPLC-MS(ES⁺Short acidic): 2.04 min, M/z 583.4[ M + H]⁺。

1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5-methyl-pyrazole-4-carboxylic acid Amines as pesticides

Trifluoroacetic acid (0.04mmol) was added to 1-cyclopentyl-N- [ (2, 4-dimethoxyphenyl) methyl at 0 deg.C]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5-methyl-pyrazole-4-carboxamide (0.04mmol) in DCM (0.4mL) and the reaction mixture was stirred at room temperature for 48 h. Additional trifluoroacetic acid (0.04mmol) was then added every 24 hours for 3 days while the reaction mixture was stirred at room temperature. The reaction mixture was then basified with saturated sodium carbonate solution. The layers were separated and the aqueous layer was extracted with DCM (× 3), combined, filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification by flash column chromatography on silica eluting with 0-6% MeOH in DCM followed by reverse phase chromatography with 20-70% MeCN in 0.1% formic acid additive in water afforded the title compound (0.02mmol) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.62 min, M/z 433.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.70 min, M/z 433.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆δ 8.70(t, J ═ 6.0Hz,1H),7.75(dd, J ═ 7.6,1.8Hz,1H),7.60(d, J ═ 8.2Hz,2H),7.51-7.45(m,1H),7.34(d, J ═ 8.2Hz,2H),7.24-7.17(m,2H),7.16(d, J ═ 8.3Hz,1H),7.08-7.01(m,1H),4.71 (quintuple, J ═ 7.3Hz,1H),4.51(d, J ═ 6.0Hz,2H),3.90(s,3H),2.37(s,3H),2.11-1.91(m,4H),1.91-1.80(m,2H), 1.91-1.55H), 1.55-1.71 (m, 1H).

Example 25: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [2- (1H-tetrazol-5-yl) ethyl ] pyrazole-4-carboxamide

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [2- (1H-tetrazol-5-yl)) Second step Base of]Pyrazole-4-carboxamides

To 5-amino-1- (2-cyanoethyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]To a solution of pyrazole-4-carboxamide (0.27mmol) in DMF (2mL) were added sodium azide (0.28mmol) and ammonium chloride (0.30 mmol). The reaction mixture was heated to 110 ℃ for 16 hours. Additional sodium azide (0.28mmol) and ammonium chloride (0.30mmol) were added and the mixture was heated to 110 ℃ for 16 h, cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica eluting with 0-20% MeOH in DCM to give the title compound (0.02 mmol). UPLC-MS (ES) ⁺Short acidic): 1.22 min, M/z 462.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.70 min, M/z 462.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),8.32(br s,1H),7.76(dd,J＝7.6,1.9Hz,1H),7.45-7.52(m,1H),7.44-7.38(m,4H),7.16(d,J＝7.7Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.48(s,2H),4.55(d,J＝6.2Hz,2H),4.33(t,J＝7.1Hz,2H),3.90(s,3H),3.27(t,J＝7.2Hz,2H)。

Example 26: 5-amino-1- (4, 4-dimethylcyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (4, 4-Dimethylcyclohexylidene) amino group]Carbamic acid tert-butyl ester

Following general procedure E, using 4, 4-dimethylcyclohexanone (0.79mmol) the title compound (0.78mmol) was obtained as an off-white powder.¹H NMR(400MHz,CDCl₃,δ):7.49(br s,1H),2.45-2.39(m,2H),2.26-2.20(m,2H),1.55-1.44(m,13H),1.02(s,6H)。

5-amino-3- (4-bromophenyl) -1- (4, 4-dimethylcyclohexyl) pyrazole-4-carbonitrile

General procedure O, using N- [ (4, 4-dimethylcyclohexylidene) amino]Carbamic acid tert-butyl esterButyl ester (0.78mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) gave the title compound (0.36mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 2.33 min, M/z 375.1[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4, 4-dimethylcyclohexyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, starting from 5-amino-3- (4-bromophenyl) -1- (4, 4-dimethylcyclohexyl) pyrazole-4-carbonitrile (0.13mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.15mmol) gave the title compound (0.13mmol) as an off-white powder. UPLC-MS (ES) ⁺Short acidic): 1.99 min, M/z 458.3[ M + H ]]⁺。

5-amino-1- (4, 4-dimethylcyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical] Pyrazole-4-carboxamides

General procedure M, further purification by reverse phase chromatography, eluting with 20-60% MeCN in aqueous solution containing 0.1% formic acid additive, was performed on N- [ [4- [ 5-amino-4-cyano-1- (4, 4-dimethylcyclohexyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.07mmol) gave the title compound (0.02mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.74 min, M/z 476.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.04 min, M/z 476.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.52-7.38(m,5H),7.16(d,J＝8.3Hz,1H),7.08-7.01(m,1H),6.31(s,2H),4.55(d,J＝6.1Hz,2H),4.10-3.98(m,1H),3.91(s,3H),2.00-1.86(m,2H),1.71-1.60(m,2H),1.52-1.42(m,2H),1.42-1.29(m,2H),0.95(s,6H)。

Example 27: 5-amino-1- (4-hydroxy-4-methyl-cyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

8-methyl-1, 4-dioxaspiro [4.5 ]]Decan-8-ol

A solution of methylmagnesium bromide (2.2M in diethyl ether, 2.82mmol) was added to a solution of 1, 4-cyclohexanedione monovinylacetal (2.56mmol) in THF (5mL) and cooled to 0 ℃. The reaction mixture was stirred at RT for 2h and then quenched with saturated aqueous ammonium chloride. The layers were separated between DCM (20mL) and water (20 mL). The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the title compound (2.50mmol) as a clear oil. ¹H NMR(400MHz,CDCl₃,δ):4.02-3.91(m,4H),1.96-1.84(m,2H),1.78-1.65(m,4H),1.65-1.56(m,2H),1.29(s,3H),1.15(s,1H)。

4-hydroxy-4-methyl-cyclohexanone

Following general procedure J, using 8-methyl-1, 4-dioxaspiro [4.5 ]]A solution of decan-8-ol (2.50mmol) in THF (2.5mL) gave the crude title compound (2.50mmol) as a brown oil.¹H NMR(400MHz,CDCl₃,δ):2.71-2.59(m,2H),2.23-2.12(m,2H),1.96-1.86(m,2H),1.85-1.73(m,2H),1.31(s,3H),1.23(s,1H)。

N- [ (4-hydroxy-4-methylcyclohexylidene) amino group]Carbamic acid tert-butyl ester

Following general procedure E, using 4-hydroxy-4-methyl-cyclohexanone (2.50mmol) the title compound (1.36mmol) was obtained as a clear oil. UPLC-MS (ES)⁺Short acidic): 1.21 min, M/z 243.1[ M + H]⁺。

5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carbonitrile

Purification by flash column chromatography according to general procedure O eluting with 55% EtOAc in heptane and then 0-8% MeOH in DCM gave N- [ (4-hydroxy-4-methyl-cyclohexylidene) amino]Carbamic acid tert-butyl ester (0.83mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.68mmol) gave the title compound as an off-white powder (isomer 1,0.43mmol) and as an off-white solid (isomer 2,0.09 mmol). UPLC-MS (ES)⁺Short acidity; isomer 1): 1.65 min, M/z 375.0[ M ]]⁺。UPLC-MS(ES⁺Short acidity; isomer 2): 1.72 min, M/z 375.1[ M ]]⁺。

5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carboxamide

Following general procedure L, using 5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carbonitrile (isomer 1) (50mg, 0.13mmol) gave 5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carboxamide (44mg, 0.11mmol, 84%) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.35 min, M/z 394.9[ M +2 ]]⁺。

5-amino-1- (4-hydroxy-4-methylcyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure K, using 5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carboxamide (0.11mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.12mmol) gave the title compound (0.09mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.33 min, M/z 478.5[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.98 min, M/z 478.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.52-7.37(m,5H),7.16(d,J＝8.3Hz,1H),7.08-7.01(m,1H),6.29(s,2H),4.55(d,J＝6.2Hz,2H),4.12(s,1H),4.08-3.97(m,1H),3.91(s,3H),2.24-2.07(m,2H),1.70-1.60(m,2H),1.60-1.50(m,2H),1.50-1.37(m,2H),1.15(s,3H)。

Example 28: 5-amino-1- (4-benzyloxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

8-benzyloxy-1, 4-dioxaspiro [4.5 ]]Decane

In N₂Next, sodium hydride (60% dispersed in mineral oil, 1.90mmol) was added to 1, 4-dioxaspiro [4.5 ]]Decan-8-ol (1.26mmol) in THF (2.4mL) was cooled to 0C. The reaction mixture was stirred at 0 ℃ for 30 minutes, then benzyl bromide (1.90mmol) was added. The mixture was stirred at RT overnight, quenched with saturated ammonium chloride solution and the layers separated. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification by flash column chromatography on silica eluting with 30% EtOAc in heptane afforded the title compound (0.81mmol) as a clear oil. UPLC-MS (ES) ⁺Short acidic): 1.76 min, M/z 249.0[ M + H ]]⁺。

4-Benzyloxycyclohexanone

General procedure J, using 8-benzyloxy-1, 4-dioxaspiro [4.5 ]]Decane (0.81mmol) gave the crude title compound (0.81mmol) as a clear oil.¹H NMR(400MHz,CDCl₃,δ):7.44-7.29(m,5H),4.63(s,2H),3.88-3.82(m,1H),2.71-2.60(m,2H),2.35-2.25(m,2H),2.24-2.12(m,2H),2.05-1.94(m,2H)。

N- [ (4-benzyloxycyclohexylidene) amino group]Carbamic acid tert-butyl ester

Following general procedure E, using 4-benzyloxycyclohexanone (0.81mmol) gave the title compound (0.81mmol) as a clear oil. UPLC-MS (ES)⁺Short acidic): 1.74 min, M/z 319.2[ M + H]⁺。

5-amino-1- (4-benzyloxycyclohexyl) -3- (4-bromophenyl) pyrazole-4-carbonitrile

Following general procedure O, N- [ (4-benzyloxycyclohexylene) amino group]Carbamic acid tert-butyl ester (0.81mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.68mmol) gave the title compound (0.68mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic, cis/trans mixture): 2.18 min and 2.20 min, M/z 453.1[ M +2 ]]⁺。

5-amino-1- (4-benzyloxycyclohexyl) -3- (4-bromophenyl) pyrazole-4-carboxamide

General procedure L, using 5-amino-1- (4-benzyloxycyclohexyl) -3- (4-bromophenyl) pyrazole-4-carbonitrile (0.13mmol) to give the title compound (0.13mmol) as a clear oil. UPLC-MS (ES)⁺Short acidic, cis/trans mixture): 1.91 min, M/z 471.0[ M +2 ] ]⁺。

5-amino-1- (4-benzyloxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

Following general procedure K, using 5-amino-1- (4-benzyloxycyclohexyl) -3- (4-bromophenyl) pyrazole-4-carboxamide (0.13mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.15mmol) gave the title compound as a mixture of diastereomers (0.12mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.73 min, M/z 554.5[ M + H]⁺1.77 min, M/z 554.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.02 min, M/z 554.3[ M + H ]]⁺4.11 min, M/z 554.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝5.9Hz,1H),7.76(dd,J＝7.6,1.6Hz,1H),7.53-7.31(m,9H),7.31-7.23(m,1H),7.16(d,J＝8.4Hz,1H),7.08-7.01(m,1H),6.34(s,1H),6.32(s,1H),4.59-4.46(m,4H),4.20-4.06(m,1H),3.90(s,3H),3.69-3.62(m,0.5),3.46-3.35(m,0.5H),2.20-1.94(m,3H),1.93-1.73(m,2H),1.68-1.46(m,2H),1.46-1.25(m,1H)。

Example 29: 5-amino-1-cyclopropyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-cyclopropyl-pyrazole-4-carbonitrile

Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM according to general procedure H gave 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.46mmol) and cyclopropylhydrazine hydrochloride(0.55mmol) to give the title compound (0.34mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.73 min, M/z 303.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopropylpyrazol-3-yl) phenyl ]Methyl radical]-2-methoxy-benzamide

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM was repeated using 5-amino-3- (4-bromophenyl) -1-cyclopropyl-pyrazole-4-carbonitrile (0.32mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.45mmol) gave the title compound (0.34mmol) as a crude brown solid. UPLC-MS (ES)⁺Short acidic): 1.51 min, M/z 388.2[ M + H ]]⁺。

5-amino-1-cyclopropyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure L, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- (5-amino-4-cyano-1-cyclopropylpyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.32mmol) gave the title compound (0.15mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 406.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.95 min, M/z 406.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.0Hz,1H),7.76(dd,J＝7.7,1.3Hz,1H),7.53-7.34(m,5H),7.16(d,J＝8.3Hz,1H),7.06-7.03(m,1H),6.33(s,2H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.32-3.24(m,1H),1.04-0.92(m,4H)。

Example 30: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-methyl-pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-methylpyrazole-4-carbonitrile

Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM according to general procedure H gave 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (1.14mmol) and methylhydrazine (1.37mmol) gave an inseparable mixture of regioisomers of the title compound (0.47mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.57 min and 1.67 min, M/z 277.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-methyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, further purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane, was performed by combining a mixture of 5-amino-3- (4-bromophenyl) -1-methyl-pyrazole-4-carbonitrile and 3-amino-5- (4-bromophenyl) -1-methyl-pyrazole-4-carbonitrile (0.43mmol) with trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (1.37mmol) gave the title compound (0.11mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 362.2[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-methylpyrazole-4-carboxamide

General procedure L, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- (5-amino-4-cyano-1-methyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.09mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.24 min, M/z 380.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.76 min, M/z 380.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.2Hz,1H),7.76(dd,J＝7.8,1.7Hz,1H),7.51-7.39(m,5H),7.16(dd,J＝8.4,0.9Hz,1H),7.07-7.03(m,1H),6.28(s,2H),4.55(d,J＝6.2Hz,2H),3.90(s,3H),3.56(s,3H)。

Example 31: 5-amino-1- (2-hydroxyethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2-hydroxyethyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 10-100% EtOAc in heptane, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (1.14mmol) and 2-hydroxyethylhydrazine (1.37mmol) gave the title compound (0.40mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 307.0[ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-hydroxyethyl) pyrazol-3-yl ] amino acids]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed using 5-amino-3- (4-bromophenyl) -1- (2-hydroxyethyl) pyrazole-4-carbonitrile (0.35mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.49mmol) gave the title compound (0.22mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 392.1[ M + H ]]⁺。

5-amino-1- (2-hydroxyethyl) -3- [4- [ [ (2-methoxybenzoyl) amino group ]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure L, further purification by flash column chromatography on silica gel, eluting with 0-10% MeOH in DCM, leaving N- [ [4- [ 5-amino-4-cyano-1- (2-hydroxyethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.21mmol) gave the title compound (0.09mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.20 min, M/z 410.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.66 min, M/z 410.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.2Hz,1H),7.76(dd,J＝7.8,1.7Hz,1H),7.52-7.39(m,5H),7.16(m,1H),7.05(m,1H),6.21(s,2H),5.00-4.94(m,1H),4.56(d,J＝6.2Hz,2H),3.98(t,J＝5.9Hz,2H),3.90(s,3H),3.71(q,J＝5.71Hz,2H)。

Example 32: 5-amino-1- (3-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (3-fluorophenyl) pyrazole-4-carbonitrile

General procedure H, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed using (3-fluorophenyl) hydrazine chloride (0.68mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.57mmol) gave the title compound (0.22mmol, 38% yield) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.97 min, M/z 357.1[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-fluorophenyl) pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed with 5-amino-3- (4-bromophenyl) -1- (3-fluorophenyl) pyrazole-4-carbonitrile (0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.30mmol) gave the title compound (0.05mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 442.2[ M + H ]]⁺。

5-amino-1- (3-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure L, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- [ 5-amino-4-cyano-1- (3-fluorophenyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.05mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 460.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.52 min, M/z 460.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.1Hz,1H),7.76(dd,J＝7.5,1.6Hz,1H),7.62-7.55(m,3H),7.52-7.45(m,5H),7.26(t,J＝8.6Hz,1H),7.16(d,J＝8.2Hz,1H),7.05(t,J＝7.58Hz,1H),6.62(s,2H),4.57(d,J＝6.1Hz,2H),3.91(s,3H)。

Example 33: 5-amino-1- (4-hydroxy-4-methyl-cyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carboxamide

Following general procedure L, using 5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carbonitrile (isomer 2) (0.09mmol) gave crude title compound (0.09mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.38 min, M/z 395.1[ M +2 ]]⁺。

5-amino-1- (4-hydroxy-4-methylcyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure K, using 5-amino-3- (4-bromophenyl) -1- (4-hydroxy-4-methyl-cyclohexyl) pyrazole-4-carboxamide (0.09mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.09mmol) gave the title compound (0.04mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.30 min, M/z 478.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.94 min, M/z 478.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.0Hz,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.52-7.37(m,5H),7.16(d,J＝8.3Hz,1H),7.08-7.00(m,1H),6.33(s,2H),4.55(d,J＝6.0Hz,2H),4.42(s,1H),4.18-4.05(m,1H),3.90(s,3H),1.92-1.71(m,4H),1.70-1.60(m,2H),1.60-1.48(m,2H),1.17(s,3H)。

Examples 34a (isomer 1) and 34b (isomer 2): 5-amino-1- (4-hydroxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (4-hydroxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

To 5-amino-1- (4-benzyloxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (0.13mmol) in MeOH (1.3mL) and ammonium formate (0.40mmol solution to which palladium (10 wt% on carbon powder, dry) was added, the reaction mixture was stirred at 60 deg.C for 2 hours, then ammonium formate (1.34mmol) was added, and the mixture was stirred at 60 deg.C for 1 hour, acetic acid (0.5mL) was added, and the reaction mixture was stirred at 60 deg.C for 14 hours, cooled to room temperature, and passed through And (4) filtering by using a plug. The stopper was washed with DCM and the filtrate was concentrated under reduced pressure. The residue was basified with saturated sodium bicarbonate solution and extracted with DCM (× 3). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification by flash column chromatography on silica eluting with 0-10% MeOH in DCM gave the title compound as a white solid (isomer 1, 0.02mmol) and a brown solid (isomer 2, 0.09 mmol).

UPLC-MS(ES⁺Short acidity; isomer 1): 1.27 min, M/z 464.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidity; isomer 1): 2.84 min, M/z 464.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ) (isomer 1):8.74(t, J ═ 6.0Hz,1H),7.76(dd, J ═ 7.6,1.7Hz,1H),7.52 to 7.37(m,5H),7.16(d, J ═ 8.3Hz,1H),7.08 to 7.00(m,1H),6.30(s,2H),4.55(d, J ═ 6.0Hz,2H),4.40(d, J ═ 2.6Hz,1H),4.13 to 4.02(m,1H),3.90(s,3H),3.86(br s,1H),2.23 to 2.07(m,2H),1.84 (m,1H), 1.18 (H), or a mixture thereof-1.72(m,2H),1.61-1.47(m,4H)。

UPLC-MS(ES⁺Short acidity; isomer 2): 1.26 min, M/z 464.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidity; isomer 2): 2.82 min, M/z 464.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ) (isomer 2):8.74(t, J ═ 6.1Hz,1H),7.76(dd, J ═ 7.7,1.7Hz,1H),7.52 to 7.37(m,5H),7.16(d, J ═ 8.3Hz,1H),7.08 to 7.00(m,1H),6.33(s,2H),4.63(d, J ═ 4.5Hz,1H),4.55(d, J ═ 6.1Hz,2H),4.13 to 4.01(m,1H),3.90(s,3H),3.51 to 3.39(m,1H),1.96 to 1.86(m,2H),1.86 to 1.74(m,4H),1.39 to 1.25(m, 2H).

Example 35: 5-amino-1-cyclobutyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- (Cyclobutylideneamino) carbamic acid tert-butyl ester

To a solution of cyclobutanone (2.0mmol) in heptane (2mL) was added tert-butyl carbazate (2.2mmol) and the reaction was heated to reflux and stirred for 2 hours. The volatiles were removed under reduced pressure to give the title compound (2.0mmol, 100% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.61 min, M/z 185.0[ M + H ]]⁺。

Salt of cyclobutylhydrazine

Tert-butyl N- (cyclobutylideneamino) carbamate (0.27mmol) was dissolved in THF (5mL) and dimethylsulfide borane (0.46mmol) was added. The reaction was stirred at room temperature for 1 hour. When TLC showed consumption of starting material, the solvent was removed in vacuo. The residue was dissolved in hydrogen chloride-methanol solution (7.6mL), and the reaction was heated to reflux and stirred overnight. The solvent was evaporated to give the title compound (0.27mmol) as a pale yellow gum, which was used without any further purification.¹H NMR(400MHz,DMSO-d₆,δ):3.66-3.54(m,1H),2.16-1.97(m,4H),1.83-1.64(m,2H)。

5-amino-3- (4-bromophenyl) -1-cyclobutyl-pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 20-80% EtOAc in heptane, was performed by contacting cyclobutylhydrazine hydrochloride (0.25mmol) and 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.21mmol) gave the title compound (0.14mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.95 min, M/z 317.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclobutyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

Following general procedure K, using 5-amino-3- (4-bromophenyl) -1-cyclobutyl-pyrazole-4-carbonitrile (0.14mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.19mmol) gave the title compound (0.13mmol) as a white powder. UPLC-MS (ES +, short acidic): 1.67 min, M/z 402.2[ M + H]⁺。

5-amino-1-cyclobutyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure L, using N- [ [4- (5-amino-4-cyano-1-cyclobutyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.05mmol) gave the title compound as a white powder. UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 420.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.29 min, M/z 420.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.2Hz,1H),7.76(dd,J＝7.9,2.2Hz,1H),7.50-7.41(m,5H),7.16(d,J＝8.3Hz,1H),7.04(t,J＝7.5Hz,1H),6.30(s,2H),4.81-4.73(m,1H),4.55(d,J＝6.0Hz,2H),3.91(s,3H),2.33-2.26(m,4H),1.78-1.69(m,2H)。

Example 36: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N-tetrahydrofuran-3-ylideneamino]Carbamic acid tert-butyl ester

To a solution of dihydro (3(2H) -furanone (1.95mmol) in ethanol (2mL) was added tert-butyl carbazate (2.35mmol), the reaction was heated to reflux and stirred overnight, and the volatiles were removed under reduced pressure to give the title compound (1.95mmol) as a white solid. ¹H NMR(400MHz,CDCl₃δ, isomer mixture) 7.25(s,0.75H),7.12(s,0.25H),4.34(t, J ═ 1.2Hz,1.5H),4.24(t, J ═ 1.2Hz,0.5H),4.12(t, J ═ 6.9Hz,1.5H),4.02(t, J ═ 6.9Hz,0.5H),2.78(td, J ═ 6.9,1.2Hz,0.5H),2.48(td, J ═ 6.9,1.2Hz,1.5H),1.54(s,7.5H),1.53(s, 1.5H).

Tetrahydrofuran-3-yl hydrazine hydrochloride

Reacting N- [ tetrahydrofuran-3-ylideneamino group]Tert-butyl carbamate (0.25mmol) was dissolved in THF (5mL) and dimethylsulfide borane (0.42mmol) was added. The reaction was stirred at room temperature for 1 hour until TLC showed complete consumption of starting material. The solvent was removed in vacuo. The residue was dissolved in hydrogen chloride in MeOH (1.25M, 6.99mL) and the reaction was heated to reflux and stirred overnight. The solvent was evaporated to give the title compound (0.25mmol) as a pale yellow gum, which was used without any further purification.¹H NMR(400MHz,DMSO-d₆,δ):3.86-3.59(m,6H),2.11-1.96(m,1H),1.95-1.84(m,1H)。

5-amino-3- (4-bromophenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 20-80% EtOAc in heptane, was combined tetrahydrofuran-3-ylhydrazine (0.23mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile gave the title compound (0.09mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 333.1[ M ]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, using 5-amino-3- (4-bromophenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.10mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.14mmol) gave the title compound (0.06mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.51 min, 418.2M/z [ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydrofuran-3-yl-pyrazole- 4-carboxamides

General procedure L, using N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.06mmol) gave the title compound (0.03mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 458.2[ M + Na ]]⁺。UPLC-MS(ES⁺Long acidic): 2.95 min, M/z 436.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝5.8Hz,1H),7.75(dd,J＝7.4,1.8Hz,1H),7.50-7.40(m,5H),7.16(d,J＝7.7Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.40(s,2H),4.97-4.90(m,1H),4.55(d,J＝6.0Hz,2H),4.00-3.94(m,2H),3.90(s,3H),3.83-3.78(m,2H),2.28-2.24(m,2H)。

Example 37: 5-amino-1- [ (1S, 3S) -3-chlorocyclopentyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- [ (1S, 3S) -3-chlorocyclopentyl]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

Thionyl chloride (0.67mmol) was added to 5-amino-1- [ (1S, 3R) -3-hydroxycyclopentyl ]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (0.22mmol) in DCM (3mL) was cooled to 0 ℃. The reaction was allowed to warm to room temperature and stirred at this temperature for 48 hours. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography eluting with 30-80% MeCN in 0.1% formic acid additive in water to give the title compound (0.07 m)mol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 468.1[ M]⁺。UPLC-MS(ES⁺Long acidic): 3.62 min, M/z 468.1[ M]⁺。

¹H NMR(400MHz,CDCl₃,δ):8.29-8.20(m,2H),7.56-7.42(m,5H),7.15-7.11(m,1H),6.99(d,J＝8.2Hz,1H),5.46(br.s,2H),5.15(br.s,2H)4.80-4.70(m,3H),4.68-4.63(m,1H),3.95(s,3H),2.77-2.67(m,1H),2.55-2.37(m,3H),2.23-2.11(m,1H),2.11-2.01(m,1H)。

Example 38: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ [ (3R) -3-piperidinyl ] methyl ] pyrazole-4-carboxamide

(3R) -3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (3R) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (0.87mmol) in anhydrous THF (10mL) was added borane-tetrahydrofuran (1:1, 2.62mmol) dropwise at RT. The reaction was stirred for 4 hours and saturated NH was used₄The Cl solution (2mL) was quenched and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane afforded the title compound (0.84mmol) as a white solid. ¹H NMR(400MHz,DMSO-d₆,δ):4.52-4.46(m,1H),4.01-3.86(m,1H),3.83-3.75(m,1H),3.30-3.26(m,1H),3.22-3.16(m,1H),2.75-2.63(m,1H),1.70-1.62(m,1H),1.61-1.53(m,1H),1.50-1.40(m,1H),1.38(s,9H),1.36-1.21(m,2H),1.13-1.01(m,1H)。

(3R) -3- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester

General procedure I, purification by flash column chromatography on silica gel eluting with 0-50% EtOAc in heptane, tert-butyl (3R) -3- (hydroxymethyl) piperidine-1-carboxylate (0.84mmol) and methanesulfonyl chloride (0.88mmol) gave the title compound (0.58mmol) as colorlessAn oil. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 316.1[ M + Na ]]⁺。

(3R) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] carbonyl]Methyl radical]Phenyl radical] Pyrazol-1-yl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester

General procedure N, purification by silica gel flash column chromatography, of 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1H-pyrazole-4-carboxamide (0.29mmol) and (3R) -3- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester (0.58mmol) to give the title compound (0.19mmol) and (3R) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-2-yl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester, as a mixture of regioisomers. UPLC-MS (ES)⁺Short acidic): 1.58 and 1.60 min, M/z 563.3[ M + H [ ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ [ (3R) -3-piperidinyl ]First of all Base of]Pyrazole-4-carboxamides

Reacting (3R) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.19mmol) and (3R) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Piperidin-1-yl radical]Methyl radical]The regioisomeric mixture of tert-butyl piperidine-1-carboxylate was dissolved in DCM (5mL) and trifluoroacetic acid (4.7mmol) was added. The reaction was stirred at RT overnight. The solvent was removed in vacuo. The residue was dissolved in MeOH and passed through a SPE SCX cartridge eluting with 0-100% 1N ammonia in MeOH. Further purification by mass directed semi-preparative HPLC afforded the title compound (0.02 mmol). UPLC-MS (ES)⁺Short acidic): 1.10 min, M/z463.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.41 min, M/z 463.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.0Hz,1H),8.38(s,2H),7.76(dd,J＝7.4,1.5Hz,1H),7.51-7.40(m,5H),7.16(d,J＝8.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.37(s,2H),4.55(d,J＝6.0Hz,2H),3.90(s,3H),3.83(d,J＝7.1Hz,2H),2.95-2.88(m,2H),2.43-2.38(m,1H),2.09-1.99(m,1H),1.70-1.64(m,2H),1.46-1.36(m,1H),1.24-1.15(m,1H)。

Example 39: 5-amino-1- (2-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2-fluorophenyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, was performed by dissolving (2-fluorophenyl) hydrazine hydrochloride (0.68mmol) and 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.57mmol) gave the title compound (0.29mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.88 min, M/z 357.1[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-fluorophenyl) pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed with 5-amino-3- (4-bromophenyl) -1- (2-fluorophenyl) pyrazole-4-carbonitrile (0.29mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.40mmol) gave the title compound (0.23mmol) as a red solid. UPLC-MS (ES +, short acidic): 1.62 min, M/z 442.1[ M + H ]]⁺。

5-amino-1- (2-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure L, further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- [ 5-amino-4-cyano-1- (2-fluorophenyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.23mmol) gave the title compound (0.02mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 460.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.32 min, M/z 460.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.0Hz,1H),7.76(dd,J＝7.6,1.6Hz,1H),7.60-7.53(m,4H),7.50-7.43(m,4H),7.38(t,J＝7.75Hz,1H),7.16(d,J＝8.4Hz,1H),7.05(t,J＝7.4Hz,1H),6.42(s,2H),4.57(d,J＝6.0Hz,2H),3.91(s,3H)。

Example 40: 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] cyclohexanecarboxylic acid ethyl ester

4- (tert-Butoxycarbonylhydrazono) cyclohexanecarboxylic acid ethyl ester

General procedure E, using ethyl 4-oxocyclohexanecarboxylate (3.14mmol) gave the title compound (2.96mmol) as a clear oil. UPLC-MS (ES)⁺Short acidic): 1.52 min, M/z 285.1[ M + H ]]⁺。

4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Cyclohexanecarboxylic acid ethyl ester

General procedure O, using ethyl 4- (tert-butoxycarbonylhydrazono) cyclohexanecarboxylate (1.93mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (1.63mmol) gave the title compound (1.56mmol, cis/trans isomer mixture) as a white powder. UPLC-MS (ES)⁺Short acidic): 2.00 min, M/z 419.1[ M +2 ]]⁺2.06 min, M/z 419.1[ M +2 ]]⁺。

4- [ 5-amino-3- (4-bromophenyl) -4-carbamoyl-pyrazol-1-yl]Cyclohexanecarboxylic acid ethyl ester

General procedure L, using 4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Ethylcyclohexanecarboxylate (0.91mmol) gave the title compound (0.91mmol, cis/trans isomer mixture) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.70 min, M/z 437.1[ M +2 ]]⁺1.72 min, M/z 437.1[ M +2 ]]⁺。

4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group ]Methyl radical]Phenyl radical]Pyrazole- 1-radical]Cyclohexanecarboxylic acid ethyl ester

General procedure K, using trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (1.00mmol) and 4- [ 5-amino-3- (4-bromophenyl) -4-carbamoyl-pyrazol-1-yl]Ethyl cyclohexanecarboxylate (0.91mmol) gave the title compound (0.68mmol, cis/trans isomer mixture) as a white powder. UPLC-MS (ES)⁺Short acidic): 1.57 min, M/z 520.3[ M + H]⁺1.59 min, M/z 520.3[ M + H ]^]+。UPLC-MS(ES⁺Long acidic): 3.63 min, M/z 520.3[ M + H]⁺3.67 min, M/z 520.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ)8.73(t,J＝6.1Hz,1H),7.79-7.73(m,1H),7.52-7.38(m,5H),7.16(d,J＝8.4Hz,1H),7.08-7.00(m,1H),6.35(s,0.8H),6.33(s,1.2H),4.55(d,J＝6.1Hz,2H),4.18-4.03(m,3H),3.90(s,3H),2.73-2.29(m,1H),2.22-2.11(m,1H),2.06-1.95(m,1H),1.92-1.42(m,6H),1.23-1.15(m,3H)。

Example 41: 5-amino-1- [ (1S, 3S) -3-fluorocyclopentyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- [ (1S, 3S) -3-fluorocyclopentyl group]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

(diethylamino) sulfur trifluoride (0.96mmol) was added dropwise to 5-amino-1- [ (1S, 3R) -3-hydroxycyclopentyl group]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (0.24mmol) in DCM (2mL) was cooled to-20 ℃. The reaction mixture was allowed to return to room temperature and then stirred for an additional 2 hours. The mixture was diluted with DCM and then saturated NaHCO₃The aqueous solution was quenched. The aqueous layer was extracted with DCM. The organic layers were combined, filtered through a hydrophobic frit and concentrated under reduced pressure And (4) shrinking. The resulting residue was purified by flash column chromatography on silica, eluting with 0-10% MeOH in DCM. Further purification by reverse phase chromatography eluting with 30-80% MeCN in 0.1% formic acid additive solution afforded the title compound (0.02mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.49 min, M/z 452.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.39 min, M/z 452.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝6.1Hz,1H),7.74(dd,J＝1.8,7.7,1H),7.50-7.37(m,5H),7.14(d,J＝8Hz,1H),7.03(td,J＝1.0,7.5Hz,1H),6.39(br s,2H),5.32(d,J＝53.6Hz,1H),4.94-4.83(m,1H),4.53(d,J＝6.1Hz,2H),3.89(s,3H),2.31-1.79(m,6H)。

Example 42: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ [ (3S) -3-piperidinyl ] methyl ] pyrazole-4-carboxamide

(3S) -3- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester

Purification by flash column chromatography on silica eluting with 0-50% EtOAc in heptane afforded the title compound (0.72mmol) as a colorless oil after elution of (3S) -3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (0.82mmol) and methanesulfonyl chloride (0.86 mmol). UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 316.1[ M + Na ]]⁺。

(3S) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] carbonyl]Methyl radical]Phenyl radical] Pyrazol-1-yl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester

General procedure N, purification by silica gel flash column chromatography, of 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical ]Phenyl radical]-1H-pyrazole-4-carboxamide (0.23mmol) and (3S) -3- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester (0.47mmol) to give the title compound and (3S) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methyl-4-carbonyl ] amino acidOxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-2-yl]Methyl radical]Tert-butyl piperidine-1-carboxylate (0.13mmol), as a mixture of regioisomers as a beige solid. UPLC-MS (ES)⁺Short acidic): 1.59 and 1.60 min, M/z 563.3[ M + H [ ]]⁺。

3-amino-5- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ [ (3S) -3-piperidinyl]First of all Base of]Pyrazole-4-carboxamides and 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-[[(3S)-3- Piperidinyl group]Methyl radical]Pyrazole-4-carboxamides

Reacting (3S) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester and (3S) -3- [ [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-2-yl]Methyl radical]Tert-butyl piperidine-1-carboxylate (0.13mmol) was dissolved in DCM (5mL) and trifluoroacetic acid (3.3mmol) was added. The reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The residue was dissolved in MeOH and passed through a SPE SCX cartridge eluting with 0-100% 1M ammonia in MeOH. The mixture of regioisomers was then purified by mass directed semi-preparative HPLC to give 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1- [ [ (3S) -3-piperidinyl]Methyl radical]Pyrazole-4-carboxamide (0.01 mmol). UPLC-MS (ES)⁺Short acidic): 1.09 min, M/z 463.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.41 min, M/z 463.3[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝5.8Hz,1H),8.42(s,2H),7.75(dd,J＝7.5,1.5Hz,1H),7.50-7.40(m,5H),7.16(d,J＝8.2Hz,1H),7.06-7.03(m,1H),6.36(s,2H),4.55(d,J＝5.8Hz,2H),3.90(s,3H),3.82(d,J＝7.1Hz,2H),2.91-2.86(m,2H),2.40-2.38(m,2H),2.03-1.99(m,1H),1.69-1.62(m,2H),1.40-1.34(m,1H),1.21-1.15(m,1H)。

Example 43: 5-amino-1- (4-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (4-fluorophenyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, was performed by contacting 4- (fluorophenyl) hydrazine hydrochloride (0.68mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile gave the title compound (0.41mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.94 min, M/z 359.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4-fluorophenyl) pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed by reacting 5-amino-3- (4-bromophenyl) -1- (4-fluorophenyl) pyrazole-4-carbonitrile (0.41mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.57mmol) gave the title compound (0.38mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 442.2[ M + H ] ]⁺。

5-amino-1- (4-fluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, after further purification by mass directed semi-preparative HPLC, N- [ [4- [ 5-amino-4-cyano-1- (4-fluorophenyl) pyrazol-3-yl ] was]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.33mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.52 min, M/z 460.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.45 min, M/z 460.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.1Hz,1H),7.77(dd,J＝7.7,1.7Hz,1H),7.66-7.63(m,2H),7.56-7.54(m,2H),7.51-7.44(m,3H),7.41(m,2H),7.16(d,J＝8.1Hz,1H),7.07-7.03(m,1H),6.47(s,2H),4.57(d,J＝6.1Hz,2H),3.91(s,3H)。

Example 44: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (p-tolyl) Pyrazole-4-carboxamides

5-amino-3- (4-bromophenyl) -1- (p-tolyl) pyrazole-4-carbonitrile

General procedure H, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed by contacting p-tolylhydrazine hydrochloride (0.34mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile gave the title compound (0.29mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 2.00 min, M/z 353.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (p-tolyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, afforded trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.30mmol) and 5-amino-3- (4-bromophenyl) -1- (p-tolyl) pyrazole-4-carbonitrile (0.21mmol) gave the title compound (0.09mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.75 min, M/z 438.3[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (p-tolyl) pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, further purification by preparative HPLC, gave N- [ [4- [ 5-amino-4-cyano-1- (p-tolyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.09mmol) gave the title compound (0.01mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.57 min, M/z 456.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.59 min, M/z 456.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝5.9Hz,1H),7.77(dd,J＝7.7,1.8Hz,1H),7.55-7.53(m,2H),7.51-7.44(m,5H),7.34-7.33(m,2H),7.16(d,J＝8.6Hz,1H),7.07-7.03(m,1H),6.41(s,2H),4.56(d,J＝6.2Hz,2H),3.91(s,3H),2.38(s,3H)。

Example 45: 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Benzene and its derivatives Base of]Pyrazol-1-yl]Benzoic acid methyl ester

4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Benzoic acid methyl ester

Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure H gave methyl 4-chlorobenzoate (0.55mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.46mmol) gave the title compound (0.27mmol) as an orange solid. UPLC-MS (ES) ⁺Short acidic): 1.96 min, M/z 397.1[ M]⁺。

4- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Benzene and its derivatives Formic acid methyl ester

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was used to purify 4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Methyl benzoate (0.27mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]The title compound (0.20mmol) was obtained as a white solid. UPLC-MS (ES)⁺Short acidic): 1.70 min, 482.3M/z [ M + H]⁺。

4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 1-radical]Benzoic acid methyl ester

General procedure M, further purification by mass directed preparative HPLC, was performed using 4- [ 5-amino-4-cyano-3-[4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Methyl benzoate (0.20mmol) gave the title compound (0.01mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 500.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.52 min, M/z 500.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.3Hz,1H),8.10(d,J＝8.5Hz,2H),7.83(d,J＝8.5Hz,2H),7.76(dd,J＝7.7,1.7Hz,1H),7.57(d,J＝8.4Hz,2H),7.50-7.45(m,3H),7.16(d,J＝8.4Hz,1H),7.04(t,J＝7.4Hz,1H),6.7(s,2H),4.58(d,J＝6.0Hz,2H),3.90(s,3H),3.89(s,3H)。

Example 46: 5-amino-1- [ (1S, 3S) -3-hydroxycyclopentyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

[ (1S) -3- [ (1S) -5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] cyclopentyl ]2, 2-dimethylpropionate

To 5-amino-1- [ (1S, 3R) -3-hydroxycyclopentyl group]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (160mg, 0.36mmol) in THF (1.8mL) was added triphenylphosphine (0.71mmol) and trimethylacetic acid (0.53mmol) and cooled to 0 deg.C. Diisopropyl azodicarboxylate (0.71mmol) was then added and the mixture was stirred at this temperature for 15 minutes, then warmed to room temperature and stirred at this temperature for 48 hours. The reaction was concentrated and then purified by flash column chromatography on silica, eluting with 0-100% EtOAc in heptane, to give the title compound (0.18 mmol). UPLC-MS (ES)⁺Short acidic): 1.73 min, 534.3M/z [ M + H]⁺。

5-amino-1- [ (1S, 3S) -3-hydroxycyclopentyl radical]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

To [ (1S, 3S) -3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) ammonia [ ]Base of]Methyl radical]Phenyl radical]Pyrazol-1-yl]Cyclopentyl group]To a solution of dimethyl 2, 2-propionate (0.22mmol) in THF (1mL) was added lithium hydroxide (1.79 mmol). The reaction mixture was then heated to 80 ℃ for 4 days, cooled and diluted with DCM and partitioned with water. The mixture was passed through a phase separator and the aqueous layer was extracted several times with DCM. The organic layers were combined and concentrated. The resulting residue was purified by flash column chromatography on silica eluting with 0-10% MeOH in DCM to give the title compound (0.05mmol, 23% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.28 min, M/z 450.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.86 min, M/z 450.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆δ 8.72(t, J ═ 6.1Hz,1H),7.74(dd, J ═ 1.8,7.6Hz,1H),7.50-7.45(m,1H),7.43(d, J ═ 8.3Hz,2H),7.39(d, J ═ 8.3Hz,2H),7.15(d, J ═ 8.5Hz,1H),7.03(td, J ═ 1.0,7.5Hz,1H),6.33(br.s,2H),4.82 (quintuple, J ═ 8.1,15.3Hz,1H),4.62(d, J ═ 3.4Hz,1H),4.54(d, J ═ 6.1Hz,2H),4.35-4.28(m,1H, 3.89 (m, 3.0, 3.4H), 1.06 (m,1H), 1.06 (m,2H), 1.06-1H, 1.26H, 1H, and 1.06.

Example 47: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (o-tolyl) Pyrazole-4-carboxamides

5-amino-3- (4-bromophenyl) -1- (o-tolyl) pyrazole-4-carbonitrile

Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure H gave o-tolylhydrazine hydrochloride (0.68mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile gave the title compound (0.53mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.94 min, M/z 355.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (o-tolyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, afforded trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.30mmol) and 5-amino-3- (4-bromophenyl) -1- (o-tolyl) pyrazole-4-carbonitrile (0.21mmol) gave the title compound (0.19mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 438.3[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (o-tolyl) pyrazole-4-carboxylic acid ester Amides of carboxylic acids

General procedure M, further purification by flash column chromatography on silica gel, eluting with 0-10% MeOH in DCM, N- [ [4- [ 5-amino-4-cyano-1- (o-tolyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.19mmol) gave the title compound (0.06mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 456.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.42 min, M/z 456.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.81(t,J＝6.0Hz,1H),7.82(dd,J＝7.4,1.7Hz,1H),7.60-7.58(m,2H),7.56-7.49(m,5H),7.45-7.40(m,2H),7.21(d,J＝8.2Hz,1H),7.10(t,J＝7.3Hz,1H),6.21(s,2H),4.62(d,J＝6.0Hz,2H),3.96(s,3H),2.19(s,3H)。

Example 48: 5-amino-1- (3-hydroxycyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

Sodium borohydride (836mg, 22.10mmol) was added to 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (3-oxocyclohexyl) pyrazole-4-carboxamide (0.44mmol) in MeOH (15mL) and cooled to 0 ℃. The reaction was allowed to return to room temperature and once gas evolution ceased, it was then heated to 60 ℃ for 14 hours. The reaction was cooled back to 0 ℃ and more sodium borohydride was added (22.1mmol) and the reaction was heated again to 60 ℃. The mixture was then cooled and quenched with ammonium chloride, then extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the title compound (0.09mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.30 min, M/z 464.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.90 min, M/z 464.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.75(dd,J＝7.5,1.8Hz,1H),7.51-7.37(m,5H),7.17-7.13(m,1H),7.04(td,J＝7.6,0.9Hz,1H),6.32(s,2H),4.70(d,J＝4.9Hz,1H),4.54(d,J＝6.0Hz,2H),4.17-4.06(m,1H),3.90(s,3H),3.56-3.45(m,1H),2.05-1.96(m,1H),1.88-1.80(m,1H),1.79-1.71(m,2H),1.71-1.61(m,1H),1.61-1.51(m,1H),1.39-1.21(m,1H),1.15-1.01(m,1H)。

Example 49: 5-amino-1- [4- (hydroxymethyl) phenyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

To 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]To a solution of benzoic acid (0.05mmol) in THF (3mL) was added borane-dimethyl sulfide (0.24 mmol). The reaction mixture was stirred at RT for 5h, quenched by addition of saturated ammonium chloride solution (1mL) and partitioned. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by mass directed semi-preparative HPLC to give the title compound (0.01mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.31 min, M/z 472.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.95 min, M/z 472.3[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.0Hz,1H),7.78-7.72(m,1H),7.59-7.51(m,4H),7.51-7.41(m,5H),7.18-7.13(m,1H),7.06-7.01(m,1H),6.44(s,2H),5.35-5.27(m,1H),4.60-4.52(m,4H),3.90(s,3H)。

Example 50: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (m-tolyl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (m-tolyl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-80% EtOAc in heptane, afforded 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.29mmol) and m-tolylhydrazine (0.34mmol) gave the title compound (0.21mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 2.02 min, M/z 353.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (m-tolyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica eluting with 10-100% EtOAc in heptane, afforded trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.39mmol) and 5-amino-3- (4-bromophenyl) -1- (m-tolyl) pyrazole-4-carbonitrile gave the title compound (0.19mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.76 min, M/z 438.3[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (m-tolyl) pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, gave N- [ [4- [ 5-amino-4-cyano-1- (M-tolyl) pyrazol-3-yl ]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.19mmol) gave the title compound (0.02 mmol). UPLC-MS (ES)⁺Short acidic): 1.57 min, M/z 456.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.59 min, M/z 456.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.75(t,J＝6.2Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.57-7.52(m,2H),7.51-7.37(m,6H),7.24-7.19(m,1H),7.18-7.13(m,1H),7.07-7.01(m,1H),6.46(s,2H),4.56(d,J＝6.2Hz,2H),3.90(s,3H),2.39(s,3H)。

Example 51: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-pyridinyl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (3-pyridyl) pyrazole-4-carbonitrile

General procedure H, without triethylamine, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.42mmol) and 3-pyridylhydrazine (0.46mmol) gave the title compound (0.42mmol) as a white solid. LC-MS (ES)⁺Short acidic): 5.21 min, M/z 339.9[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-pyridinyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM, was performed using 5-amino-3- (4-bromophenyl) -1- (3-pyridyl) pyrazole-4-carbonitrile (0.42mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.46mmol) gave the title compound (0.30mmol) as an off-white solid. LC-MS (ES)⁺Short acidic): 4.44 min, M/z 425.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1- (3-pyridinyl) pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, gave N- [ [4- [ 5-amino-4-cyano-1- (3-pyridinyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.14mmol) gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.29Min, M/z 443.4[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.86 min, M/z 443.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.86(d,J＝2.5Hz,1H),8.76(t,J＝6.2Hz,1H),8.60(dd,J＝4.9,1.6Hz,1H),8.06-8.03(m,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.60-7.54(m,3H),7.50-7.44(m,3H),7.17-7.14(m,1H)7.03(td,J＝7.7,1.1Hz,1H),6.63(br s,2H),4.56(d,J＝6.1Hz,2H),3.90(s,3H)。

Example 52: 5-amino-1-indan-2-yl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- (indan-2-ylideneamino) carbamic acid tert-butyl ester

General procedure E, purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane, was followed by 2-indanone (1.14mmol) and tert-butyl carbazate (1.36mmol) to give the title compound (0.89mmol) as a light yellow solid.¹H NMR(400MHz,DMSO-d₆,δ):9.54(s,1H),7.31-7.26(m,2H),7.23-7.20(m,2H),3.72(s,2H),3.69(s,2H),1.47(s,9H)。

Indan-2-ylhydrazine hydrochloride

Tert-butyl N- (indan-2-ylideneamino) carbamate (0.89mmol) was dissolved in THF (5mL) and borane dimethylsulfide complex solution (2M in THF, 1.52mmol) was added. The reaction was stirred at room temperature for 2 hours until TLC showed complete consumption of starting material. Saturated NH for reaction₄Aqueous Cl solution was quenched and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved with hydrogen chloride solution (1.25M in MeOH, 9.04mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure to give crude indan-2-ylhydrazine hydrochloride (0.89 mmol). UPLC-MS: (ES) ⁺Short acidic): 0.83 min, M/z 149.0[ M-HCl + H]⁺。

5-amino-3- (4-bromophenyl) -1-indan-2-yl-pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-80% EtOAc in heptane, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.68mmol) and indan-2-ylhydrazine hydrochloride (0.82mmol) gave the title compound (0.45mol) as an orange solid. UPLC-MS: (ES)⁺Short acidic): 2.09 min, M/z 381.1[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed with 5-amino-3- (4-bromophenyl) -1-indan-2-yl-pyrazole-4-carbonitrile (0.45mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.63mmol) gave the title compound benzamide (0.34mol) as an off-white solid.¹H NMR(400MHz,CDCl₃,δ):8.27(dd,J＝7.8,1.8Hz,1H),8.24-8.19(m,1H),7.91-7.89(m,2H),7.50-7.47(m,1H),7.44-7.41(m,2H),7.28-7.25(m,4H),7.14-7.10(m,1H),7.01-6.99(m,1H),5.09-5.01(m,1H),4.73(d,J＝5.6Hz,2H),4.27(s,2H),3.95(s,3H),3.61(dd,J＝16.1,7.1Hz,2H),3.45(dd,J＝16.4,8.7Hz,2H)。

5-amino-1-indan-2-yl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure L, purification by flash column chromatography eluting with 0-10% MeOH in DCM, was performed to give N- [ [4- (5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl) phenyl ] residue ]Methyl radical]-2-methoxy-benzamide (0.11mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.65 min, M/z 482.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.85 min, M/z 482.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝6.0Hz,1H),7.74(dd,J＝6.2,1.7Hz,1H),7.50-7.38(m,5H),7.25-7.23(m,2H),7.19-7.14(m,3H),7.05-7.01(m,1H),6.45(s,2H),5.23-5.15(m,1H),4.53(d,J＝6.0Hz,2H),3.89(s,3H),3.39-3.28(m,4H)。

Example 53: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2-pyridinyl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2-pyridyl) pyrazole-4-carbonitrile

General procedure H, without triethylamine, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (1.24mmol) and 2-hydrazinopyridine (1.36mmol) gave the crude title compound (1.24mmol, assumed quantitative) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.03 min, M/z 340.1[ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-pyridinyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed using 5-amino-3- (4-bromophenyl) -1- (2-pyridyl) pyrazole-4-carbonitrile (0.44mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.48mmol) gave the title compound (0.31mmol, 70% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 425.1[ M + H ]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2-pyridinyl) pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was used to purify N- [ [4- [ 5-amino-4-cyano-1- (2-pyridyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.31mmol) gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 443.1[ M + H]⁺。UPLC-MS(ES⁺Long acidity): 3.67 min, M/z 443.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.3Hz,1H),8.49-8.47(m,1H),8.01-7.96(m,1H),7.88-7.86(m,1H),7.76(dd,J＝7.7,1.9Hz,1H),7.69(br s,2H),7.59-7.56(m,2H),7.51-7.46(m,3H),7.34-7.31(m,1H),7.17-7.15(m,1H),7.04(td,J＝7.6,0.8Hz,1H),4.58(d,J＝6.0Hz,2H),3.91(s,3H)。

Example 54: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (4-pyridinyl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (4-pyridyl) pyrazole-4-carbonitrile

Following general procedure H, without triethylamine, 4-pyridylhydrazine (1.44mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (1.31mmol) gave the crude title compound (1.31mmol) as a white solid. LC-MS (ES)⁺Short acidic): 4.66 min, M/z 341.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4-pyridinyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed using 5-amino-3- (4-bromophenyl) -1- (4-pyridyl) pyrazole-4-carbonitrile (0.44mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group ]Methyl radical]Potassium borane (0.48mmol) gave the title compound (0.36mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 425.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (4-pyridinyl) pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

General procedure M, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was used to purify N- [ [4- [ 5-amino-4-cyano-1- (4-pyrido) pyridinePyridyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.36mmol) gave the title compound (0.13mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.19 min, M/z 443.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.67 min, M/z 443.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.2Hz,1H),8.69-8.67(m,2H),7.75(dd,J＝7.6,1.8Hz,1H),7.73-7.71(m,2H),7.58-7.55(m,2H),7.50-7.45(m,3H),7.17-7.14(m,1H),7.03(td,J＝7.6,1.0Hz,1H),6.81(br s,2H),4.57(d,J＝6.0Hz,2H),3.90(s,3H)。

Example 55: 3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] cyclohexanecarboxylic acid ethyl ester (isomer 1)

3- (tert-Butoxycarbonylhydrazono) cyclohexanecarboxylic acid ethyl ester

General procedure E, ethyl 3-oxocyclohexanecarboxylate (5.04mmol) and tert-butyl carbazate (5.30mmol) were stirred at room temperature for 3 hours. The reaction mixture was quenched with MeOH, then concentrated under reduced pressure. The residue was diluted with DCM and saturated NH₄And (4) washing with an aqueous Cl solution. The organic layer was passed through a phase separator and concentrated under reduced pressure to give the title compound (3.77mmol) as crude. UPLC-MS (ES) ⁺Short acidic): 1.55 min, M/z 285.1[ M + H ]]⁺。

3- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Cyclohexanecarboxylic acid ethyl ester

General procedure O, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, ethyl 3- (tert-butoxycarbonylhydrazono) cyclohexanecarboxylate (3.77mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile gave the title compound (isomer 1, 1.47mmol) and the title compound (isomer 2, 1.21 mmol). UPLC-MS (ES)⁺Short acidic, isomer 1): 2.05 min, M/z 419.1[ M +2 ]]⁺。UPLC-MS(ES⁺Short acidic, isomer 2): 2.11 min, M/z 419.1[ M +2 ]]⁺。

3- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Ring (C) Hexane Carboxylic acid ethyl ester (isomer 1)

General procedure K, coupling of trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (1.11mmol) and 3- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]Methyl cyclohexanecarboxylate (isomer 1, 0.72mmol) was stirred at 80 ℃ for 16 h. Passing the reaction mixture throughThe pad was filtered and washed with DCM. The solution was diluted with water and extracted with DCM (× 3). The combined organic layers were passed through a phase separator and concentrated under reduced pressure to give the crude title compound (isomer 1, 0.72 mmol). UPLC-MS (ES) ⁺Short acidic): 1.83 min, M/z 502.3[ M + H]⁺。

3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 1-radical]Cyclohexanecarboxylic acid ethyl ester (isomer 1)

General procedure L, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, was performed to give 3- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazol-1-yl]Ethyl cyclohexanecarboxylate (isomer 1, 0.30mmol) gave the title compound (isomer 1, 0.03mmol, 10%). UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 520.4[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.76 min, M/z 520.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.39(m,5H),7.17-7.15(m,1H),7.04(td,J＝7.6,1.0Hz,1H),6.27(br s,2H),4.55(d,J＝6.2Hz,2H),4.34-4.25(m,1H),4.15-4.09(m,2H),3.90(s,3H),3.01-2.94(m,1H),2.11-2.04(m,2H),1.93-1.43(m,6H),1.22(t,J＝6.9Hz,3H)。

Example 56: 5-anilino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-anilino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

To a solution of 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.15mmol), phenylboronic acid (0.30mmol), and copper (II) acetate (0.15mmol) in DCM (1mL) was added triethylamine (0.30 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. Purification by flash column chromatography on silica eluting with 20-60% EtOAc in heptane afforded the title compound (0.10mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 2.30 min, M/z 407.0[ M]⁺。

N- [ [4- (5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure K, purification by flash column chromatography on silica gel eluting with 20-80% EtOAc in heptane, gave 5-anilino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.10mmol) as a white powder. UPLC-MS (ES)⁺Short acidic): 2.04 min, M/z 492.1[ M + H ]]⁺。

5-anilino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid esters Amines as pesticides

General procedure L, purification by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM, was performed with N- [ [4- (5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.09mmol) gave the title compound (0.07mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.88 min, M/z 510.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.47 min, M/z 510.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.0Hz,1H),7.83(s,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.67(d,J＝8.2Hz,2H),7.52-7.44(m,1H),7.35(d,J＝8.2Hz,2H),7.22-7.09(m,4H),7.08-6.95(m,2H),6.80-6.72(m,1H),6.61(d,J＝7.7Hz,2H),4.67-4.57(m,1H),4.53(d,J＝6.0Hz,2H),3.91(s,3H),2.01-1.76(m,6H),1.63-1.48(m,2H)。

Example 57: 5-amino-1- [4- (dimethylcarbamoyl) cyclohexyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (isomer 1, example 57a, and isomer 2, example 57b)

5-amino-1- [4- (dimethylcarbamoyl) cyclohexyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

Propylphosphonic anhydride solution (50 wt% in EtOAc, 0.14mmol) was added to dimethylamine (2M in THF, 0.92mmol), N-diisopropylethylamine (0.27mmol) and 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Cyclohexanecarboxylic acid (0.09mmol) in THF (0.50 mL). The reaction mixture was heated to 40 ℃ and stirred for 16 hours. Additional dimethylamine (2M in THF, 0.92mmol), N-diisopropylethylamine (0.27mmol) and propylphosphonic anhydride (50 wt% in EtOAc, 0.14mmol) were added sequentially and the reaction mixture was held at 40 ℃ for 48 h then cooled to room temperature. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a hydrophobic frit and all volatiles were removed under reduced pressure. Further purification by flash column chromatography on silica eluting with 0-8% MeOH in DCM gave the title compound (isomer 1: 0.04mmol, 42% yield) and the title compound (isomer 2: 0.02mmol) as white solids. UPLC-MS (ES) ⁺Short acidity; isomer 1): 1.40 min, M/z 519.3[ M + H ]]⁺。UPLC-MS(ES⁺Long acidity; isomer 1): 3.71 min, M/z519.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ, isomer 1):8.73(t, J ═ 6.0Hz,1H),7.76(dd, J ═ 7.7,1.7Hz,1H),7.52 to 7.38(m,5H),7.16(d, J ═ 8.4Hz,1H),7.08 to 7.01(m,1H),6.30(s,2H),4.55(d, J ═ 6.0Hz,2H),4.21 to 4.10(m,1H),3.91(s,3H),3.00(s,3H),2.90 to 2.82(m,1H),2.80(s,3H),2.22 to 2.08(m,2H),2.03 to 1.90(m,2H),1.74 to 1.64(m,2H),1.64 to 1.53(m, 2H).

UPLC-MS(ES⁺Short acidity; isomer 2): 1.37 min, M/z519.2[ M + H]⁺。UPLC-MS(ES⁺Long acidity; isomer 2): 3.67 min, M/z519.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ, isomer 2) 8.74(t, J ═ 6.1Hz,1H),7.78-7.73(m,1H),7.52-7.37(m,5H),7.16(d, J ═ 9.0Hz,1H),7.08-7.01(m,1H),6.35(s,2H),4.55(d, J ═ 6.0Hz,2H),4.20-4.06(m,1H),3.90(s,3H),3.03(s,3H),2.81(s,3H),2.73-2.61(m,1H),1.96-1.82(m,4H),1.82-1.73(m,2H),1.62-1.44(m, 2H).

Example 58: 3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] cyclohexanecarboxylic acid ethyl ester (isomer 2)

3- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Ring (C) Hexane Carboxylic acid ethyl ester (isomer 2)

General procedure K, using 3- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl ]Cyclohexanecarboxylic acid ethyl ester (isomer 2, 0.72mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (1.11mmol) gave the crude title compound (isomer 2, 0.72mmol, assuming quantitative yield). UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 502.3[ M + H]⁺。

3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 1-radical]Cyclohexanecarboxylic acid ethyl ester (isomer 2)

General procedure L, Rapid on silica gelPurifying by column chromatography, eluting with 0-10% MeOH in DCM to obtain 3- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Ethyl cyclohexanecarboxylate (isomer 2, 0.30mmol) gave the title compound (isomer 2, 0.02mmol, 6% yield). UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 520.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.23 min, M/z 520.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.52-7.38(m,5H),7.17-7.15(m,1H),7.04(td,J＝7.5,0.7Hz,1H),6.35(br s,2H),4.55(d,J＝6.1Hz,2H),4.23-4.12(m,1H),4.11-4.02(m,2H),3.90(s,3H),2.49-2.43(m,1H),2.08-1.99(m,1H),1.94-1.66(m,5H),1.51-1.36(m,1H),1.35-1.21(m,1H),1.17(t,J＝7.0Hz,3H)。

Example 59: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-oxoindan-1-yl) pyrazole-4-carboxamide

N- [ (3-oxoindan-1-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, purification by flash column chromatography on silica gel eluting with 10-50% EtOAc in heptane, was followed by 1, 3-indandione (1.37mmol) and tert-butyl carbazate (1.44mmol) to give the title compound (0.86mmol, 62% yield) as a yellow solid. ¹H NMR(400MHz,DMSO-d₆,δ):10.19(s,1H),7.90-7.88(m,1H),7.81-7.76(m,1H),7.63-7.59(m,1H),7.63-7.59(m,1H),3.41(s,2H),1.50(s,9H)。

N- [ (3-oxoindan-1-yl) amino group]Carbamic acid tert-butyl ester

General procedure F, Using N- [ (3-oxoindan-1-ylidene) amino group]Tert-butyl carbamate (0.75mmol) gave the crude title compound (0.57mmol) as a colorless oil. UPLC-MS (ES)⁺Short acidic): 1.41 min, M/z 285.1[ M + Na ]]⁺。

[(3-oxoindan-1-yl) amino]Ammonium; 2,2, 2-Trifluoroacetate salt

To N- [ (3-oxoindan-1-yl) amino group]To a solution of tert-butyl carbamate (0.57mmol) in DCM (5mL) was added TFA (60 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the crude title compound (0.57 mmol).¹H NMR(400MHz,DMSO-d₆,δ):7.89-7.35(m,4H),5.21-5.10(m,1H),3.19-3.05(m,1H),2.88-2.75(m,1H)。

5-amino-3- (4-bromophenyl) -1- (3-oxoindan-1-yl) pyrazole-4-carbonitrile

Following general procedure H, purification by flash column chromatography on silica eluting with 0-80% EtOAc in heptane, yielded 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.46mmol) and [ (3-oxoindan-1-yl) amino group]Ammonium; 2,2, 2-Trifluoroacetate (0.10mmol) gave the title compound (0.10mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.84 min, M/z 394.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-oxoindan-1-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed with 5-amino-3- (4-bromophenyl) -1- (3-oxoindan-1-yl) pyrazole-4-carbonitrile (0.1mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.13mmol) gave the title compound (0.03mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 478.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (3-oxoindan-1-yl) pyri Azole-4-carboxamides

General procedure L, after purification by mass directed semi-preparative HPLC, N- [ [4- [ 5-amino-4-cyano-1- (3-oxoindan-1-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.03mmol) gave the title compound (0.02mmol) as an off-white solid. UPLC-CMS (ES)⁺Short acidity): 1.47 min, M/z 496.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.74 min, M/z 496.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.69(t,J＝6.0Hz,1H),7.75-7.71(m,3H),7.56(t,J＝7.8Hz,1H),7.49-7.47(m,2H),7.34(s,4H),7.14(d,J＝6.0Hz,1H),7.05-7.00(m,1H),6.72(s,2H),6.20(dd,J＝7.7,3.5Hz,1H),4.50(d,J＝6.1Hz,2H),3.87(s,3H),3.25(dd,J＝18.5,7.6Hz,1H),3.03(dd,J＝18.6,3.4Hz,1H)。

Example 60: 1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5- (methylamino) pyrazole-4-carboxamide

3- (4-bromophenyl) -1-cyclopentyl-5- (methyleneamino) pyrazole-4-carbonitrile

To a solution of 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol) in MeOH (3mL) was added paraformaldehyde (0.91mmol) and sodium methoxide (25 wt.% in MeOH, 1.81 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and then partitioned between DCM and water. The aqueous layer was extracted with DCM (× 3) and the combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure to give the crude title compound (0.30 mmol). UPLC-MS (ES) ⁺Short acidic): 2.09 min, M/z 377.0[ M + MeOH +2]⁺。

3- (4-bromophenyl) -1-cyclopentyl-5- (methylamino) pyrazole-4-carbonitrile

To a solution of 3- (4-bromophenyl) -1-cyclopentyl-5- (methyleneamino) pyrazole-4-carbonitrile (0.30mmol) in MeOH (3mL) at 0 deg.C was added sodium borohydride (3.02 mmol). The reaction mixture was stirred at room temperature for 72 hours. Then carefully use saturated NH₄And (4) quenching by using a Cl aqueous solution. The aqueous layer was then extracted with DCM (× 3) and the combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure. Purification by flash column chromatography on silica eluting with 20-60% EtOAc in heptane afforded the title compound (0.20mmol) as a white solid. UPLC-MS(ES⁺Short acidic): 2.14 min, M/z 347.0[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-1-cyclopentyl-5- (methylamino) pyrazol-3-yl ] amino]Phenyl radical]Methyl radical]-2-methoxy-benzyl Amides of carboxylic acids

General procedure K, purification by column chromatography on silica gel eluting with 20-60% EtOAc in heptane, was performed by contacting 3- (4-bromophenyl) -1-cyclopentyl-5- (methylamino) pyrazole-4-carbonitrile (0.20mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.22mmol) gave the title compound (0.11mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 430.1[ M + H ] ]⁺。

1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5- (methylamino) pyrazole-4- Carboxamides

General procedure L, purification by flash column chromatography on silica gel eluting with 0-4% MeOH in DCM and by reverse phase column chromatography eluting with 20-70% MeCN in 1% formic acid in water, leaving N- [ [4- [ 4-cyano-1-cyclopentyl-5- (methylamino) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.11mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 448.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.30 min, M/z 448.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.54-7.46(m,3H),7.37-7.34(m,2H),7.17-7.15(m,1H),7.07-7.02(m,1H),5.85-5.81(m,1H),4.73-4.64(m,1H),4.52(d,J＝6.0Hz,2H),3.90(s,3H),2.83(d,J＝5.6Hz,3H),2.06-1.89(m,4H),1.89-1.76(m,2H),1.69-1.54(m,2H)。

Example 61: 5-amino-1- (2, 5-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2, 5-difluorophenyl) pyrazole-4-carbonitrile

Following general procedure H, purification by flash column chromatography on silica gel eluting with 0-60% EtOAc in heptane at RT, afforded 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and (2, 5-difluorophenyl) hydrazine (0.76mmol) gave the title compound (0.24mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.92 min, M/z 375.0[ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2, 5-difluorophenyl) pyrazol-3-yl group ]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with 5-amino-3- (4-bromophenyl) -1- (2, 5-difluorophenyl) pyrazole-4-carbonitrile (0.24mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.26mmol) gave the title compound (0.24mmol) as a dark yellow gum. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 460.2[ M + H ]]⁺。

5-amino-1- (2, 5-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure M, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was performed with N- [ [4- [ 5-amino-4-cyano-1- (2, 5-difluorophenyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.26mmol) to give the title compound (0.03mmol, 10% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 478.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.42 min, M/z 478.3[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.1Hz,1H),7.76(dd,J＝1.8,7.7Hz,1H),7.57-7.41(m,8H),7.17-7.15(m,1H),7.07-7.01(m,1H),6.54(s,2H),4.57(d,J＝6.1Hz,2H),3.90(s,3H)。

Example 62: 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] -3-methyl-phenyl ] pyrazole-4-carboxamide

N- [ (4-bromo-2-methyl-phenyl) methyl group]-2-methoxy-benzamide

To a solution of 4-bromo-2-methyl-benzonitrile (5.10mmol) in THF (30mL) at 0 deg.C was added a solution of borane tetrahydrofuran complex (1M in THF, 15.30 mmol). The solution was stirred at 0 ℃ for 30 minutes, then warmed to room temperature and stirred for 18 hours. The reaction was quenched dropwise with MeOH. The volatiles were concentrated under reduced pressure and the residue was partitioned with aqueous NaOH (1M) and EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude (4-bromo-2-methyl-phenyl) methylamine, which was then dissolved in THF (20mL) and N, N-diisopropylethylamine (15.29mmol) was added. The solution was cooled to 0 ℃ and then 2-methoxybenzoyl chloride (5.61mmol) was added. It was then stirred at 0 ℃ for 20 minutes, then the reaction was warmed to room temperature and stirred for 16 hours. Saturated NH for reaction₄Aqueous Cl was quenched, worked up and purified (column chromatography, 0-30% EtOAc in heptane) to provide the title compound (2.49 mmol). UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 336.1[ M +2 ]]⁺。

2-methoxy-N- [ [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]First of all Base of]Benzamide derivatives

General procedure R, using N- [ (4-bromo-2-methyl-phenyl) methyl]-2-methoxy-benzamide gave the crude title compound (2.49 mmol). UPLC-MS (ES) ⁺Short acidic): 1.95 min, M/z 382.2[ M + H ]]⁺。

N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-methyl-phenyl]Methyl radical]-2-methoxy-benzoyl Amines as pesticides

General procedure D, purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, was performed to give 2-methoxy-N- [ [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-bisOxaborane-2-yl) phenyl]Methyl radical]Benzamide (2.04mmol) gave the title compound (0.48 mmol). UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 362.3[ M + H ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-methyl-phenyl]Methyl radical]-2-methoxy- Benzamide derivatives

Cesium carbonate (0.63mmol) was added to N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-methyl-phenyl ] -N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl)]Methyl radical]-2-methoxy-benzamide (0.48mmol) and bromocyclopentane (0.53mmol) in DMF (5 mL). The reaction was heated to 80 ℃ for 16 hours. After workup and purification by flash column chromatography eluting with 0-1% MeOH in DCM, the title compound was obtained (0.15 mmol). UPLC-MS (ES)⁺Short acidic): 1.81 min, M/z 430.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]-3-methyl-phenyl]Pyrazole- 4-carboxamides

General procedure L, purification by flash column chromatography on silica gel eluting with 25-100% EtOAc in heptane, was used to purify N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-methyl-phenyl]Methyl radical]-2-methoxy-benzamide (0.15mmol) gave the title compound (0.04 mmol). UPLC-MS (ES)⁺Short acidic): 1.70 min, M/z 448.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.04 min, M/z 448.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.61(t,J＝5.8Hz,1H),7.73(dd,J＝7.7,1.7Hz,1H),7.50-7.46(m,1H),7.35(d,J＝7.6Hz,1H),7.30-7.23(m,2H),7.15(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.32(s,2H),4.64-4.56(m,1H),4.50(d,J＝5.8Hz,2H),3.89(s,3H),2.36(s,3H),2.03-1.84(m,4H),1.84-1.73(m,2H),1.63-1.54(m,2H)。

Example 63: 5-amino-1- (3-hydroxyindan-1-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (3-hydroxyindan-1-yl) amino group]Carbamic acid tert-butyl ester

Reacting tert-butyl N- [ (3-oxoindan-1-ylidene) amino group]Tert-butyl carbamate (0.58mmol) was dissolved in THF (5mL) and borane dimethyl sulfide complex solution (2M in THF, 3.45mmol) was added. The reaction was stirred at RT for 14 h. Adding saturated NH₄Aqueous Cl, workup and concentration gave the crude title compound (0.57mmol) as a pale orange solid. UPLC-MS (ES)⁺Short acidic): 1.57 min, M/z 287.0[ M + Na ]]⁺。

[ (3-hydroxyindan-1-yl) amino]Ammonium; 2,2, 2-Trifluoroacetate salt

To N- [ (3-hydroxyindan-1-yl) amino group]To a solution of tert-butyl carbamate (0.57mmol) in DCM (5mL) was added trifluoroacetic acid (57mmol) and the reaction mixture was stirred at room temperature for 1 h. Concentrating the volatiles under reduced pressure to obtain crude [ (3-hydroxyindan-1-yl) amino group ]Ammonium; 2,2, 2-Trifluoroacetate (0.57 mmol).¹H NMR(400MHz,DMSO-d₆,δ):7.57-7.31(m,4H),5.04-4.99(m,1H),2.83-2.78(m,1H),2.09-1.98(m,1H)。

5-amino-3- (4-bromophenyl) -1- (3-hydroxyindan-1-yl) pyrazole-4-carbonitrile

General procedure H, purification by flash column chromatography on silica eluting with 0-80% EtOAc in heptane, was performed to give 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.46mmol) and [ (3-hydroxyindan-1-yl) amino group]Ammonium; 2,2, 2-Trifluoroacetate (0.55mmol) gave the title compound (0.28mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.87 min, 396.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-hydroxyindan-1-yl) pyrazol-3-yl ] amine]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, purification by flash column chromatography on silica eluting with 0-100% EtOAc in heptane, was used to purify 5-amino-3- (4-bromo)Phenyl) -1- (3-hydroxyindan-1-yl) pyrazole-4-carbonitrile (0.28mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.39mmol) gave the title compound (0.25mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.75 min, M/z 480.1[ M + H]⁺。

5-amino-1- (3-hydroxyindan-1-yl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

General procedure L, after purification by mass directed semi-preparative HPLC, the N- [ [4- [ 5-amino-4-cyano-1- (3-hydroxyindan-1-yl) pyrazol-3-yl group ]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.10mmol) gave the title compound (0.05mmol) as an off-white solid. UPL-CMS (ES)⁺Short acidic): 1.60 min, M/z 498.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.68 min, M/z 498.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.0Hz,1H),7.74(dd,J＝7.7,1.7Hz,1H),7.50-7.36(m,6H),7.34-7.30(m,1H),7.27-7.24(m,1H),7.14(d,J＝8.3Hz,1H),7.05-7.00(m,2H),6.58(s,2H),5.76-5.71(m,1H),5.68(d,J＝7.4Hz,1H),5.06-5.01(m,1H),4.52(d,J＝6.0Hz,2H),3.88(s,3H),2.89-2.82(m,1H),2.41-2.36(m,1H)。

Example 64: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, was followed by reaction of 5-amino-3- (4-bromophenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.27mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.30mmol) gave the title compound (0.19mmol, 72% yield) as a dark yellow gumA compound (I) is provided. UPLC-MS (ES)⁺Short acidic): 1.51 min, M/z 432.3[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-4-yl-pyrazole- 4-carboxamides

General procedure M, purification by flash column chromatography on silica eluting with 0-10% MeOH in DCM and then SPE SCX eluting with MeOH, afforded N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl) phenyl ]Methyl radical]-2-methoxy-benzamide (0.33mmol) gave the title compound (0.15mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 450.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.57 min, M/z 450.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.50-7.40(m,5H),7.17-7.15(m,1H),7.06-7.02(m,1H),6.38(s,2H),4.55(d,J＝6.0Hz,2H),4.40-4.32(m,1H),3.99-3.95(m,2H),3.90(s,3H),3.46-3.40(m,2H),2.03-1.94(m,2H),1.79-1.76(m,2H)。

Example 65: 5-amino-1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

8- (trifluoromethyl) -1, 4-dioxaspiro [4.5 ]]Decan-8-ols

To a solution of 1, 4-cyclohexanedione monovinylacetal (6.40mmol) in anhydrous THF (20mL) under a nitrogen atmosphere at 0 deg.C was added trimethyl (trifluoromethyl) silane (12.8mmol) followed by tetrabutylammonium fluoride (1.0M in THF, 13.4 mmol). The reaction mixture was then warmed to 25 ℃ and stirred for 2 hours. Saturated aqueous ammonium chloride (10mL) was then added. The reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure. Work-up and purification gave the title compound (5.83mmol) as a pale yellow oil.¹H NMR(400MHz,CDCl₃,δ):4.00-3.92(m,4H),1.97-1.88(m,4H),1.83-1.79(m,2H),1.69-1.67(m,2H)。

4-hydroxy-4- (trifluoromethyl) cyclohexanone

To 8- (trifluoromethyl) -1, 4-dioxaspiro [4.5 ]]To a solution of decan-8-ol (5.84mmol) in acetone (29mL) was added hydrochloric acid (4M, 8.75 mmol). The reaction mixture was stirred at room temperature for 18 h to afford, after workup and purification, the title compound (5.12mmol) as a white solid. ¹H NMR(400MHz,DMSO-d₆,δ):6.26(br s,1H),2.62-2.52(m,2H),2.19-2.15(m,2H),2.04-1.92(m,2H),1.79-1.62(m,2H)。

N- [ [ 4-hydroxy-4- (trifluoromethyl) cyclohexylene]Amino group]Carbamic acid tert-butyl ester

General procedure E using 4-hydroxy-4- (trifluoromethyl) cyclohexanone (5.12mmol) gave the title compound (2.29mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):9.60(br s,1H),6.02(br s,1H),2.83-2.79(m,1H),2.42-2.37(m,2H),2.24-2.20(m,1H),1.85-1.79(m,2H),1.70-1.55(m,2H),1.43(s,9H)。

5-amino-3- (4-bromophenyl) -1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl]Pyrazole-4-carbonitriles

General procedure O, Synthesis of N- [ [ 4-hydroxy-4- (trifluoromethyl) cyclohexylene]Amino group]Carbamic acid tert-butyl ester (2.29mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.89mmol) gave the title compound (0.12mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.94 min, M/z 430.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl group]Pyrazol-3-yl]Phenyl radical]First of all Base of]-2-methoxy-benzamide

General procedure K using 5-amino-3- (4-bromophenyl) -1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl]Pyrazole-4-carbonitrile (0.42mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.46mmol) gave the title compound (0.24mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.82 minutes, m/z 514.1[M+H]⁺。

5-amino-1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl]-3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical ]Pyrazole-4-carboxamides

General procedure L, using N- [ [4- [ 5-amino-4-cyano-1- [ 4-hydroxy-4- (trifluoromethyl) cyclohexyl]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.24mmol) gave the title compound (0.095mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 532.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.91 min, M/z 532.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.6Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.50-7.39(m,5H),7.16-7.14(m,1H),7.04(td,J＝7.5,1.0Hz,1H),6.34(br s,2H),5.86(br s,1H),4.54(d,J＝6.0Hz,2H),4.18-4.11(m,1H),3.90(s,3H),2.18-2.07(m,2H),1.85-1.83(m,2H),1.73-1.63(m,4H)。

Example 66: 5-amino-1- [1- (chloromethyl) -2-hydroxy-ethyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- (Oxetan-3-ylideneamino) carbamic acid tert-butyl ester

Following general procedure E, after washing the crude product with heptane, 3-oxetanone (6.94mmol) and tert-butyl carbazate (7.29mmol) were allowed to afford the title compound (4.51mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):10.25(s,1H),5.19-5.15(m,4H),1.43(s,9H)。

N- (Oxetan-3-ylamino) carbamic acid tert-butyl ester

Following general procedure F, after 2 days tert-butyl N- (oxetan-3-ylideneamino) carbamate (4.40mmol) gave the title compound (3.84mmol) as a colorless oil.¹H NMR(400MHz,DMSO-d₆,δ):8.38(s,1H),4.96-4.94(m,1H),4.51(t,J＝6.8Hz,2H),4.37(t,J＝6.2Hz,2H),4.07-3.99(m,1H),1.40(s,9H)。

Oxetan-3-ylhydrazine hydrochloride

Following general scheme G, using tert-butyl N- (oxetan-3-ylamino) carbamate (3.84mmol) gave the title compound (2.88mmol) as a brown oil. ¹H NMR(400MHz,DMSO-d₆,δ):3.81-3.71(m,2H),3.61-3.53(m,2H),3.25-3.19(m,1H)。

5-amino-3- (4-bromophenyl) -1- [1- (chloromethyl) -2-hydroxy-ethyl]Pyrazole-4-carbonitriles

Following general procedure H, at 85 ℃ for 2H, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.38mmol) and oxetan-3-ylhydrazine hydrochloride (0.46mmol) gave the title compound as a white solid. UPLC-MS (ES)⁺Short acidic): 1.76 min, M/z 357.1[ M +2 ]]⁺。

N- [ [4- [ 5-amino-1- [1- (chloromethyl) -2-hydroxy-ethyl ] ester]-4-cyano-pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

General procedure K, using 5-amino-3- (4-bromophenyl) -1- [1- (chloromethyl) -2-hydroxy-ethyl]Pyrazole-4-carbonitrile (0.20mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.28mmol) gave the title compound (0.13mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 440.2[ M]⁺。

5-amino-1- [1- (chloromethyl) -2-hydroxy-ethyl]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

General procedure L, using N- [ [4- [ 5-amino-1- [1- (chloromethyl) -2-hydroxy-ethyl)]-4-cyano-pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.11mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.33 min, M/z 458.2[ M ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.51-7.41(m,5H),7.16(d,J＝8.0Hz,1H),7.07-7.03(m,1H),6.42(s,2H),5.11(t,J＝5.4Hz,1H),4.59-4.52(m,3H),4.02-3.93(m,2H),3.91(s,3H),3.78-3.67(m,2H)。

Example 67: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (4-methylthiazol-2-yl) pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (4-methylthiazol-2-yl) pyrazole-4-carbonitrile

Following general procedure H, at 85 ℃ for 2H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and (4-methylthiazol-2-yl) hydrazine (0.91mmol) gave the title compound (0.32mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 362.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4-methylthiazol-2-yl) pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (4-methylthiazol-2-yl) pyrazole-4-carbonitrile (86mg, 0.24mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (100mg, 0.37mmol) gave the title compound (0.08mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.64 min, M/z 445.2[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (4-methylthiazol-2-yl) pyri dine Azole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (4-methylthiazol-2-yl) pyrazol-3-yl ] was reacted ]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.05mmol) gave the title compound (0.02mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.34 min, M/z 463.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.01 min, M/z 463.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.80-8.72(m,1H),7.77(dd,J＝7.8,1.9Hz,1H),7.52-7.47(m,1H),7.44-7.35(m,4H),7.30-7.29(m,1H),7.17-7.15(m,1H),6.38-6.35(m,1H),5.97(s,2H),4.59(d,J＝6.9Hz,2H),3.91(s,3H),2.14(d,J＝1.2Hz,3H)。

Example 68: 5-amino-1- (4, 4-difluorocyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

(4, 4-Difluorocyclohexyl) hydrazine hydrochloride

To a solution of 4, 4-difluorocyclohexanol (5.40mmol) in toluene (20mL) were added triphenylphosphine (8.10mmol) and di-tert-butyl azodicarboxylate (6.48mmol), and the reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was concentrated. MeOH (30mL) was added followed by hydrogen chloride solution (4M in 1, 4-dioxane, 10.8mL, 43.19mmol) and the mixture was stirred at room temperature for 14 hours. After filtration, the filtrate was concentrated and EtOAc was added to give the title compound (3.52mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.11-3.05(m,1H),2.11-1.78(m,6H),1.63-1.53(m,2H)。

5-amino-3- (4-bromophenyl) -1- (4, 4-difluorocyclohexyl) pyrazole-4-carbonitrile

Following general procedure H, at 85 ℃ for 2H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (133mg, 0.51mmol) and (4, 4-difluorocyclohexyl) hydrazine hydrochloride (113mg, 0.61mmol) gave the title compound (114mg, 0.30mmol, 59% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 2.01 min, M/z 383.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluorocyclohexyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy- Benzamide derivatives

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (4, 4-difluorocyclohexyl) pyrazole-4-carbonitrile (0.30mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.45mmol) gave the title compound (0.26mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.79 min, M/z 466.1[ M + H ]]⁺。

5-amino-1- (4, 4-difluorocyclohexyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

After purification, according to general procedure L, N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluorocyclohexyl) pyrazol-3-yl ] is reacted]Phenyl radical]Methyl radical]-2-methoxy-benzamide (160mg, 0.34mmol) gave the title compound (0.11mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 484.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.09 min, M/z 484.1[ M + H [)]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.50-7.39(m,5H),7.16-7.14(m,1H),7.05-7.01(m,1H),6.36(s,2H),4.54(d,J＝6.1Hz,2H),4.34-4.26(m,1H),3.89(s,3H),2.20-1.89(m,8H)。

Example 69: 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -N-methyl-pyrazole-4-carboxamide

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical ]Phenyl radical]Pyrazole-4-carboxylic acids

Reacting 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]A mixture of pyrazole-4-carboxylic acid ethyl ester (0.22mmol), sodium hydroxide (5M in water, 1mL, 5.00mmol) and MeOH (3mL) in THF (5mL) was stirred at 80 deg.C for 48 h. The mixture was then cooled and MeOH removed under reduced pressure. The residue was neutralized with hydrochloric acid (6M) at 0 ℃ until precipitation was observedAnd (4) precipitating. The aqueous layer was then extracted and concentrated to give the crude title compound (0.20mmol) as a light brown solid. LC-MS (ES)⁺Short acidic): 4.87 min, M/z 435.2[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-N-methylpyrazole- 4-carboxamides

Under nitrogen, 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid (30mg, 0.07mmol) was dissolved in DMF (3 mL). HATU (34mg, 0.09mmol) and N, N-diisopropylethylamine (36. mu.L, 0.21mmol) were added at RT. The mixture was stirred for 45 minutes. Methylamine (2M in THF, 104 μ L, 0.21mmol) was then added and the mixture was stirred for 48 hours. After work-up and purification, the title compound (0.04mmol) was obtained as a white solid. UPLC-MS (ES)⁺Short acidic): 1.80 min, M/z 448.2[ M + H ]⁺。UPLC-MS(ES⁺Long acidic): 4.21 min, M/z 448.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.51-7.45(m,3H),7.39-7.37(m,2H),7.17-7.15(m,1H),7.07-7.03(m,1H),6.18-6.11(m,1H),6.11(s,2H),4.64-4.57(m,1H),4.54(d,J＝6.1Hz,2H),3.91(s,3H),2.59(d,J＝4.7Hz,3H),2.03-1.76(m,6H),1.64-1.56(m,2H)。

Example 70: 5-amino-1- [3- (dimethylcarbamoyl) cyclohexyl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (isomer 1)

Lithium-3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyridine (II) Azol-1-yl]Cyclohexanecarboxylic acid ester (isomer 1)

Lithium hydroxide (9mg, 0.39mmol) was added to 3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-1-carboxylic acid ethyl ester (isomer 1, 0.19 mm)ol) in THF (1.5mL) and water (0.4mL) was heated to 60 ℃ for 16 h. The reaction was concentrated to give the crude title compound (isomer 1, 0.19mmol) which was used immediately in the next step. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 492.1[ M + H ]]⁺。

5-amino-1- [3- (dimethylcarbamoyl) cyclohexyl]-3- [4- [ [ (2-methoxybenzoyl) amino] Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (isomer 1)

Lithium-3- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]A solution of methyl cyclohexanecarboxylate (isomer 1,95mg, 0.19mmol) in THF (2mL) was stirred with a solution of dimethylamine (2M in THF, 0.05mL, 0.96mmol) and propylphosphonic anhydride (50 wt% in EtOAc, 0.34mL, 0.57mmol) at room temperature for 48 h. After work-up and purification, the title compound (isomer 1, 0.03mmol) was obtained. UPLC-MS (ES) ⁺Short acidic): 1.67 min, M/z 519.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.87 min, M/z 519.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.0Hz,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.51-7.38(m,5H),7.16(d,J＝8.2Hz,1H),7.08-7.01(m,1H),6.24(br s,2H),4.70-4.60(m,1H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.54-3.42(m,1H),2.98(s,3H),2.81(s,3H),2.04-1.95(m,1H),1.89-1.51(m,7H)。

Example 71: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2-oxaspiro [3.5] non-7-yl) pyrazole-4-carboxamide

N- (2-oxaspiro [3.5]]Nonan-7-ylideneamino) carbamic acid tert-butyl ester

Following general procedure E, using 2-oxaspiro [3.5]]Nonan-7-one (120mg, 0.86mmol) and tert-butyl carbazate (136mg, 1.03mmol) to give crude N- (2-oxaspiro [3.5] oxaspiro]Nonan-7-ylideneAmino) carbamic acid tert-butyl ester (0.86mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):9.58(s,1H),4.33(s,4H),2.28-2.25(m,2H),2.16-2.13(m,2H),1.88-1.85(m,2H),1.81-1.78(m,2H),1.43(s,9H)。

5-amino-3- (4-bromophenyl) -1- (2-oxaspiro [3.5]]Non-7-yl) pyrazole-4-carbonitriles

Reacting N- (2-oxaspiro [3.5]]Non-7-ylideneamino) carbamic acid tert-butyl ester (0.85mmol) was dissolved in THF (10mL) and borane dimethylsulfide complex solution (2M in THF, 0.73mL, 1.45mmol) was added. The reaction was stirred at room temperature for 2 hours. The volatiles were concentrated and the residue was dissolved in DCM (5mL) and TFA (0.88mL, 4.27mmol) was added. The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was dissolved in EtOH (10 mL). Then 2- [ (4-bromophenyl) -methoxy-methylene is added ]Malononitrile (0.65mmol) and triethylamine (3.23 mmol). The reaction mixture was heated to 80 ℃ for 3 hours, then cooled to room temperature and concentrated. Purification gave the title compound (0.30mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.96 min, M/z 386.9[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-oxaspiro [3.5 ]]Non-7-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2- Methoxy-benzamides

Following general procedure K, 5-amino-3- (4-bromophenyl) -1- (2-oxaspiro [3.5 ]]Non-7-yl) pyrazole-4-carbonitrile (0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.31mmol) purified to give the title compound (0.21mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.78 min, 472.2M/z [ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2-oxaspiro [3.5 ]]Nonane-7- Yl) pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2-oxaspiro [3.5 ] oxa-spiro [ sic ]]Non-7-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.24 mm)ol) to give the title compound (0.06mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.65 min, M/z 490.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.89 min, M/z 490.2[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.8Hz,1H),7.51-7.46(m,1H),7.44-7.39(m,4H),7.18-7.13(m,1H),7.06-7.02(m,1H),6.34(s,2H),4.54(d,J＝6.7Hz,2H),4.36(s,2H),4.26(s,2H),4.11-4.00(m,1H),3.90(s,3H),2.21-2.11(m,2H),1.79-1.62(m,4H),1.61-1.49(m,2H)。

Example 72: 1-cyclopentyl-5- (isopropylamino) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

3- (4-bromophenyl) -1-cyclopentyl-5- (isopropylamino) pyrazole-4-carbonitrile

A mixture of 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol), cesium carbonate (0.91mmol), and 2-bromopropane (0.72mmol) in DMF (10mL) was heated to 50 deg.C for 16 h. After work-up and purification, the title compound (0.13mmol) was obtained as a brown solid. UPLC-MS: (ES)⁺Short acidic): 2.45 min, M/z 375.0[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-1-cyclopentyl-5- (isopropylamino) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 3- (4-bromophenyl) -1-cyclopentyl-5- (isopropylamino) pyrazole-4-carbonitrile (0.13mol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.18mmol) gave the title compound (0.12mmol) as a light brown solid. UPLC-MS: (ES)⁺Short acidic): 2.18 min, M/z 458.2[ M + H ]]+。

1-cyclopentyl-5- (isopropylamino) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure L, after purification, N- [ [4- [ 4-cyano-1-cyclopentyl-5- (isopropylamino) pyrazol-3-yl ] was ]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.12mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS: (ES)⁺Long acidic): 4.99 min, M/z 476.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.4Hz,1H),7.76(dd,J＝8.0,2.0Hz,1H),7.54(d,J＝8.4Hz,2H),7.51-7.46(m,1H),7.36(d,J＝8.4Hz,2H),7.17-7.15(m,1H),7.07-7.01(m,1H),5.29(d,J＝9.2Hz,1H),4.78-4.70(m,1H),4.53(d,J＝6.0Hz,2H),3.90(s,3H),3.48-3.36(m,1H),2.06-1.79(m,6H),1.69-1.59(m,2H),1.11(d,J＝6.4Hz,6H)。

Example 73: 1-cyclopentyl-5- (ethylamino) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

3- (4-bromophenyl) -1-cyclopentyl-5- (ethylamino) pyrazole-4-carbonitrile

A mixture of 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol) and cesium carbonate (295mg, 0.91mmol) and iodoethane (0.36mmol) in DMF (5mL) was stirred at RT for 14 h. After work-up and purification, the title compound (0.15mmol) was obtained as an off-white solid. UPLC-MS: (ES)⁺Short acidic): 2.33 min, M/z 361.0[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-1-cyclopentyl-5- (ethylamino) pyrazol-3-yl ] amino]Phenyl radical]Methyl radical]-2-methoxy-benzyl Amides of carboxylic acids

General procedure K, after purification, 3- (4-bromophenyl) -1-cyclopentyl-5- (ethylamino) pyrazole-4-carbonitrile (0.15mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.22mmol) gave the title compound (0.14mmol) as an off-white solid. UPLC-MS: (ES)⁺Short acidic): 2.11 min, M/z 444.2[ M + H ]]⁺。

1-cyclopentyl-5-, ( Ethylamino) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure L, after purification, N- [ [4- [ 4-cyano-1-cyclopentyl-5- (ethylamino) pyrazol-3-yl ] is]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.14mmol) gave the title compound (0.06mmol) as a white solid. UPLC-MS (ES)⁺Long acidic): 4.84 min, M/z 462.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.3Hz,1H),7.75(dd,J＝7.6,1.8Hz,1H),7.53(d,J＝8.3Hz,2H),7.51-7.46(m,1H),7.36(d,J＝8.4Hz,2H),7.17-7.15(m,1H),7.06-7.00(m,1H),5.63(t,J＝6.4Hz,1H),4.74-4.68(m,1H),4.53(d,J＝6.1Hz,2H),3.90(s,3H),3.18-3.11(m,2H),2.04-1.78(m,6H),1.66-1.57(m,2H),1.12(t,J＝7.1Hz,3H)。

Example 74: example 78: 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] cyclohexanecarboxylic acid

4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 1-radical]Cyclohexanecarboxylic acids

Lithium hydroxide (6.16mmol) was added to 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]Ethylcyclohexanecarboxylate (0.62mmol) in THF (3mL) and water (1 mL). The reaction mixture was stirred at 50 ℃ for 16 hours and then cooled to room temperature. The reaction mixture was acidified to-pH 2 with hydrochloric acid (1M). Work-up and purification gave an inseparable mixture of cis and trans title compound (0.39mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 492.3[ M + H ] ]⁺。UPLC-MS(ES⁺Long acidic): 3.67 min, M/z 492.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ, cis/trans mixture) 12.1(br s,1H),8.73(t, J ═ 5.9Hz,1H),7.76(dd,J＝7.6,1.6Hz,1H),7.52-7.38(m,5H),7.16(d,J＝8.3Hz,1H),7.08-7.01(m,1H),6.40-6.25(m,2H),4.55(d,J＝6.0Hz,2H),4.17-4.04(m,1H),3.90(s,3H),2.64-2.10(m,1H),2.07-1.94(m,2H),1.93-1.39(m,6H)。

Example 75: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [4- (methoxycarbamoyl) cyclohexyl ] pyrazole-4-carboxamide

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [4- (methoxycarbamoyl) Radical) cyclohexyl]Pyrazole-4-carboxamides

Propylphosphonic anhydride (50% by weight in EtOAc, 0.27mmol), N-diisopropylethylamine (0.92mmol), methoxylamine hydrochloride (0.22mmol) and 4- [ 5-amino-4-carbamoyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazol-1-yl]A solution of cyclohexanecarboxylic acid (0.18mmol) in THF (1mL) was stirred at 80 ℃ for 16 h and cooled to room temperature. Work up and purify to give the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 521.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.58 min, M/z 521.2[ M + H]⁺。

Example 76: 5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

(4-bromo-2-fluoro-phenyl) methylamine

A solution of 4-bromo-2-fluorobenzonitrile (5.00mmol) in THF (30mL) was cooled to 0 deg.C. A borane tetrahydrofuran complex solution (1M in THF, 15.0mL) was added dropwise. The solution was stirred at 0 ℃ for 20 minutes, then warmed to room temperature and stirred for 16 hours. MeOH (30mL) was added dropwise and the solution was concentrated under reduced pressure And (4) shrinking. The residue was partitioned between aqueous NaOH (1M) and EtOAc. The organic layer was treated to give the title compound (5.00mmol) as a yellow oil.¹H NMR(400MHz,CDCl₃,δ):7.42-7.27(m,1H),7.25-7.16(m,2H),3.65(t,J＝6.6Hz,2H)。

N- [ (4-bromo-2-fluoro-phenyl) methyl group]-5-fluoro-2-methoxy-benzamide

A solution of (4-bromo-2-fluoro-phenyl) methylamine (5.00mmol) in THF (8mL) was added dropwise to a mixture of 5-fluoro-2-methoxybenzoic acid (1.03g, 6.04mmol), N-diisopropylethylamine (5.22mL, 30.0mmol) and a solution of propylphosphonic anhydride (50 wt% in EtOAc, 4.46mL, 7.50mmol) in THF (17 mL). The reaction was heated at 80 ℃ for 4 hours. Work up and concentrate to give the title compound (3.18 mmol). UPLC-MS (ES)⁺Short acidic): 1.98 min, M/z 357.9[ M +2 ]]⁺。

5-fluoro-N- [ [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl radical]-2-methyl Oxy-benzamides

General procedure R, purification, isolation of N- [ (4-bromo-2-fluoro-phenyl) methyl]-5-fluoro-2-methoxy-benzamide (3.34mmol) gave the title compound (3.30 mmol). UPLC-MS (ES)⁺Short acidic): 2.14 min, M/z 404.0[ M + H ]]⁺。

N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzyl Amides of carboxylic acids

General procedure D, after purification, 5-fluoro-N- [ [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] was reacted ]Methyl radical]-2-methoxy-benzamide (1.65mmol) and 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1.34mmol) to give the title compound (0.78 mmol). UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 384.0[ M + H ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy Phenyl-carboxamides

Cesium carbonate (1.64mmol), N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]A solution of-5-fluoro-2-methoxy-benzamide (1.27mmol) and bromocyclopentane (1.39mmol) in DMF (10mL) was heated to 80 ℃ for 18 h. Work up and purify to give the title compound (0.21 mmol). UPLC-MS (ES)⁺Short acidic): 2.04 min, M/z 452.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

General procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.11mmol) gave the title compound (0.07 mmol). UPLC-MS (ES)⁺Short acidic): 1.93 min, M/z 470.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 5.12 min, M/z 470.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.81(t,J＝5.9Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.46-7.40(m,1H),7.38-7.25(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.25(s,2H),4.67-4.58(m,1H),4.56(d,J＝5.9Hz,2H),3.90(s,3H),2.03-1.84(m,4H),1.84-1.74(m,2H),1.65-1.54(m,2H)。

Example 77: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ 2-methyltetrahydrofuran-3-yl ] pyrazole-4-carboxamide (isomer 1)

N- [ (2-methyltetrahydrofuran-3-ylidene) amino group]Carbamic acid tert-butyl ester

A solution of tert-butyl carbazate (11.99mmol) and 2-methyltetrahydro-3-furanone (9.99mmol) in EtOH (25mL) was heated at reflux for 16 h, cooled and concentrated under reduced pressure. The residue was dissolved with DCM, followed by water and saturated NaHCO₃The solution was washed, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (9.99mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.22(s,1H),4.39-4.31(m,1H),4.27-4.19(m,1H),3.97-3.88(m,1H),2.53-2.46(m,2H),1.54(s,9H),1.44(d,J＝6.4Hz,3H)。

(2-methyltetrahydrofuran-3-yl) hydrazine

General procedures T and U, purification by SPE SCX cartridge using 1MNH₃After elution of the MeOH solution (b), the N- [ (2-methyltetrahydrofuran-3-ylidene) amino group is caused to react]Tert-butyl carbamate (9.99mmol) gave (2-methyltetrahydrofuran-3-yl) hydrazine (9.33 mmol).¹H NMR(400MHz,CDCl₃,δ):4.03-3.66(m,3H),3.31-3.24(m,1H),2.18-2.05(m,1H),1.95-1.85(m,1H),1.30-1.22(m,3H)。

5-amino-3- (4-bromophenyl) -1- (2-methyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (1.90mmol) and (2-methyltetrahydrofuran-3-yl) hydrazine (2.28mmol) gave the title compound (600mg, 1.73mmol, 91% yield) as an inseparable diastereoisomer. UPLC-MS (ES)⁺Short acidic, mixture of diastereomers): 2.02 min, M/z 349.0[ M +2 ]]⁺And 2.07 minutes, M/z 349.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyltetrahydrofuran-3-yl ] amino acid ]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2-methyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile (0.86mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane gave the title compound (isomer 1, 0.17mmol) and (isomer 2, 0.32 mmol). UPLC-MS (ES)⁺Short acidic, isomer 1): 1.98 min, M/z 432.1[ M + H ]]⁺。UPLC-MS(ES⁺Short acidic, isomer 2): 1.96 min, M/z 432.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ 2-methyltetrahydrofuran-3- Base of]Pyrazole-4-carboxamide (isomer 1)

After purification, according to general procedure L, N- [ [4- [ 5-amino-4-cyano group)-1- [ 2-methyltetrahydrofuran-3-yl]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (isomer 1, 0.17mmol) gave the title compound (isomer 1, 0.09 mmol). UPLC-MS (ES)⁺Short acidic): 2.03 min, M/z 450.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.49 min, M/z 450.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.3Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.51-7.38(m,5H),7.15(d,J＝8.5Hz,1H),7.08-7.00(m,1H),6.43(br s,2H),4.55(d,J＝5.9Hz,2H),4.51-4.44(m,1H),4.08-4.02(m,1H),3.95-3.90(m,2H),3.90(s,3H),2.38-2.18(m,2H),1.21(d,J＝6.2Hz,3H)。

Example 78: 5-chloro-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

3- (4-bromophenyl) -1H-pyrazol-5-ol

A solution of ethyl 3- (4-bromophenyl) -3-oxopropanoate (12.2mmol) in EtOH (20mL) and hydrazine hydrate solution (55-60% in water, 12.2mmol) was stirred at RT for 40 min. The reaction mixture was then heated to reflux for 1 hour, then cooled to RT and concentrated under reduced pressure to give the crude title compound (12.2mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.57 min, M/z 240.6[ M +2 ]]⁺。

3- (4-bromophenyl) -5-chloro-1H-pyrazole-4-carbaldehyde

Anhydrous DMF (1.0mL) was added slowly to phosphorus oxychloride (29.3mmol) under nitrogen at 0 ℃. The reaction mixture was then warmed to room temperature and stirred for 5 minutes, then 3- (4-bromophenyl) -1H-pyrazol-5-ol (4.18mmol) was added to the reaction mixture at 0 ℃. After the addition was complete, the reaction mixture was heated at 85 ℃ for 24 hours. The reaction mixture was cooled to room temperature, quenched with saturated potassium carbonate solution (20mL), and extracted with EtOAc (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification to give the title compound(2.31mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 286.8[ M + H ]]⁺。

3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde

General procedure N, after purification, 3- (4-bromophenyl) -5-chloro-1H-pyrazole-4-carbaldehyde (2.31mmol), cesium carbonate (4.62mmol), and bromocyclopentane (3.47mmol) gave the title compound (1.35mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.49 min, M/z 354.9[ M + H ]]⁺。

3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carboxylic acid

To a suspension of 3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde (0.46mmol) in water (5mL) at RT was added potassium permanganate (0.91 mmol). The reaction mixture was heated at 100 ℃ for 18 hours and then cooled to RT, by Filtered and washed with water and EtOAc. The layers were separated and the aqueous layer was acidified to pH 1 with 1M HCl solution. The aqueous layer was then extracted with EtOAc (3X 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound and 3- (4-bromophenyl) -5-chloro-1H-pyrazole-4-carboxylic acid (1:2 ratio) (0.86mmol), which was used as such in the next step. UPLC-MS (ES)⁺Short acidic): 2.31 min, M/z 370.9[ M + H ]]⁺。

3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carboxamide

A mixture (0.86mmol) of 3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carboxylic acid and 3- (4-bromophenyl) -5-chloro-1H-pyrazole-4-carboxylic acid (1:2 ratio) in thionyl chloride (4.30mmol) was heated at 80 ℃ for 1 hour. Excess thionyl chloride was removed under reduced pressure to give a brown oil which was dissolved in anhydrous DCM (1.9mL) under nitrogen at 0 ℃ in an ice bath. Ammonium hydroxide (30 wt% in water, 8.58mmol) was added dropwise to the cooled reaction mixture, which was then stirred to room temperature for 16 h. The reaction mixture was then diluted in DCM and washed with water. The aqueous layer was washed with DCM (curve)3) Extraction and combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 2.24 min, M/z 369.9[ M + H ]]⁺。

5-chloro-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

General procedure K, after purification, 3- (4-bromophenyl) -5-chloro-1-cyclopentyl-pyrazole-4-carboxamide (0.10mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (29mg, 0.11mmol) gave the title compound (0.03mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.23 min, M/z 453.0[ M]⁺。UPLC-MS(ES⁺Long acidic): 6.07 min, M/z 453.1[ M]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.0Hz,1H),7.74(dd,J＝7.6,1.8Hz,1H),7.67(br s,1H),7.63(d,J＝8.5Hz,2H),7.53(br s,1H),7.50-7.44(m,1H),7.36(d,J＝8.4Hz,2H),7.14(d,J＝7.8Hz,1H),7.06-7.00(m,1H),4.90-4.83(m,1H),4.51(d,J＝6.2Hz,2H),3.89(s,3H),2.13-2.05(m,2H),2.03-1.94(m,2H),1.91-1.81(m,2H),1.72-1.64(m,2H)。

Example 79: 5-amino-1-cyclopentyl-3- [4- [1- [ (2-methoxybenzoyl) amino ] ethyl ] phenyl ] pyrazole-4-carboxamide

N- [1- (4-bromophenyl) ethyl]-2-methoxy-benzamide

A solution of 4-bromo-. alpha. -methylbenzylamine (6.57mmol) and N, N-diisopropylethylamine (9.85mmol) in dry THF (30mL) and 2-methoxybenzoyl chloride (7.22mmol) at 0 ℃ is then brought back to RT and stirred for 15 h. The mixture was quenched with saturated ammonium chloride solution (40mL) and extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with water (2 × 30mL), saturated brine solution (30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Further purification gave the title compound (6.19mmol) as a white solid. UPLC- MS(ES⁺Short acidic): 1.96 min, M/z 336.1[ M +2 ]]⁺。

2-methoxy-N- [1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl radical]Benzyl benzene Amides of carboxylic acids

General procedure J, after purification, the N- [1- (4-bromophenyl) ethyl group]-2-methoxy-benzamide (0.90mmol) gave the title compound (0.87mmol) as an orange oil. UPLC-MS (ES)⁺Short acidic): 2.12 min, M/z 382.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [4- [1- [ (2-methoxybenzoyl) amino group]Ethyl radical]Phenyl radical]Pyrazole-4-carboxylic acid esters Amines as pesticides

General procedure D, after purification, 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (0.26mmol) and 2-methoxy-N- [1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] borane]Ethyl radical]Benzamide (0.26mmol) gave the title compound (0.03mmol) as a light brown solid. UPLC-MS (ES +, short acidic): 2.47 min, M/z 448.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 5.82 min, M/z 448.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.52(d,J＝8.0Hz,1H),7.63(dd,J＝7.7,1.8Hz,1H),7.50-7.42(m,5H),7.14(d,J＝7.8Hz,1H),7.05-6.98(m,1H),6.30(br s,2H),5.22-5.12(m,1H),4.65-4.55(m,1H),3.90(s,3H),2.02-1.84(m,4H),1.84-1.70(m,2H),1.64-1.51(m,2H),1.48(d,J＝7.0Hz,3H)。

Example 80: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

Modified general procedure H, purification at RT, to obtain 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.49mmol) and tetrahydropyran-3-ylhydrazine hydrochlorideSalt (0.49mmol) gave the title compound (0.24mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.17 min, M/z 346.9[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.24mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.24mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 432.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-3-yl-pyrazole- 4-carboxamides

General procedure M, purified, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide (0.21mmol) gave the title compound (0.04mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 450.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 5.07 min, M/z 450.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.52-7.38(m,5H),7.16(d,J＝8.2Hz,1H),7.05(m,1H),6.42(s,2H),4.55(d,J＝6.1Hz,2H),4.30-4.21(m,1H),3.93-3.81(m,5H),3.59-3.49(m,1H),3.37-3.27(m,1H),2.05-1.96(m,2H),1.80-1.64(m,2H)。

Example 81: 5-amino-1- (2, 3-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (2, 3-difluorophenyl) pyrazole-4-carbonitrile

According to general procedure H, pureAfter the reaction, 2- [ (4-bromophenyl) -methoxy-methylene) is reacted]Malononitrile (0.38mmol) and (2, 3-difluorophenyl) hydrazine (0.46mmol) gave the title compound as an orange solid. UPLC-MS (ES)⁺Short acidic): 2.08 min, M/z 376.9[ M +2]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2, 3-difluorophenyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2, 3-difluorophenyl) pyrazole-4-carbonitrile (0.29mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.41mmol) gave the title compound (0.14mmol) as a grey solid. UPLC-MS (ES)⁺Short acidic): 1.89 min, M/z 460.1[ M + H]⁺。

5-amino-1- (2, 3-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure M, after purification, the N- [ [4- [ 5-amino-4-cyano-1- (2, 3-difluorophenyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.14mmol) gave the title compound (0.03mmol, 22% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 478.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.21 min, M/z 478.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.0Hz,1H),7.77(dd,J＝7.6,1.6Hz,1H),7.66-7.34(m,8H),7.16(d,J＝8.4Hz,1H),7.06-7.02(m,1H),6.58(s,2H),4.56(d,J＝6.4Hz,2H),3.90(s,3H)。

Example 82: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2,5, 5-tetramethyltetrahydrofuran-3-yl) carboxamide

N- [ (2,2,5, 5-tetramethyltetrahydrofuran-3-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, dihydro-2, 2,5, 5-tetramethyl-3 (2H) -furanone (1.63mmol) and tert-butyl carbazate (258mg, 1.95mmol) gave the crude title compound (1.62mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.11(s,1H),2.47(s,2H),1.51(s,9H),1.42(s,6H),1.34(s,6H)。

5-amino-3- (4-bromophenyl) -1- (2,2,5, 5-tetramethyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile

Reacting N- [ (2,2,5, 5-tetramethyltetrahydrofuran-3-ylidene) amino group]Tert-butyl carbamate (1.62mmol) was dissolved in THF (10mL) and borane dimethyl sulfide complex solution (2M in THF, 2.75mmol) was added. The reaction mixture was stirred at room temperature for 2 hours until TLC showed complete consumption of starting material. Volatiles were removed under reduced pressure. The residue was dissolved with DCM (5mL) and TFA (8.10mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in EtOH (10mL) and 2- [ (4-bromophenyl) -methoxy-methylene) was added]Malononitrile (0.65mmol) and triethylamine (3.23 mmol). The reaction mixture was heated to 80 ℃ for 24 hours. The solvent was removed under reduced pressure and the residue was purified to give the title compound (0.23mmol) as a solid. UPLC-MS (ES) ⁺Short acidic): 2.33 min, M/z 389.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2,5, 5-tetramethyltetrahydrofuran-3-yl) pyrazol-3-yl]Phenyl radical]First of all Base of]-2-methoxy-benzamide

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2,5, 5-tetramethyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile (0.23mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.32mmol) gave the title compound (0.19mmol) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 2.09 min, M/z 474.2[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2,5, 5-tetramethyltetrahydro-tetrahydro-2 Furan-3-yl) pyrazole-4-carboxamides

General procedure L, after purification, the N- [, ]4- [ 5-amino-4-cyano-1- (2,2,5, 5-tetramethyltetrahydrofuran-3-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.19mmol) gave the title compound (0.10mmol) as a solid. UPLC-MS (ES)⁺Short acidic): 2.02 min, M/z 492.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.79 min, M/z 492.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.2Hz,1H),7.75(dd,J＝7.5,1.7Hz,1H),7.49-7.40(m,5H),7.15(d,J＝8.6Hz,1H),7.05-7.01(m,1H),6.43(s,2H),4.92-4.87(m,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),2.81-2.73(m,1H),2.13-2.09(m,1H),1.30(s,6H),1.26(s,3H),0.90(s,3H)。

Example 83 a: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ (3S) -tetrahydrofuran-3-yl ] pyrazole-4-carboxamide

[ (3S) -tetrahydrofuran-3-yl ]Hydrazine hydrochloride

A solution of (3R) -tetrahydrofuran-3-ol (11.35mmol) in toluene (20mL), triphenylphosphine (17.0mmol) and di-tert-butyl azodicarboxylate (13.6mmol) were stirred under nitrogen at room temperature for 48h, then concentrated under reduced pressure and the residue redissolved in MeOH (50 mL). Hydrogen chloride solution (4M in dioxane, 90.79mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc and MeOH to give the title compound (7.32mmol) as an off-white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.81-3.72(m,3H),3.69-3.62(m,2H),2.07-1.98(m,1H),1.96-1.88(m,1H)。

N- [ [4- [ 5-amino-4-cyano-1- [ (3S) -tetrahydrofuran-3-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carbonitrile (0.39mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.59mmol) gave the title compound (0.35mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.94 min, M/z 418.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ (3S) -tetrahydrofuran-3- Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ (3S) -tetrahydrofuran-3-yl ] ethanol ]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide to give the title compound (0.08mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 436.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.96 min, M/z 436.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.7Hz,1H),7.50-7.40(m,5H),7.15(d,J＝7.7Hz,1H),7.06-7.02(m,1H),6.39(s,2H),4.93-4.90(m,1H),4.54(d,J＝6.0Hz,2H),4.00-3.92(m,2H),3.90(s,3H),3.83-3.79(m,2H),2.30-2.20(m,2H)。

Example 83 b: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ (3R) -tetrahydrofuran-3-yl ] pyrazole-4-carboxamide

[ (3R) -tetrahydrofuran-3-yl]Hydrazine hydrochloride

A solution of (S) - (-) -3-hydroxytetrahydrofuran (11.4mmol) in toluene (20mL), triphenylphosphine (17.0mmol) and di-tert-butylazodicarboxylate (13.6mmol) were stirred at RT for 48 h at 0 ℃ under nitrogen. Volatiles were removed under reduced pressure. MeOH (50mL) and hydrogen chloride solution (4M in dioxane, 90.8mmol) were then added. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc to give the title compound (5.4mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.82-3.62(m,5H),2.08-1.99(m,1H),1.94-1.87(m,1H)。

N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydrofuran-3-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [ (3R) -tetrahydrofuran-3-yl]Pyrazole-4-carbonitrile (0.27mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.41mmol) gave the title compound (0.27mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 418.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ (3R) -tetrahydrofuran-3- Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydrofuran-3-yl)]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.30mmol) gave the title compound (0.11mmol) as a white solid. LC-MS (ES)⁺Short acidic): 3.94 min, M/z 436.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.96 min, M/z 436.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.50-7.39(m,5H),7.16-7.14(m,1H),7.06-7.01(m,1H),6.39(s,2H),4.96-4.90(m,1H),4.54(d,J＝6.1Hz,2H),4.01-3.92(m,2H),3.90(s,3H),3.82-3.77(m,2H),2.28-2.23(m,2H)。

Example 84: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ 2-methyltetrahydrofuran-3-yl ] pyrazole-4-carboxamide (isomer 2)

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ 2-methyltetrahydrofuran-3- Base of]Pyrazole-4-carboxamide (isomer 2)

General procedure M, purification, N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyltetrahydrofuran-3-Base of]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (isomer 2, 0.32mmol) gave the title compound (isomer 2, 0.07 mmol). UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 450.1[ M + H ] ]⁺。UPLC-MS(ES⁺Long acidic): 3.02 min, M/z 450.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.75(dd,J＝7.7,1.7Hz,1H),7.51-7.39(m,5H),7.16(d,J＝8.2Hz,1H),7.06-7.02(m,1H),6.39(br s,2H),4.88-4.80(m,1H),4.55(d,J＝6.0Hz,2H),4.14-4.05(m,1H),4.05-3.96(m,1H),3.90(s,3H),3.64(q,J＝8.1Hz,1H),2.54-2.44(m,1H),2.41-2.31(m,1H),0.83(d,J＝6.1Hz,3H)。

Example 85: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2-methyltetrahydropyran-4-yl) pyrazole-4-carboxamide

N- [ (2-Methyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, 2-methylhydro-2H-pyran-4 (3H) -one (2.03mmol) and tert-butyl carbazate (2.23mmol) gave the crude title compound (2.04mmol) as a pale yellow solid.¹H NMR(400MHz,CDCl₃,δ):7.56(s,1H),4.17-4.12(m,1H),3.65-3.59(m,1H),3.53-3.49(m,1H),2.62-2.55(m,1H),2.52-2.47(m,1H),2.24-2.16(m,1H),1.90-1.84(m,1H),1.54(s,9H),1.33-1.27(m,3H)。

5-amino-3- (4-bromophenyl) -1- (2-methyltetrahydropyran-4-yl) pyrazole-4-carbonitrile

At RT, the N- [ (2-methyltetrahydropyran-4-ylidene) amino group]A solution of tert-butyl carbamate in THF (10mL) and borane dimethyl sulfide complex solution (2M in THF, 3.45mmol) was stirred until TLC indicated complete consumption of starting material. Volatiles were removed under reduced pressure. The residue was dissolved in DCM (10mL) and TFA (10.1mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL). Adding 2- [ (4-bromophenyl) -methylOxy-methylene]Malononitrile (0.95mmol) and triethylamine (4.75 mmol). The reaction mixture was heated to 80 ℃ for 24 hours, cooled and concentrated under reduced pressure. Further purification gave the title compound (0.25mmol mixture of diastereomers) as an off-white solid. UPLC-MS: (ES) ⁺Short acidic): 1.85 min, M/z 362.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-methyltetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2-methyltetrahydropyran-4-yl) pyrazole-4-carbonitrile (0.23mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.33mmol) gave the title compound (0.22mmol) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 1.58 min, M/z 446.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2-methyltetrahydropyran-4-) Yl) pyrazole-4-carboxamides

Procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2-methyltetrahydropyran-4-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (100mg, 0.22mmol) gave the title compound (0.04mmol) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.40 and 1.43 minutes, M/z 464.1[ M + H ]]⁺。UPLC-MS：(ES⁺Long acidic): 3.12 and 3.20 min, M/z 464.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆δ, mixture of diastereomers 8.74(t, J ═ 6.3Hz,1H),7.76(dd, J ═ 7.6,1.7Hz,1H),7.51-7.41(m,5H),7.16(d, J ═ 8.2Hz,1H),7.07-7.03(m,1H),6.38(s,2H),4.55(d, J ═ 6.0Hz,2H),4.42-4.34(m,1H),3.98-3.95(m,1H),3.91(s,3H),3.55-3.44(m,2H),1.92-1.82(m,2H),1.77-1.62(m,2H),1.16-1.12(m, 3H).

Example 86: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (3-methyltetrahydropyran-4-yl) pyrazole-4-carboxamide

N- [ (3-methyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, using 3-methylhydro-2H-pyran-4 (3H) -one (1.75mmol) and tert-butyl carbazate (1.93mmol) gave the crude title compound (1.69mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.52(s,1H),3.94-3.90(m,1H),3.89-3.84(m,1H),3.75-3.69(m,1H),3.49-3.44(m,1H),2.69-2.61(m,1H),2.52-2.46(m 1H),2.31-2.23(m,1H),1.53(s,9H),1.20(d,J＝6.9Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (3-methyltetrahydropyran-4-yl) pyrazole-4-carbonitrile

Reacting N- [ (3-methyltetrahydropyran-4-ylidene) amino group]A solution of tert-butyl carbamate (1.69mmol) in THF (10mL) and borane dimethyl sulfide complex (2M in THF, 2.86mmol) was stirred for 2 hours until TLC indicated complete consumption of starting material. The solvent was removed under reduced pressure. The residue was dissolved in DCM (7mL) and TFA (8.43mmol) was added. The reaction mixture was stirred at RT for 2h and then concentrated under reduced pressure. The residue was dissolved in EtOH (10mL) and 2- [ (4-bromophenyl) -methoxy-methylene) was added]Malononitrile (1.37mmol) and triethylamine (6.84 mmol). The reaction mixture was heated to 80 ℃ for 24 hours, cooled and concentrated under reduced pressure. Further purification gave the title compound (1.15mmol) as a white solid. UPLC-MS: (ES) ⁺Short acidic): 1.83 min and 1.86 min, M/z 362.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-methyltetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (3-methyltetrahydropyran-4-yl) pyrazole-4-carbonitrile (0.48mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.71mmol) gave the title compound (0.48mmol) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.59 min and 1.61 min, M/z 446.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (3-methyltetrahydropyran-4-) Yl) pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (3-methyltetrahydropyran-4-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.14mmol) gave the title compound (0.09mmol) as a solid. UPLC-MS: (ES)⁺Short acidic): 1.36 min, 1.38 min, M/z 464.1[ M + H ]]⁺。UPLC-MS：(ES⁺Short acidic): 3.06 min, 3.13 min, M/z 464.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆δ, mixture of diastereomers 8.74(t, J ═ 6.0Hz,1H),7.76(dd, J ═ 7.6,2.0Hz,1H),7.51-7.41(m,5H),7.15(d, J ═ 8.2Hz,1H),7.07-7.03(m,1H),6.40(s,2H),4.55(d, J ═ 6.1Hz,2H),4.52-4.47(m,1H),4.06-4.01(m,1H),3.91(s,3H),3.72(dd, J ═ 11.3,3.5Hz,1H),3.58(dd, J ═ 11.2,2.6Hz,1H),3.51-3.41(m,1H), 2.36.36H, 1H, 1.17-7H, 14H, 1H, 7.71H, 7.7.7, 7H, 1H, and J ═ 14H.

Example 87: 1-cyclobutyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5- (methylamino) pyrazole-4-carboxamide

3- (4-bromophenyl) -1-cyclobutyl-5- (methylamino) pyrazole-4-carbonitrile

A solution of 5-amino-3- (4-bromophenyl) -1-cyclobutyl-pyrazole-4-carbonitrile (0.28mmol) in MeOH (2.8mL), paraformaldehyde (0.85mmol) and sodium methoxide (25 wt% in MeOH, 1.70mmol) were heated at 70 deg.C for 1 h and then cooled to room temperature. Sodium borohydride (2.84mmol) was added and the reaction mixture was stirred at room temperature for a further 16 h. The reaction mixture was then carefully quenched with water. The aqueous layer was then extracted with DCM (. times.3). The combined organic layers were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification gave the title compound (0.23mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.25 pointsClock, M/z 331.0[ M ]]⁺。

N- [ [4- [ 4-cyano-1-cyclobutyl-5- (methylamino) pyrazol-3-yl ] amino]Phenyl radical]Methyl radical]-2-methoxy-benzyl Amides of carboxylic acids

General procedure K, after purification, 3- (4-bromophenyl) -1-cyclobutyl-5- (methylamino) pyrazole-4-carbonitrile (0.23mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.25mmol) gave the title compound (0.21mmol) as a white powder. UPLC-MS (ES) ⁺Short acidic): 2.11 min, M/z 416.1[ M + H]⁺。

1-cyclobutyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5- (methylamino) pyrazole-4- Carboxamides

General procedure L, after purification, N- [ [4- [ 4-cyano-1-cyclobutyl-5- (methylamino) pyrazol-3-yl ] is]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.17mmol) gave the title compound (0.09mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 434.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝6.0Hz,1H),7.75(dd,J＝7.7,1.7Hz,1H),7.54(d,J＝8.2Hz,2H),7.51-7.44(m,1H),7.37(d,J＝8.2Hz,2H),7.15(d,J＝8.2Hz,1H),7.07(br s,1H),7.07-7.00(m,1H),6.36(br s,1H),5.92(q,J＝5.6Hz,1H),4.84-4.80(m,1H),4.53(d,J＝6.0Hz,2H),3.90(s,3H),2.81(d,J＝5.4Hz,3H),2.64-2.44(m,2H),2.38-2.24(m,2H),1.83-1.70(m,2H)。

Example 88: 5-amino-1-cyclopentyl-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-1H-pyrazol-3-yl) phenyl]Methyl radical]-5-fluoro-2-methoxy- Benzamide derivatives

General procedure K, purification, isolation of trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.23mmol) and 5-amino-3- (4-bromophenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.17mmol) gave the title compound (0.17mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 434.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-1H-pyrazol-3-yl) phenyl ] was reacted ]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.17mmol) gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 452.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.62 min, M/z 452.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.44(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),7.37-7.30(m,1H),7.18(dd,J＝9.2,4.3Hz,1H),6.31(s,2H),4.65-4.66(m,1H),4.54(d,J＝6.1Hz,2H),3.89(s,3H),2.02-1.84(m,4H),1.82-1.73(m,2H),1.63-1.52(m,2H)。

Example 89: 5-amino-1- (3, 3-dimethyltetrahydropyran-4-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (3, 3-dimethyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, using 3, 3-dimethyldihydro-2H-pyran-4 (3H) -one (1.72mmol) and tert-butyl carbazate (1.89mmol) gives the title compound (1.70mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.46(s,1H),3.77(t,J＝6.1Hz,2H),3.46(s,2H),2.36(t,J＝6.0Hz,2H),1.50(s,9H),1.19(s,6H)。

[ (3, 3-Dimethyltetrahydropyran-4-yl) amino]Ammonium; 2,2, 2-Trifluoroacetate salt

Reacting N- [ (3, 3-dimethyltetrahydropyran-4-ylidene) amino group]A solution of tert-butyl carbamate (1.69mol) in THF (10mL) and borane dimethyl sulfide complex solution (2M in THF, 2.88mmol) was stirred at RT for 2h until TLC indicated complete consumption of starting material. Volatiles were removed under reduced pressure. The residue was dissolved in DCM (7mL) and TFA (8.46mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were then removed under reduced pressure to give the crude title compound (1.70 mmol). ¹H NMR(400MHz,DMSO-d₆,δ):3.93-3.89(m,1H),3.33(d,J＝11.2Hz,1H),3.29-3.22(m,1H),3.01(d,J＝11.5Hz,1H),2.71-2.67(m,1H),1.88-1.84(m,1H),1.53-1.43(m,1H),0.88(d,J＝11.2Hz,6H)。

5-amino-3- (4-bromophenyl) -1- (3, 3-dimethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and [ (3, 3-dimethyltetrahydropyran-4-yl) amino]Ammonium; 2,2, 2-Trifluoroacetate (0.91mmol) gave the title compound (0.72mmol) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.91 min, M/z376.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3, 3-dimethyltetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (3, 3-dimethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile (0.27mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.40mmol) gave the title compound (0.21mmol) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 1.64 min, M/z 460.1[ M + H]⁺。

5-amino-1- (3, 3-dimethyltetrahydropyran-4-yl) -3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (3, 3-dimethyltetrahydropyran-4-yl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzoylAmine (0.21mmol) gave the title compound (0.13mmol) as a solid. UPLC-MS: (ES) ⁺Short acidic): 1.44 min, M/z 478.1[ M + H]⁺。UPLC-MS：(ES⁺Long acidic): 3.30 min, M/z 478.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.50-7.40(m,5H),7.15(d,J＝8.3Hz,1H),7.05-7.02(m,1H),6.40(s,2H),4.54(d,J＝6.5Hz,2H),4.21(dd,J＝11.1,4.0Hz,1H),4.04-3.90(m,4H),3.51-3.39(m,2H),3.20(d,J＝11.1Hz,1H),2.39-2.29(m,1H),1.58-1.54(m,1H),1.01(s,3H),0.81(s,3H)。

Example 90: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) carboxamide

N- [ (2,2,6, 6-tetramethyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, after purification, 2,6, 6-tetramethylcycloalkane-4-one (1.60mmol) and tert-butyl carbazate (2.44mmol) gave the title compound (1.44mmol) as an off-white solid.¹H NMR(400MHz,CDCl₃,δ):7.47(s,1H),2.52(s,2H),2.25(s,2H),1.51(s,9H),1.29(s,6H),1.23(s,6H)。

5-amino-3- (4-bromophenyl) -1- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile

Reacting tert-butyl N- [ (2,2,6, 6-tetramethyltetrahydropyran-4-ylidene) amino group at 0 deg.C]Tert-butyl carbamate (1.47mmol) was dissolved in THF (15mL) and borane dimethyl sulfide complex solution (2M in THF, 4.40mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed under reduced pressure. The residue was dissolved in DCM (5mL) and TFA (36.10mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was dissolved in EtOH (10mL) and 2- [ (4-bromophenyl) -methoxy-methylene) was added]Malononitrile (0.76mmol) and triethylamine (3.80 mmol). Mixing the reaction mixture Heated to 80 ℃ for 16 hours, cooled and concentrated under reduced pressure. Further purification gave the title compound (0.19mmol) as a brown solid. UPLC-MS: (ES)⁺Short acidic): 2.09 min, M/z 405.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]First of all Base of]-2-methoxy-benzamide

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile (0.19mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound as a yellow solid (0.08 mmol). UPLC-MS: (ES)⁺Short acidic): 1.78 min, M/z 488.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2,6, 6-tetramethyltetrahydro-2-ol Pyran-4-yl) pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.08mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.57 min, M/z 506.2[ M + H]⁺。UPLC-MS：(ES⁺Long acidic): 3.63 min, M/z 506.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.50-7.39(m,5H),7.15(d,J＝7.9Hz,1H),7.06-7.02(m,1H),6.48(s,2H),4.75-4.67(m,1H),4.54(d,J＝6.2Hz,2H),3.90(s,3H),1.74(d,J＝7.8Hz,4H),1.34(s,6H),1.15(s,6H)。

Example 91: 3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5- (methylamino) -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

3- (4-bromophenyl) -5- (methylamino) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

A solution of 5-amino-3- (4-bromophenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.86mmol) in MeOH (8mL), paraformaldehyde (2.57mmol) and sodium methoxide (25 wt% in MeOH, 5.15mmol) were heated at 70 deg.C for 1h, then cooled to RT. Sodium borohydride (8.58mmol) was added and the reaction was stirred at room temperature for 16 h, then carefully quenched with water. The aqueous layer was extracted with DCM (3 × 20mL) and the combined organic layers were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification gave the title compound (0.65mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.80 min, M/z 362.9[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-5- (methylamino) -1-tetrahydropyran-4-yl-pyrazol-3-yl ] amino]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 3- (4-bromophenyl) -5- (methylamino) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.65mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.71mmol) gave the title compound (0.44mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.57 min, M/z 446.1[ M + H]⁺。

3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-5- (methylamino) -1-tetrahydropyran-4- Yl-pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 4-cyano-5- (methylamino) -1-tetrahydropyran-4-yl-pyrazol-3-yl ] is]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.44mmol) gave the title compound (0.04mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 464.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.08 min, M/z 464.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.6Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.54(d,J＝8.1Hz,2H),7.48(td,J＝8.4,1.8Hz,1H),7.35(d,J＝8.2Hz,2H),7.15(d,J＝8.3Hz,1H),7.04(td,J＝8.1,0.7Hz,1H),6.7(br s,1H),5.80(q,J＝5.2Hz,1H),4.53(d,J＝6.0Hz,2H),4.42-4.34(m,1H),3.97(dd,J＝11.2,3.8Hz,2H),3.90(s,3H),3.53-3.40(m,2H),2.84(d,J＝5.6Hz,3H),2.12-2.00(m,2H),1.80-1.77(m,2H)。

Example 92: 5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (2-methoxy-5-methyl-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (4-bromo-2-fluoro-phenyl) methyl group]-2-methoxy-5-methyl-benzamide

A solution of (4-bromo-2-fluoro-phenyl) methylamine (5.00mmol) in THF (4mL), a solution of propylphosphonic anhydride (50 wt% in EtOAc, 7.50mmol) in THF (6mL), 2-methoxy-5-methylbenzoic acid (6.04mmol) and N, N-diisopropylethylamine (8.88mmol) was stirred at 80 ℃ for 18 h. The reaction was cooled to room temperature and washed with EtOAc and saturated NH₄The layers were separated between aqueous Cl solutions. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified to give the title compound (3.51 mmol). UPLC-MS (ES)⁺Short acidic): 2.05 min, M/z 353.9[ M +2 ] ]⁺。

N- [ [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl ester]Methyl radical]-2-methoxy- 5-methyl-benzamides

General procedure R, purification, isolation of N- [ (4-bromo-2-fluoro-phenyl) methyl]-2-methoxy-5-methyl-benzamide (3.51mmol) gave the title compound (3.51 mmol). UPLC-MS (ES)⁺Short acidic): 2.18 min, M/z 400.1[ M + H]⁺。

N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-5-methyl-benzene Carboxamides

General procedure D, after purification, N- [ [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] was reacted]Methyl radical]-2-methoxy-5-methyl-benzamide (3.51mmol) gave the title compound (1.03 mmol). UPLC-MS (ES)⁺Short acidic): 1.86 min, M/z 380.0[ M + H ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-5- Methyl-benzamides

Cesium carbonate (1.34mmol), N- [ [4- (5-amino-4-cyano-1H-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]A solution of-2-methoxy-5-methyl-benzamide (1.03mmol) and bromocyclopentane (1.13mmol) in DMF (10mL) was stirred at 80 ℃ for 3.5 h, then cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Further purification gave the title compound (0.07 mmol). UPLC-MS (ES) ⁺Short acidic): 2.21 min, M/z 448.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (2-methoxy-5-methylbenzoyl) amino]Methyl radical]Phenyl radical] Pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-5-methyl-benzamide (0.07mmol) gave the title compound (0.02mmol, 24% yield). UPLC-MS (ES)⁺Short acidic): 2.10 min, M/z 466.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.88 min, M/z 466.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.68(t,J＝6.0Hz,1H),7.57(d,J＝2.3Hz,1H),7.41(t,J＝7.9Hz,1H),7.34-7.30(dd,J＝7.9,1.5Hz,1H),7.30-7.28(m,1H),7.28-7.25(m,1H),7.05(d,J＝8.5Hz,1H),6.25(s,2H),4.65-4.60(m,1H),4.56(d,J＝6.0Hz,2H),3.87(s,3H),2.27(s,3H),2.03-1.85(m,4H),1.83-1.72(m,2H),1.65-1.52(m,2H)。

Example 93: 5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

2-[(4-bromo-3-fluoro-phenyl) -hydroxy-methylene]Malononitrile

General procedure W, 4-bromo-3-fluorobenzoyl chloride (5.29mmol) and malononitrile (0.37mL, 5.81mmol) gave the title compound (5.15mmol) as a pale brown solid. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 266.9[ M]⁺。

2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile

General procedure X, after purification, 2- [ (4-bromo-3-fluoro-phenyl) -hydroxy-methylene]Malononitrile (5.11mmol) and dimethyl sulfate (15.3mmol) gave the title compound as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):8.06-8.02(m,1H),7.86(dd,J＝9.1,1.9Hz,1H),7.54-7.52(m,1H),3.92(s,3H)。

5-amino-3- (4-bromo-3-fluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (200mg, 0.71mmol) and cyclopentylhydrazine hydrochloride (117mg, 0.85mmol) gave the title compound (0.48mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.06 min, M/z 348.9[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.46mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.69mmol) gave the title compound (0.19mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.80 min, M/z 434.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-benzylAmide (0.18mmol) gave the title compound (0.07mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 452.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.66 min, M/z 452.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.8Hz,1H),7.51-7.47(m,1H),7.43(t,J＝7.7Hz,1H),7.34-7.27(m,2H),7.16(d,J＝8.2Hz,1H),7.07-7.03(m,1H),6.26(s,2H),4.68-4.60(m,1H),4.57(d,J＝6.0Hz,2H),3.91(s,3H),2.01-1.88(m,4H),1.84-1.76(m,2H),1.63-1.55(m,2H)。

Example 94: 5-amino-1- [ trans-4-hydroxytetrahydrofuran-3-yl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

Trans-4-hydrazinotetrahydrofuran-3-ol

To 3, 6-dioxabicyclo [3.1.0 ] cooled to 0 DEG C]Hexane (11.62mmol) in EtOH (39mL) was added hydrazine hydrate (55-60% in water, 29.04mmol) dropwise. The reaction was stirred at room temperature for 10 minutes and then heated at 60 ℃ for 16 hours. The reaction was concentrated under reduced pressure to give the crude title compound (11.61 mmol).¹H NMR(400MHz,DMSO-d₆,δ):4.06-4.02(m,1H),3.80-3.71(m,2H),3.52-3.43(m,2H),3.07-3.02(m,1H)。

5-amino-3- (4-bromophenyl) -1- [ trans-4-hydroxytetrahydrofuran-3-yl]Pyrazole-4-carbonitriles

General procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (5.7mmol) and trans-4-hydrazinotetrahydrofuran-3-ol (6.97mmol) gave the title compound (5.09 mmol).¹H NMR(400MHz,DMSO-d₆,δ):7.77-7.64(m,4H),6.85(m,2H),5.52(d,J＝4.1Hz,1H),4.71-4.66(m,1H),4.61-4.55(m,1H),4.17-4.11(m,1H),4.09-4.04(m,1H),3.82-3.77(m,1H),3.67-3.61(m,1H)。

5-amino-3- (4-bromophenyl) -1- [ trans-4- [ tert-butyl (dimethyl) silaneBase of]Oxytetrahydrofuran-3- Base of]Pyrazole-4-carbonitriles

To 5-amino-3- (4-bromophenyl) -1- [ trans-4-hydroxytetrahydrofuran-3-yl]To a solution of pyrazole-4-carbonitrile (1.43mmol) in DMF (7.2mL) were added imidazole (3.44mmol) and tert-butylchlorodimethylsilane (3.15 mmol). The reaction was heated at 50 ℃ for 16 h, cooled and then partitioned between water and EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. Further purification gave the title compound (0.54 mmol). UPLC-MS (ES) ⁺Short acidic): 2.27 min, M/z465.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-1- [ trans-4- [ tert-butyl (dimethyl) silyl group)]Oxytetrahydrofuran-3-yl]-4- Cyanopyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.76mmol) and 5-amino-3- (4-bromophenyl) -1- [ trans-4- [ tert-butyl (dimethyl) silyl]Oxytetrahydrofuran-3-yl]Pyrazole-4-carbonitrile (0.54mmol) gave the title compound (0.39mmol, 72% yield). UPLC-MS (ES)⁺Short acidic): 2.00 min, M/z 548.2[ M]⁺。

5-amino-1- [ trans-4-hydroxytetrahydrofuran-3-yl]-3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

General procedure M, after purification, the reaction product of N- [ [4- [ 5-amino-1- [ trans-4- [ tert-butyl (dimethyl) silyl)]Oxytetrahydrofuran-3-yl]-4-cyanopyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.23mmol) gave the title compound (0.04 mmol). UPLC-MS (ES)⁺Long acidic): 2.74 min, M/z 452.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.39(m,5H),7.15(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.40(br s,2H),5.46(d,J＝4.2Hz,1H),4.69-4.62(m,1H),4.57-4.51(m,3H),4.15(dd,J＝9.0,6.9Hz,1H),4.00(dd,J＝9.3,5.3Hz,1H),3.90(s,3H),3.81(dd,J＝9.2,4.6Hz,1H),3.62(dd,J＝9.1,2.2Hz,1H)。

Example 95: 5-amino-1- [ 3-fluorotetrahydropyran-4-yl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (isomer 1)

N- [ (3-Fluorotetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, 3-fluoro dihydro-2H-pyran-4 (3H) -one (1.48mmol) and tert-butyl carbazate (2.22mmol) gave the crude title compound (1.48 mmol).¹H NMR(400MHz,CDCl₃,δ):7.79(s,1H),5.00(d,J＝47.8Hz,1H),4.33(d,J＝13.7Hz,1H),4.20-4.13(m,1H),3.79-3.63(m,1H),3.54-3.45(m,1H),2.68-2.57(m,1H),2.53-2.45(m,1H),1.54(s,9H)。

5-amino-3- (4-bromophenyl) -1- (3-fluorotetrahydropyran-4-yl) pyrazole-4-carbonitrile

General procedure O, purification, Synthesis of N- [ (3-Fluorotetrahydropyran-4-ylidene) amino]THF (4.9mL) solution of tert-butyl carbamate and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.99mmol) gave the title compound (isomer 1,0.50mmol) and the title compound (isomer 2, 0.22 mmol). UPLC-MS (ES)⁺Short acidic isomer 1): 1.66 min, M/z 366.9[ M +2 ]]⁺。UPLC-MS(ES⁺Short acidic, isomer 2): 1.77 min, M/z 366.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3-fluorotetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy group Yl-benzamide (isomer 1)

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.70mmol) and 5-amino-3- (4-bromophenyl) -1- (3-fluorotetrahydropyran-4-yl) pyrazole-4-carbonitrile (isomer 1,0.50mmol) gave the title compound (isomer 1, 0.40 mmol). UPLC-MS (ES)⁺Short acidic): 1.47 min, M/z 450.1[ M + H ]⁺。

5-amino-1- [ 3-fluorotetrahydropyran-4-yl]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical] Pyrazole-4-carboxamide (isomer 1)

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (3-fluorotetrahydropyran-4-yl) pyrazol-3-yl ] is]Phenyl radical]Methyl radical]-2-methoxy-benzamide (isomer 1, 0.40mmol) gave the title compound (isomer 1, 0.31mmol) as a white solid. UPLC-MS (ES)⁺Long acidic): 2.92 min, M/z 468.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.2Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.51-7.39(m,5H),7.15(d,J＝8.1Hz,1H),7.05-7.03(m,1H),6.45(br s,2H),4.94-4.74(m,1H),4.62-4.48(m,3H),4.09-3.98(m,2H),3.90(s,3H),3.72-3.44(m,2H),2.63(dd,J＝13.0,4.9Hz,1H),1.81-1.71(m,1H)。

Example 96: 5-amino-1- [ 3-fluorotetrahydropyran-4-yl ] -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (isomer 2)

N- [ [4- [ 5-amino-4-cyano-1- (3-fluorotetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy group Yl-benzamide (isomer 2)

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.31mmol) and 5-amino-3- (4-bromophenyl) -1- (3-fluorotetrahydropyran-4-yl) pyrazole-4-carbonitrile (isomer 2, 0.22mmol) gave the title compound (isomer 2, 0.16mmol, 72% yield). UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 450.1[ M + H]⁺。

5-amino-1- [ 3-fluorotetrahydropyran-4-yl]-3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical] Pyrazole-4-carboxamide (isomer 2)

General procedure L, purification by flash column chromatography on silica gelDissolving, eluting with 0-10% MeOH in DCM, recrystallizing from DCM, and reacting to obtain N- [ [4- [ 5-amino-4-cyano-1- (3-fluorotetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (isomer 2, 0.16mmol) to give 5-amino-1- [ 3-fluorotetrahydropyran-4-yl]-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (isomer 2, 0.02 mmol). UPLC-MS (ES)⁺Long acidic): 3.09 min, M/z 468.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.6Hz,1H),7.52-7.40(m,5H),7.16(d,J＝8.2Hz,1H),7.04(t,J＝7.7Hz,1H),6.45(br s,2H),5.03-4.82(m,1H),4.65-4.52(m,3H),4.18(dd,J＝10.6,5.4Hz,1H),3.97-3.91(m,1H),3.91(s,3H),3.49-3.38(m,1H),3.33(m,1H),2.09-1.91(m,2H)。

Example 97: 3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5- (methylamino) -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

3- (4-bromophenyl) -5- (methylamino) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

Following general procedure W, after purification, 5-amino-3- (4-bromophenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (100mg, 0.30mmol) gave the title compound (64mg, 0.18mmol, 61% yield) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.80 min, M/z 348.9[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-5- (methylamino) -1-tetrahydrofuran-3-yl-pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 3- (4-bromophenyl) -5- (methylamino) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.18mmol) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 1.58 min, M/z 432.1[ M + H ]]⁺。

3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5- (methylamino) -1-tetrahydrofuran-3- Yl-pyrazole-4-carboxamides

Following general procedure L, after purification, N- [ [4- [ 4-cyano-5- (methylamino) -1-tetrahydrofuran-3-yl-pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.13mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS: (ES)⁺Short acidic): 1.36 min, M/z 450.1[ M + H]⁺。UPLC-MS：(ES⁺Long acidic): 3.08 min, M/z 450.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.6Hz,1H),7.54(d,J＝8.2Hz,2H),7.51-7.44(m,1H),7.36(d,J＝8.2Hz,2H),7.15(d,J＝8.3Hz,1H),7.06-7.02(m,1H),5.92(q,J＝5.4Hz,1H),5.04-4.95(m,1H),4.53(d,J＝5.9Hz,2H),4.07-3.95(m,2H),3.90(s,3H),3.88-3.79(m,2H),2.85(d,J＝5.5Hz,3H),2.33-2.24(m,2H)。

Example 98: 5-amino-1- (3, 4-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (3, 4-difluorophenyl) pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.57mmol) and (3, 4-difluorophenyl) hydrazine chloride (0.68mmol) gave the title compound (0.30mmol, 53% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.96 min, M/z 376.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3, 4-difluorophenyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (3, 4-difluorophenyl) pyrazole-4-carbonitrile (0.30mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.46mmol) gave the title compound (0.08mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 460.1[ M + H]⁺。

5-amino-1- (3, 4-difluorophenyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure M, after purification, the N- [ [4- [ 5-amino-4-cyano-1- (3, 4-difluorophenyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.08mmol) gave the title compound (0.02mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 478.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.60 min, M/z 478.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.76(t,J＝6.1Hz,1H),7.77-7.70(m,2H),7.66-7.44(m,7H),7.17-7.15(m,1H),7.07-7.02(m,1H),6.59(s,2H),4.57(d,J＝6.0Hz,2H),3.91(s,3H)。

Example 99: 5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

2- [ (4-bromo-2-fluoro-phenyl) -hydroxy-methylene]Malononitrile

General procedure W, using 4-bromo-2-fluorobenzoyl chloride (14.1mmol) and malononitrile (15.5mmol) gave crude title compound (14.1 mmol). UPLC-MS (ES) ^-Short acidic): 1.21 min, M/z 266.7[ M ]]^-。

2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile

General procedure X, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -hydroxy-methylene]Malononitrile (14.6mmol) gave the title compound (10.52mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 280.8[ M]⁺。

5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.92mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.11mmol) gave the title compound (0.82mmol) as a colorless film. UPLC-MS (ES)⁺Short acidic): 1.65 min, M/z 366.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.74mmol) and 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.49mmol) gave the title compound (0.28mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.48 min, M/z 450.1[ M + H]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1-tetrahydropyran-4-yl- Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -3-fluoro-phenyl ] -was allowed to stand]Methyl radical]-2-methoxy-benzamide (0.28mmol) gave the title compound (0.09mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.31 min, M/z 468.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.96 min, M/z 468.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.79(t,J＝6.1Hz,1H),7.73(dd,J＝7.7,1.8Hz,1H),7.51-7.47(m,1H),7.40(dd,J＝8.2,7.5Hz,1H),7.27-7.22(m,2H),7.16(dd,J＝8.3,0.6Hz,1H),7.07-7.03(m,1H),6.34(s,2H),4.55(d,J＝6.1Hz,2H),4.41-4.31(m,1H),3.99-3.92(m,2H),3.90(s,3H),3.46-3.38(m,2H),2.02-1.89(m,2H),1.82-1.73(m,2H)。

Example 100: 5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.77mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.92mmol) gave the title compound (0.69mmol) as a colorless film. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 352.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.48mmol) and 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.37mmol) gave the title compound (0.23mmol) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.47 min, M/z 436.0[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydrofuran-3-yl- Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl ] -was allowed to stand]Methyl radical]-2-methoxy-benzamide (98mg, 0.23mmol) gave the title compound (42mg, 0.09mmol, 41% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.31 min, M/z 454.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.96 min, M/z 454.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.78(t,J＝6.0Hz,1H),7.73(dd,J＝7.7,1.8Hz,1H),7.51-7.47(m,1H),7.40(dd,J＝8.1,7.6Hz,1H),7.27-7.22(m,2H),7.18-7.13(m,1H),7.06-7.04(m,1H),6.36(s,2H),4.98-4.90(m,1H),4.55(d,J＝6.1Hz,2H),4.01-3.91(m,2H),3.90(s,3H),3.82-3.75(m,2H),2.29-2.20(m,2H)。

Example 101: 5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] -2-methyl-phenyl ] pyrazole-4-carboxamide

(4-bromo-3-methyl-phenyl) methylamine

A solution of 4-bromo-3-methylbenzonitrile (5.10mmol) in THF (30mL) and borane dimethyl sulfide complex solution (2M in THF, 15.30mmol) was stirred at 0 deg.C for 30 minutes, then warmed to RT and stirred for 18 hours. The reaction was quenched with MeOH (30mL) and concentrated under reduced pressure. The residue was partitioned between EtOAc and 1m naoh aqueous solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (5.10 mmol).¹H NMR(400MHz,CDCl₃,δ):7.43-7.50(m,1H),7.21-7.15(m,1H),6.95-7.03(m,1H),3.80(s,2H),2.39(s,3H)。

N- [ (4-bromo-3-methyl-phenyl) methyl group ]-2-methoxy-benzamide

A solution of (4-bromo-3-methyl-phenyl) methylamine (5.10mmol) in THF (20mL) and N, N-diisopropylethylamine (15.29mmol) was cooled to 0 deg.C, then 2-methoxybenzoyl chloride (5.61mmol) was added, and then stirred at 0 deg.C for 20 minutes. The reaction was warmed to room temperature and stirred for 66 hours. Saturated NH for reaction₄Aqueous Cl was quenched and concentrated under reduced pressure. The residue was extracted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification gave the title compound (5.10 mmol). UPLC-MS (ES)⁺Short acidic): 2.01 min, M/z 335.9[ M +2 ]]⁺。

2-methoxy-N- [ [ 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]First of all Base of]Benzamide derivatives

General procedure R, purification, isolation of N- [ (4-bromo-3-methyl-phenyl) methyl]-2-methoxy-benzamide (5.1mmol) gave the title compound (3.82 mmol). UPLC-MS (ES)⁺Short acidic): 2.15 min, M/z 382.1[ M + H ]]⁺。

3-amino-5-bromo-1H-pyrazole-4-carbonitrile

A solution of 3-amino-4-cyanopyrazole (46.25mmol) in MeCN (180mL) and N-bromosuccinimide (60.1mmol) at 0 deg.C was heated to RT and stirred for 16 h. The reaction was concentrated under reduced pressure and the residue was purified to give the title compound (22.4 mmol). UPLC-MS (ES) ⁺Short acidic): 0.98 min, M/z 188.8[ M +2 ]]⁺。

5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carbonitrile

A solution of cesium carbonate (33.6mmol), 3-amino-5-bromo-1H-pyrazole-4-carbonitrile (22.4mmol) and bromocyclopentane (2.64mL, 24.6mmol) in MeCN (170mL) was stirred at 80 deg.C for 19H, then cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification gave the title compound (1.00g, 3.92mmol, 18% yield). UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 256.9[ M +2 ]]⁺。

5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide

General procedure M, after purification, 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carbonitrile (3.92mmol) gave the title compound (2.87 mmol). UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 274.8[ M +2 ]]⁺。

5-amino-1-cyclopentyl-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]-2-methyl-phenyl]Pyrazole- 4-carboxamides

Potassium carbonate (2.40mmol), 2-methoxy-N- [ [ 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl radical]Benzamide (0.60mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (0.57mmol) in EtOH (3mL) and water (0.6mL) were purged and degassed with nitrogen. Adding [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (0.12 mmol). The solution was sealed and heated to 120 ℃ in a microwave for 1 h. Then the reactant is passed throughThe pad was filtered and washed with DCM, then concentrated under reduced pressure. Purification gave the title compound (0.06 mmol). UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 448.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.59 min, M/z 448.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝6.1Hz,1H),7.74(dd,J＝7.5,1.9Hz,1H),7.50-7.45(m,1H),7.29(s,1H),7.27-7.19(m,2H),7.15(d,J＝8.6Hz,1H),7.03(td,J＝7.5,1.0Hz,1H),6.37(s,2H),4.66-4.58(m,1H),4.52(d,J＝6.1Hz,2H),3.89(s,3H),2.13(s,3H),2.01-1.92(m,2H),1.92-1.82(m,2H),1.81-1.71(m,2H),1.63-1.52(m,2H)。

Example 102: 5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.82mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (0.99mmol) gave the title compound (0.42mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 366.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.63mmol) and 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.42mmol) gave the title compound (0.16mmol) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.54 min, M/z 450.0[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-3-yl- Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methoxy-benzamide (0.28mmol) gave the title compound (0.03mmol, 11% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 468.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.12 min, M/z 468.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.78(t,J＝6.1Hz,1H),7.73(dd,J＝7.6,1.7Hz,1H),7.51-7.46(m,1H),7.40(dd,J＝8.2,7.5Hz,1H),7.27-7.21(m,2H),7.16(dd,J＝8.3,0.6Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.37(s,2H),4.55(d,J＝6.1Hz,2H),4.32-4.22(m,1H),3.90(s,3H),3.89-3.80(m,2H),3.52(dd,J＝10.5Hz,1H),3.35-3.25(m,1H),2.02-1.94(m,2H),1.77-1.61(m,2H)。

Example 103: 5-amino-1- (2-fluorocyclopentyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (2-fluorocyclopentylene) amino group]Carbamic acid tert-butyl ester

A solution of N-fluorobenzenesulfonylimide (1.85mmol) and 1- (trimethylsiloxy) cyclopentene (1.69mmol) in THF (8mL) was stirred at room temperature for 5 hours, then tert-butyl carbazate (1.69mmol) was added. The reaction was stirred at room temperature for a further 16 hours and then concentrated under reduced pressure. Further purification gave the title compound (1.20mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.41 min, M/z 217[ M + H]⁺。

5-amino-3- (4-bromophenyl) -1- (2-fluorocyclopentyl) pyrazole-4-carbonitrile

General procedure O, after purification at RT, the N- [ (2-fluorocyclopentylene) amino group]Carbamic acid tert-butyl esterEster (1.20mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.80mmol) gave the title compound (0.24mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.89 min, M/z 350.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-fluorocyclopentyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzyl Amides of carboxylic acids

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2-fluorocyclopentyl) pyrazole-4-carbonitrile (0.24mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.28mmol) gave the title compound (0.24mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.65 min, M/z 434.0[ M + H ]]⁺。

5-amino-1- (2-fluorocyclopentyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2-fluorocyclopentyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.24mmol) gave the title compound (0.09mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.44 min, M/z 452.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.38 min, M/z 452.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.52-7.38(m,5H),7.16(d,J＝8.3Hz,1H),7.08-7.01(m,1H),6.39(s,2H),5.27-5.07(m,1H),4.60-4.45(m,3H),3.90(s,3H),2.65-2.41(m,1H),2.09-1.83(m,4H),1.76-1.55(m,1H)。

Example 104: 5-amino-1- (2, 6-dimethyltetrahydropyran-4-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (2, 6-dimethyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester

Following general procedure E, after purification, 2, 6-dimethyloxy-4-one (200mg, 1.56mmol) and tert-butyl carbazate (217mg, 1.64mmol) gave the title compound (0.88mmol) as an off-white solid.¹H NMR(400MHz,CDCl₃,δ):7.52(s,1H),3.69-3.61(m,1H),3.59-3.51(m,1H),2.59-2.50(m,2H),2.13-2.07(m,1H),1.82-1.75(m,1H),1.53(s,9H),1.33(d,J＝6.0Hz,3H),1.28(d,J＝5.9Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (2, 6-dimethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile

General procedure O, purification, N- [ (2, 6-Dimethyltetrahydropyran-4-ylidene) amino group]Carbamic acid tert-butyl ester (0.88mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) gave the title compound (0.29mmol) as a brown solid. UPLC-MS: (ES)⁺Short acidic): 1.91 min, M/z 376.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2, 6-dimethyltetrahydropyran-4-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2, 6-dimethyltetrahydropyran-4-yl) pyrazole-4-carbonitrile (0.29mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.61mmol) gave the title compound (0.25mmol) as a brown solid. UPLC-MS: (ES) ⁺Short acidic): 1.63 min, M/z 460.1[ M + H]⁺。

5-amino-1- (2, 6-dimethyltetrahydropyran-4-yl) -3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2, 6-dimethyltetrahydropyran-4-yl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.25mmol) gave the title compound (0.02mmol) as an off-white solid. UPLC-MS: (ES)⁺Short acidic): 1.42 min, M/z 478.2[ M + H ]]⁺。UPLC-MS：(ES⁺Short acidic): 3.26 min, M/z 478.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.2Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.50-7.39(m,5H),7.15(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.36(s,2H),4.54(d,J＝6.1Hz,2H),4.43-4.35(m,1H),3.90(s,3H),3.59-3.52(m,2H),1.83-1.79(m,2H),1.62-1.53(m,2H),1.14(d,J＝6.1Hz,6H)。

Example 105: 5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.31mmol) and trifluoro- [ [ (5-fluoro-benzoyl) amino group]Methyl radical]Potassium borane (0.34mmol) gave the title compound (0.33mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.52 min, M/z 454.1[ M + H]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ]Methyl radical]Phenyl radical]-1-tetrahydrofuran Pyran-3-yl-pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.33mmol) gave the title compound (0.06mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 472.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.08 min, M/z 472.0[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.89(t,J＝6.1Hz,1H),7.50(dd,J＝9.2,3.3Hz,1H),7.43-7.32(m,2H),7.26-7.18(m,3H),6.37(s,2H),4.98-4.91(m,1H),4.56(d,J＝6.1Hz,2H),4.01-3.92(m,2H),3.90(s,3H),3.82-3.77(m,2H),2.30-2.21(m,2H)。

Example 106: 5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.30mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.33mmol) gave the title compound (0.31mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 468.1[ M + H]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyridine Pyran-4-ylpyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl) -3-fluoro-phenyl ]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.31mmol) gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.08 min, M/z 486.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.89(t,J＝6.1Hz,1H),7.50(dd,J＝9.2,3.3Hz 1H),7.43-7.32(m,2H),7.26-7.18(m,3H),6.35(s,2H),4.56(d,J＝6.1Hz,2H),4.41-4.34(m,1H),3.99-3.95(m,2H),3.91(s,3H),3..48-3.36(m,2H),2.01-1.91(m,2H),1.80-1.70(m,2H)。

Example 107: 5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.19mmol) and trifluoro- [ [ (5-fluoro-2-methyl-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.28mmol) gave the title compound (0.21mmol, assuming quantitative yield) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.59 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyridine Pyran-3-yl-pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.21mmol) gave the title compound (0.06mmol) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.42 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.24 min, M/z 486.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.89(t,J＝6.1Hz,1H),7.50(dd,J＝9.1,3.3Hz,1H),7.42-7.32(m,2H),7.26-7.18(m,3H),6.38(s,2H),4.56(d,J＝6.1Hz,2H),4.32-4.24(m,1H),3.91(s,3H),3.87-3.83(m,2H),3.31(m,2H),2.02-1.96(m,2H),1.76-1.66(m,2H)。

Example 108: 5- (difluoromethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

4, 4-difluoro-2- (methoxymethylene) -3-oxo-butyric acid ethyl ester

Anhydrous trimethyl orthoformate (15.3mmol) and 4, 4-difluoro-3-oxoA solution of ethyl butyrate (7.64mmol) in acetic anhydride (3mL) was heated under Dean-Stark conditions at 90 deg.C for 16h, cooled and concentrated under reduced pressure to give the crude title compound (7.30mmol) as a brown oil.¹H NMR(400MHz,CDCl₃Delta, isomer mixture) 7.81(s,0.5H),7.79(s,0.5H),6.58-6.22(m,1H),4.39-4.25(m,2H),4.15(s,1.5H),4.12(s,1.5H),1.38-1.31(m, 3H).

5- (difluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

A solution of 4, 4-difluoro-2- (methoxymethylene) -3-oxo-butyric acid ethyl ester (2.40mmol) in MeOH (8mL) and hydrazine hydrate (55-60% in water, 2.40mmol) was stirred at room temperature for 16 h. All volatiles were then removed under reduced pressure. The residue was diluted with EtOAc. The layers were separated and the organic layer was washed successively with water (× 2) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.81mmol, 75% yield) as a yellow oil. UPLC-MS (ES) ⁺Short acidic): 1.25 min, M/z 190.9[ M + H ]]⁺。

3-bromo-5- (difluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

N-bromosuccinimide (2.36mmol) was added portionwise to a solution of ethyl 5- (difluoromethyl) -1H-pyrazole-4-carboxylate (1.81mmol) in MeCN (6 mL). The resulting mixture was then stirred at 80 ℃ for 72 hours. The solvent was then removed under reduced pressure. The crude product was purified to give the title compound (1.38mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.43 min, M/z 268.8[ M]⁺。

3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxylic acid ethyl ester

4-Bromometrahydro-2H-pyran (0.17mL, 1.51mmol) was added to a suspension of potassium carbonate (1.51mmol) and ethyl 3-bromo-5- (difluoromethyl) -1H-pyrazole-4-carboxylate (1.38mmol) in MeCN (2.7 mL). The reaction mixture was heated at 90 ℃ for 16 h and then partitioned between water and DCM. The aqueous layer was extracted with DCM (× 3), the combined organic phases were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification to give the title compound (b) containing traces of other regioisomers0.50mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 354.9[ M +2 ]]⁺And 1.78 min, M/z 352.9[ M]⁺。

3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxylic acid

An aqueous solution of NaOH (1M, 0.85mmol) was added to a solution of 3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxylic acid ethyl ester (0.28mmol) in THF (1.3 mL). The reaction mixture was heated at 50 ℃ for 16 h, cooled to RT, acidified to-pH 1 with hydrochloric acid (1M), and extracted with DCM (× 3). The combined organic layers were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification gave the title compound (0.10mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 326.9[ M +2 ]]⁺。

3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

One drop of DMF was added to oxalyl chloride (0.02mL, 0.25mmol) and 3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxylic acid (0.10mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 ℃ and ammonium hydroxide (28 wt% in water, 1.01mmol) was added carefully. The reaction mixture was stirred at room temperature for 20 minutes and then partitioned between water and DCM. The aqueous layer was extracted with DCM (× 3) and the combined organic layers were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification gave the title compound (0.08mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.25 min, M/z 325.9[ M +2 ] ]⁺。

5- (difluoromethyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-4- Yl-pyrazole-4-carboxamides

General procedure C, after purification, [4- [ [ (2-methoxybenzoyl) amino ] was reacted]Methyl radical]Phenyl radical]Potassium borate (0.12mmol) and 3-bromo-5- (difluoromethyl) -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide (0.08mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.49 min, M/z 485.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.42 min, M/z 485.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.70-7.61(m,3H),7.58(br s,1H),7.52-7.45(m,1H),7.40(d,J＝8.4Hz,2H),7.34(t,J＝52.3Hz,1H),7.16(d,J＝7.9Hz,1H),7.08-7.01(m,1H),4.67-4.56(m,1H),4.54(d,J＝6.1Hz,2H),4.05-3.96(m,2H),3.91(s,3H),3.55-3.45(m,2H),2.26-2.10(m,2H),1.95-1.82(m,2H)。

Example 109: 5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N- [ tetrahydrofuran-3-ylideneamino group]Carbamic acid tert-butyl ester

General procedure E, using dihydro (3(2H) -furanone (0.15mL, 1.95mmol) and tert-butyl carbazate (2.35mmol) gives the crude title compound (2.02mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.23(s,1H),4.35-4.34(m,2H),4.09(t,J＝6.9Hz,2H),2.50-2.46(m,2H),1.52(s,9H)。

5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

To N- [ tetrahydrofuran-3-ylideneamino group]To a solution of tert-butyl carbamate (0.25mmol) in THF (5mL) was added a solution of borane dimethylsulfide complex (2M in THF, 0.42 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. To the residue was added a solution of hydrogen chloride in MeOH (1.25M, 8.74mmol) and the reaction mixture was heated to reflux for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Dissolve the residue with EtOH (10mL) and add 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene ]Malononitrile (0.71mmol) and triethylamine (0.50mL, 3.56 mmol). The reaction mixture was heated at reflux for 3 hours, cooled and filtered. The solid was washed with EtOH and EtOAc. The filtrate was evaporated to dryness and the resulting solid was washed with EtOAc. The solids are combined and the solid is then,the title compound (0.71mmol) was obtained as an off-white solid. UPLC-MS: (ES)⁺Short acidic): 1.72 min, M/z 352.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.68mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.96mmol) gave the title compound (0.47mmol) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 1.54 min, M/z 436.1[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydrofuran-3-yl- Pyrazole-4-carboxamides

Modified general procedure L, 96 hours, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl ] was allowed to stand]Methyl radical]-2-methoxy-benzamide (0.23mmol) gave the title compound (80mg, 0.18mmol, 77% yield) as a white solid. UPLC-MS: (ES) ⁺Short acidic): 1.35 min, M/z 454.1[ M + H]⁺。UPLC-MS：(ES⁺Long acidic): 3.07 min, M/z 454.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.17(t,J＝5.9Hz,1H),7.75(d,J＝7.7,1.7Hz,1H),7.51-7.41(m,2H),7.34-7.28(m,2H),7.16(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.34(s,2H),4.96-4.91(m,1H),4.57(d,J＝5.9Hz,2H),4.00-3.93(m,2H),3.90(s,3H),3.83-3.78(m,2H),2.28-2.23(m,2H)。

Example 110: 3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -5- (methylamino) -1- (3-pyridinyl) pyrazole-4-carboxamide

3- (4-bromophenyl) -5- (methylamino) -1- (3-pyridyl) pyrazole-4-carbonitrile

A solution of 5-amino-3- (4-bromophenyl) -1- (3-pyridyl) pyrazole-4-carbonitrile (0.53mmol) in MeOH (8mL), paraformaldehyde (1.59mmol), and sodium methoxide (3.17mmol) was heated at 70 deg.C for 1 h. Then, it was cooled back to room temperature. Sodium borohydride (5.29mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Then carefully quenched with water and the aqueous layer extracted with chloroform (3 × 20 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification gave the title compound (0.56mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 355.9[ M +2 ]]⁺。

N- [ [4- [ 4-cyano-5- (methylamino) -1- (3-pyridinyl) pyrazol-3-yl ] amino]Phenyl radical]Methyl radical]-2-methoxy- Benzamide derivatives

General procedure K, after purification, 3- (4-bromophenyl) -5- (methylamino) -1- (3-pyridyl) pyrazole-4-carbonitrile (0.56mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group ]Methyl radical]Potassium borane (0.62mmol) gave the title compound (0.08mmol) as an off-white solid. LC-MS (ES)⁺Short acidic): 4.71 min, M/z 439.2[ M + H ]]⁺。

3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-5- (methylamino) -1- (3-pyridinyl) pyri dine Azole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 4-cyano-5- (methylamino) -1- (3-pyridinyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.11mmol) gave the title compound (0.05mmol) as an off-white solid. UPLC-MS (ES)^-Short acidic): 1.32 min, M/z 455.0[ M-H]^-。UPLC-MS(ES⁺Long acidic): 2.98 min, M/z 457.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84-8.83(m,1H),8.75(t,J＝6.2Hz,1H),8.63(dd,J＝4.8,1.5Hz,1H),8.05-8.02(m,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.62-7.56(m,3H),7.51-7.46(m,1H),7.42(d,J＝8.4Hz,2H),7.1(d,J＝7.8Hz,1H),7.04(td,J＝7.5,1.7Hz,1H),6.60(br s,1H),4.56(d,J＝6.1Hz,2H),3.90(s,3H),2.58(s,3H)。

Example 111: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [2- (trifluoromethyl) tetrahydropyran-4-yl ] pyrazole-4-carboxamide

N- [ [2- (trifluoromethyl) tetrahydropyran-4-ylidene]Amino group]Carbamic acid tert-butyl ester

A solution of 2- (trifluoromethyl) oxacyclohexan-4-one (1.51mmol) in MeOH (15mL) and tert-butyl carbazate (1.59mmol) was stirred at RT for 14 h. The reaction mixture was then washed with saturated NH₄Aqueous Cl was quenched and extracted with DCM (× 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Further purification gave the title compound (1.29mmol) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.50 min, M/z 283.0[ M + H ]]⁺。

N- [ [2- (trifluoromethyl) tetrahydropyran-4-yl]Amino group]Carbamic acid tert-butyl ester

To the N- [ [2- (trifluoromethyl) tetrahydropyran-4-ylidene group at 0 DEG C]Amino group]To a solution of tert-butyl carbamate (1.25mmol) in THF (6mL) was added a solution of borane tetrahydrofuran complex (1.0M in THF, 2.5 mmol). After that, the reaction mixture was stirred at RT for 14 hours. Subsequently, the reaction mixture was quenched with MeOH (2 mL). Water was then added and the aqueous phase was extracted with DCM (× 3). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.17mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 301.0[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1- [2- (trifluoromethyl) tetrahydropyran-4-yl]Pyrazole-4-carbonitriles

Hydrogen chloride solution (4M in dioxane, 14.5mmol) was added to the N- [ [2- (trifluoromethyl) tetrahydropyran-4-yl ester]Amino group]Tert-butyl carbamate (1.45 mmol). After that, the mixture was stirred at room temperature for 15 hours. A precipitate formed and was collected. Concentrating the filtrate under reduced pressure to obtainTo crude [2- (trifluoromethyl) tetrahydropyran-4-yl]Hydrazine hydrochloride (250mg, 1.13mmol, 79%) as a dark orange gum. Then [2- (trifluoromethyl) tetrahydropyran-4-yl is purified, after purification, at 85 ℃ according to general procedure H ]Hydrazine hydrochloride (1.13mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.57mmol) gave the title compound (0.19mmol) as an orange gum. UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 416.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [2- (trifluoromethyl) tetrahydropyran-4-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]First of all Base of]-2-methoxy-benzamide

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [2- (trifluoromethyl) tetrahydropyran-4-yl]Pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.09mmol) as an orange gum. UPLC-MS (ES)⁺Short acidic): 1.72 min, M/z 500.1[ M + H]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [2- (trifluoromethyl) tetrahydropyridine Pyran-4-yl radical]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [2- (trifluoromethyl) tetrahydropyran-4-yl ] methyl ester]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (58mg, 0.12mmol) gave the title compound (0.02mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 518.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.60 min, M/z 518.0[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.1Hz,1H),7.76(dd,J＝7.7,1.8Hz,1H),7.51-7.41(m,5H),7.17-7.15(m,1H),7.06-7.04(m,1H),6.41(s,2H),4.55(d,J＝6.1Hz,2H),4.54-4.48(m,1H),4.18-4.13(m,2H),3.91(s,3H),3.67-3.60(m,1H),2.08-1.85(m,4H)。

Example 112: 5- (difluoromethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ (3S) -tetrahydrofuran-3-yl ] pyrazole-4-carboxamide

3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxylic acid ethyl ester

To a solution of (R) - (-) -3-hydroxytetrahydrofuran (1.12mmol), triphenylphosphine (1.12mmol) and ethyl 3-bromo-5- (difluoromethyl) -1H-pyrazole-4-carboxylate (0.74mmol) in THF (3.5mL) was added diisopropyl azodicarboxylate (1.12 mmol). The mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. Further purification gave (isomer 2). UPLC-MS (ES)⁺Short acidity: isomer 1): 1.73 min, M/z 340.9[ M +2 ]]⁺。UPLC-MS(ES⁺Short acidity: isomer 2): 1.63 min, M/z 340.9[ M +2 ]]⁺。

3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxylic acids

Sodium hydroxide (1M in water, 0.95mmol) was added to 3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxylic acid ethyl ester (0.32mmol) in THF (1.3 mL). The mixture was then heated to 50 ℃ for 16 hours, cooled to room temperature, and acidified to-pH 1 with HCl (1M aqueous solution). The layers were layered. The aqueous layer was extracted with DCM (. times.3). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure to give the crude title compound (0.32mmol) as an off-white solid, which was used directly in the next step. UPLC-MS (ES) ⁺Short acidic): 1.31 min, M/z 312.8[ M +2 ]]⁺。

3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxamides

A drop of DMF was added to oxalyl chloride (0.48mmol) and 3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxylic acid (0.32mmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour, cooled to 0 ℃ and then ammonium hydroxide (28 wt% in water, 1.90mmol) was added carefully. The reaction mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and DCM and the layers were separated. Mixing waterThe layers were extracted with DCM (× 3) and the combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification gave the title compound (0.27mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.18 min, M/z 311.8[ M +2 ]]⁺。

5- (difluoromethyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ (3S) -tetrahydrofuran Pyran-3-yl radicals]Pyrazole-4-carboxamides

General procedure C, after purification, [4- [ [ (2-methoxybenzoyl) amino ] was reacted]Methyl radical]Phenyl radical]Boronic acid (0.15mmol) and 3-bromo-5- (difluoromethyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carboxamide (0.10mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.47 min, M/z 471.0[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.36 min, M/z 471.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.9Hz,1H),7.68-7.61(m,3H),7.60(br s,1H),7.52-7.45(m,1H),7.40(d,J＝8.4Hz,2H),7.33(t,J＝53.6Hz,1H),7.16(d,J＝7.8Hz,1H),7.08-7.01(m,1H),5.28-5.19(m,1H),4.53(d,J＝6.1Hz,2H),4.14-4.03(m,2H),3.94-3.83(m,5H),2.48-2.31(m,2H)。

Example 113: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-5-fluoro-2-methoxy Phenyl-carboxamides

General procedure K, purification, isolation of trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.19mmol) and 5-amino-3- (4-bromophenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.14mmol) gave the title compound (0.06mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 450[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydropyran-3- Yl-pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) phenyl ] was reacted]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.06mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.41 min, M/z 468.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.22 min, M/z 468.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.2Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.45(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),7.34(m,1H),7.19(m,1H),6.42(s,2H),4.55(d,J＝6.1Hz,2H),4.30-4.19(m,1H),3.90(s,3H),3.88-3.80(m,2H),3.54(t,J＝10.5Hz,1H),3.36-3.26(m,1H),2.06-1.95(m,2H),1.79-1.59(m,2H)。

Example 114: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.57mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.68mmol) gave the title compound (0.40mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 334.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) phenyl]Methyl radical]-5-fluoro-2-methoxy Phenyl-carboxamides

General procedure K, purification, isolation of trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.23mmol) and 5-amino-3- (4-bromophenyl) -1-tetrahydrofuranPyran-3-yl-pyrazole-4-carbonitrile (0.18mmol) gave the title compound (0.09mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 436[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydrofuran-3- Yl-pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) phenyl ] was reacted]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.09mmol) gave the title compound (0.07mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.35 min, M/z 454.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.2Hz,2H),7.41(d,J＝8.3Hz,2H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.40(s,2H),4.99-4.89(m,1H),4.55(d,J＝6.0Hz,2H),4.03-3.92(m,2H),3.90(s,3H),3.85-3.76(m,2H),2.30-2.21(m,2H)。

Example 115: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene was taken]Malononitrile (1.39g, 5.29mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.00g, 6.35mmol) gave the title compound (4.78mmol) as an off-white solid. LC-MS (ES)⁺Short acidic): 5.64 min, M/z 347.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) phenyl]Methyl radical]-5-fluoro-2-methoxy Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1-tetrakisHydropyran-4-yl-pyrazole-4-carbonitrile (4.78mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (9.56mmol) gave the title compound (1.98mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 450.1[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydropyran-4-yl Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) phenyl ] was ]Methyl radical]-5-fluoro-2-methoxy-benzamide (1.98mmol) to give the title compound formamide (1.46mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 468.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.14 min, M/z 468.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.1Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.3Hz,2H),7.41(d,J＝8.4Hz,2H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.38(s,2H),4.55(d,J＝6.1Hz,2H),4.42-4.27(m,1H),4.01-3.93(m,2H),3.90(s,3H),3.48-3.37(m,2H),2.05-1.91(m,2H),1.82-1.72(m,2H)。

Example 116: 5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.88mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.05mmol) gave the title compound (0.60mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.76 min, M/z 366.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.60mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (1.27mmol) gave the title compound (0.49mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 450.1[ M + H ]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-4-yl- Pyrazole-4-carboxamides

General M, purification followed by reaction of N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methoxy-benzamide (0.26mol) gave the title compound (0.10mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.35 min, M/z 468.0[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.08 min, M/z 468.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝5.9Hz,1H),7.75(dd,J＝7.6,1.6Hz,1H),7.51-7.42(m,2H),7.34-7.23(m,2H),7.16(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.32(s,2H),4.57(d,J＝6.1Hz,2H),4.40-4.33(m,1H),3.99-3.95(m,2H),3.91(s,3H),3.46-3.39(m,2H),2.03-1.93(m,2H),1.79-1.75(m,2H)。

Example 117: 5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.20mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (A), (B), (C), (D) and (D)0.43mmol) to give the title compound (0.16mmol) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 450.0[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran-3-yl- Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl ]Methyl radical]-2-methoxy-benzamide (0.16mmol) gave the title compound (0.09mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 468.0[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.24 min, M/z 468.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝5.9Hz,1H),7.75(dd,J＝7.5,1.8Hz,1H),7.51-7.41(m,2H),7.33-7.26(m,2H),7.16(d,J＝8.2Hz,1H),7.06-7.02(m,1H),6.35(s,2H),4.57(d,J＝6.0Hz,2H),4.30-4.22(m,1H),3.91(s,3H),3.89-3.83(m,2H),3.54(t,J＝10.5Hz,1H),3.39-3.26(m,1H),2.03-1.98(m,2H),1.77-1.65(m,2H)。

Example 118: 5-amino-1-cyclopentyl-3- [ 4-fluoro-3- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (5-bromo-2-fluoro-phenyl) methyl]-2-methoxy-benzamide

To a solution of 5-bromo-2-fluorobenzonitrile (2.50mmol) in THF (15mL) cooled to 0 deg.C was added dropwise a solution of borane-tetrahydrofuran complex (1M in THF, 7.5mL, 7.50 mmol). The reaction was stirred at 0 ℃ for 20 minutes and then at room temperature for 16 hours. The reaction mixture was quenched dropwise with MeOH (15mL) and the solution was concentrated under reduced pressure. The oil was then partitioned between aqueous NaOH (1M) and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude (5-bromo-2-fluoro-phenyl) methylamine (629mg) as a colorless oil. The oil was washed with THF (10mL)Dissolve and cool to 0 ℃. Then 2-methoxybenzoyl chloride (2.75mmol) and N, N-diisopropylethylamine (7.50mmol) were added successively. The reaction mixture was stirred at 0 ℃ for 20 minutes and then at room temperature for 16 hours. Saturated NH for the mixture ₄The aqueous Cl solution was quenched and the organics removed under reduced pressure. The residue was then extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified to give the title compound (1.30mmol) as a colorless oil. UPLC-MS (ES)⁺Short acidic): 1.75 min, M/z 339.9[ M +2 ]]⁺。

N- [ [ 2-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl ester]Methyl radical]-2-methoxy- Benzamide derivatives

General procedure R, purification, isolation of N- [ (5-bromo-2-fluoro-phenyl) methyl]-2-methoxy-benzamide (1.30mmol) gave the title compound (1.26mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.92 min, M/z 386.0[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [ 4-fluoro-3- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure D, after purification, N- [ [ 2-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] was reacted]Methyl radical]-2-methoxy-benzamide (0.65mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (0.62mmol) gave the title compound (0.05mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 452.1.0[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.59 min, M/z 452.0[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.71(t,J＝5.9Hz,1H),7.69(dd,J＝7.6,1.8Hz,1H),7.52(dd,J＝7.5,2.1Hz,1H),7.46-7.44(m,1H),7.42-7.36(m,1H),7.26(dd,J＝10.0,8.5Hz,1H),7.15-7.11(m,1H),7.04-6.99(m,1H),6.31(s,2H),4.64-4.54(m,3H),3.84(s,3H),1.98-1.90(m,2H),1.90-1.81(m,2H),1.81-1.69(m,2H),1.61-1.50(m,2H)。

Example 119: 5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (150mg, 0.53mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.64mmol) gave the title compound (0.53mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.72 min, M/z 352.8[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.23mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.32mmol) gave the title compound (0.20mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.59 min, M/z 454.0[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydrofuran Pyran-3-yl-pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl ]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.20mmol) gave the title compound (0.16mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 494.0[ M + Na [)]⁺。UPLC-MS(ES⁺Long acidic): 3.20 min, M/z 472.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.82(t,J＝6.1Hz,1H),7.50(dd,J＝9.2,3.3Hz,1H),7.43(t,J＝8.0Hz,1H),7.37-7.28(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.34(s,2H),4.97-4.91(m,1H),4.56(d,J＝5.9Hz,2H),4.01-3.93(m,2H),3.90(s,3H),3.83-3.78(m,2H),2.28-2.23(m,2H)。

Example 120: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

N- [ (2,2, 2-trifluoro-1-methyl-ethylene) amino]Benzamide derivatives

General procedure S, after washing, benzoyl hydrazine (49.9mmol) and 1,1, 1-trifluoroacetone (74.9mmol) gave the title compound as a white solid. UPLC-MS (ES)⁺Short acidic): 1.45 min, M/z 230.9[ M + H ]]⁺。

N' - (2,2, 2-trifluoro-1-methyl-ethyl) benzoyl hydrazine

To the cooled N- [ (2,2, 2-trifluoro-1-methyl-ethylene) amino group at 0 DEG C]A solution of borane tetrahydrofuran complex (1M in THF, 43.44mmol) in benzamide (21.7mmol) in THF (50mL) was added dropwise. The reaction was allowed to return to room temperature and stirred for 14 hours. The reaction was cooled to 0 ℃, quenched with MeOH (20mL), and then allowed to return to room temperature. The mixture was evaporated and DCM (75mL) was added. The slurry was filtered to remove insoluble material. The organic layer was washed with saturated ammonium chloride (50mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Petroleum ether (50mL) was added to the yellow oil, resulting in the solid being discarded. The solvent was reduced by 50%, and the slurry was cooled in an ice bath and filtered. The solid was washed with petroleum ether (25mL) to give the title compound as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.41 min, M/z 232.9[ M + H ]]⁺。

(2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride

Following general procedure U, N' - (2,2, 2-trifluoro-1-methyl-ethyl) benzoylhydrazine (4.0g, 17.2mmol) gave (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (1.7g, 10.3mmol, 60% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):9.65(br s,2H),5.97(br s,1H),3.87-3.80(m,1H),1.28(d,J＝6.8Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

To 2- [ (4-bromophenyl) -methoxy-methylene]To a solution of malononitrile (7.98mmol) in EtOH (50mL) was added triethylamine (31.9 mmol). After stirring for 10 min, (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (12.0mmol) was added. The reaction mixture was heated to 80 ℃ for 14 hours, cooled and concentrated under reduced pressure. Further purification gave the title compound (7.24mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 360.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 5-fluoro-2-methoxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (4.26mmol) and 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (2.51mmol) gave the title compound (2.17mmol) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.71 min, 462.0[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro- 1-methyl-ethyl) pyrazole-4-carboxamide

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.83mmol) gave the title compound (0.42mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 480.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.57 min, M/z 480.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.1Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.48-7.41(m,4H),7.37-7.32(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.67(s,2H),5.35-5.24(m,1H),4.56(d,J＝6.0Hz,2H),3.90(s,3H),1.62(d,J＝6.9Hz,3H)。

Example 121: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) carboxamide

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (0.92mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (1.39mmol) gave the title compound (0.41mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, M/z 444.0[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro-1-methyl- Ethyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.40mmol) gave the title compound (0.182mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.48 min, M/z 462.0[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.42 min, M/z 461.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.2Hz,1H),7.76(dd,J＝7.6,1.8Hz,1H),7.51-7.42(m,5H),7.16(d,J＝7.8Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.67(br s,2H),5.33-5.26(m,1H),4.56(d,J＝6.1Hz,2H),3.90(s,3H),1.62(d,J＝6.8Hz,3H)。

Example 122: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) carboxamide

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile

Triethylamine (380.13mmol) and 2- [ (4-bromophenyl) -methoxy-methylene were added]A solution of malononitrile (25.0g, 95.03mmol) in EtOH (600mL) was stirred for 10 minutes, then 2,2, 2-trifluoroethylhydrazine (70 wt% in water, 142.54mmol) was added to give almost immediately a clear orange solution, giving off heat from 22-29 ℃ in 2-3 minutes. The resulting mixture was then heated to reflux for 5 hours. Once the reaction was complete, the reaction mixture was concentrated under reduced pressure to give an orange solid. Further purification gave the title compound (25.3g, 73.31mmol, 77% yield) as a light yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.78 min, M/z 346.8[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-5-fluoro-2-carboxylic acid methyl ester Oxy-benzamides

Reacting 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (29.0mmol), trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]A mixture of potassium borane (58.03mmol), cesium carbonate (86.92mmol), 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (2.03mmol), THF (120mL) and water (60mL) was degassed under vacuum at RT and flushed with nitrogen three times. Palladium (II) acetate (1.01mmol) was then added and the mixture was degassed again. The reaction mixture was heated to reflux for 2h, cooled and diluted with water (100mL) and EtOAc (200mL) and filteredFiltering and separating. The aqueous layer was extracted with EtOAc (100mL) and the combined organic extracts were washed with water and then dried over magnesium sulfate. Further purification yielded a solid, which was further purified using a slurry in hot THF and EtOAc (100mL, 1: 1) and precipitated with petroleum ether and stirred to cold. The product was filtered and washed with petroleum ether to give the title compound (24.7 mmol). UPLC-MS (ES)⁺Short acidic): 1.61 min, M/z 448.0[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group ]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoroethyl) ethane Yl) pyrazole-4-carboxamides

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (30.40mmol) was added to a solution of sulfuric acid (304mmol) and TFA (912mmol) to give a light brown solution. The reaction mixture was heated to 58 ℃ for 5 h, cooled and poured slowly into an ice-cooled solution of sodium bicarbonate (153.2g, 1824mmol) in water (750mL) and extracted with EtOAc (3X 250 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Further purification gave the title compound (28.4 mmol). UPLC-MS (ES)^-Short acidic): 1.44 min, M/z 463.7[ M-H]^-。UPLC-MS(ES⁺Long acidic): 3.31 min, M/z 465.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.85(t,J＝6.0Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.47(d,J＝8.2Hz,2H),7.42(d,J＝8.2Hz,2H),7.38-7.32(m,1H),7.19(dd,J＝9.2,4.3Hz,1H),6.68(s,2H),4.94(q,J＝9.0Hz,2H),4.56(d,J＝6.1Hz,2H),3.90(s,3H)。

Example 123: 5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.22mmol) and trifluoro- [ [ (5-fluoro-2-methyl-2-methoxy-benzoyl) amino group ]Methyl radical]Potassium borane (0.31mmol) gave the title compound (0.22mmol, assuming quantitative yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.61 min, m-z 468.0[M+H]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydropyridine Pyran-4-ylpyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.22mmol) gave the title compound (0.15mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 507.9[ M + Na ]]⁺。UPLC-MS(ES⁺Long acidic): 3.20 min, M/z 486.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.81(t,J＝6.1Hz,1H),7.51(dd,J＝9.3,3.4Hz,1H),7.46-7.39(m,1H),7.37-7.27(m,3H),7.19(dd,J＝9.2,4.3Hz,1H),6.32(s,2H),4.57(d,J＝5.9Hz,2H),4.40-4.32(m,1H),3.96(dd,J＝11.5,3.4Hz,2H),3.90(s,3H),3.47-3.37(m,2H),2.03-1.96(m,2H),1.79-1.75(m,2H)。

Example 124: 5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromo-2-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.73mmol) and 2,2, 2-trifluoroethylhydrazine (70 wt% in water, 0.87mmol) gave the title compound (0.47mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.72 min, M/z 362.8[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group ]-3-fluoro-phenyl]Methyl radical]-2- Methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxylic acid methyl esterNitrile (0.23mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.34mmol) gave the title compound (0.21mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 448.0[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoroethyl) ethane Yl) pyrazole-4-carboxamides

Following general procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl ] was reacted]-3-fluoro-phenyl]Methyl radical]-2-methoxy-benzamide (0.21mmol) gave the title compound (0.15mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.41 min, M/z 488.0[ M + Na ]]⁺。UPLC-MS(ES⁺Long acidic): 3.22 min, M/z 466.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.79(t,J＝6.1Hz,1H),7.73(dd,J＝7.5,1.8Hz,1H),7.50-7.46(m,1H),7.45-7.38(m,1H),7.27-7.24(m,2H),7.16(d,J＝8.1Hz,1H),7.06-7.02(m,1H),6.64(s,2H),4.99-4.93(m,2H),4.56(d,J＝5.9Hz,2H),3.91(s,3H)。

Example 125: 5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]-3-fluoro-phenyl]Methyl radical]-5- Fluoro-2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (0.23mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group ]Methyl radical]Potassium borane (0.33mmol) gave the title compound (0.20mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.61 min, M/z 466.1[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-)Methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-(2,2,2- Trifluoroethyl) pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl ] was]-3-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.20mmol) gave the title compound (0.12mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 506.0[ M + Na ]]⁺。UPLC-MS(ES⁺Long acidic): 3.34 min, M/z 484.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.89(t,J＝6.1Hz,1H),7.50(dd,J＝9.2,3.5Hz,1H),7.45-7.38(m,1H),7.37-7.32(m,1H),7.25(d,J＝9.2Hz,2H),7.19(dd,J＝9.1,4.2Hz,1H),6.64(s,2H),4.99-4.93(m,2H),4.56(d,J＝6.1Hz,2H),3.90(s,3H)。

Example 126: 5-amino-1- (2, 2-difluoro-1-methyl-ethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (2, 2-difluoro-1-methylethylidene) amino group]Carbamic acid tert-butyl ester

Modified general procedure E, using tert-butyl carbazate (1.51mmol) and 1, 1-difluoro-propan-2-one (1.82mmol) at 60 ℃ gives the crude title compound (1.51mmol) as a white solid. UPLC-MS (ES)^-Short acidic): 1.45 min, M/z 206.8[ M-H ]]^-。

5-amino-3- (4-bromophenyl) -1- (2, 2-difluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

General procedure O, at room temperature, after purification, N- [ (2, 2-difluoro-1-methylethylidene) amino group ]Carbamic acid tert-butyl ester (0.58mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.46mmol) gave the title compound (0.43mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.83 min, M/z 340.6[ M ]]⁺。

N-[[4-[ 5-amino-4-cyano-1- (2, 2-difluoro-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2- Methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2, 2-difluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (0.15mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.22mmol) gave the title compound (0.08mmol), a white solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 426.0[ M + H ]]⁺。

5-amino-1- (2, 2-difluoro-1-methyl-ethyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2, 2-difluoro-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.08mmol) gave the title compound (0.04mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.43 min, M/z 444.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.25 min, M/z 444.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.74(dd,J＝7.6,1.8Hz,1H),7.51-7.38(m,5H),7.15(d,J＝8.3Hz,1H),7.07-7.00(m,1H),6.53(s,2H),6.21(dt,J＝55.7,5.3Hz,1H),4.85-4.70(m,1H),4.54(d,J＝6.2Hz,2H),3.89(s,3H),1.44(d,J＝6.7Hz,3H)。

Example 127: 5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, tetrahydropyran-3-ylhydrazine hydrochloride (0.77mmol) and 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.64mmol) gave the title compound (0.20mmol) as off-whiteA colored solid. UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 366.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl]Methyl radical]-5-fluoro- 2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoylamino group]Methyl radical]Potassium borane (106mg, 0.37mmol) gave the title compound (54mg, 0.12mmol, 66% yield) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 468.0[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-tetrahydropyridine Pyran-3-yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2-fluoro-phenyl ] -was allowed to stand]Methyl radical]-5-fluoro-2-methoxy-benzamide (54mg, 0.12mmol) to give the title compound (20mg, 0.04mmol, 36% yield) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.47 min, M/z 485.9[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.37 min, M/z 486.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.81(t,J＝6.0Hz,1H),7.50(dd,J＝9.2,3.3Hz,1H),7.44-7.40(m,1H),7.37-7.26(m,3H),7.19(dd,J＝9.3,4.3Hz,1H),6.35(s,2H),4.56(d,J＝6.0Hz,2H),4.30-4.22(m,1H),3.90(s,3H),3.87-3.82(m,2H),3.58-3.48(m,1H),3.37-3.27(m,1H),2.03-1.98(m,2H),1.77-1.65(m,2H)。

Example 128: 5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile

Following general procedure H, purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM, gave 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (500mg, 1.78mmol) and 2,2, 2-trifluoroethylhydrazine (70 wt% in water, 31 μ L, 2.13mmol) gave 5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (132mg, 0.36mmol, 20% yield) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.82 min, M/z 362.7[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]-2-fluoro-phenyl]Methyl radical]-5- Fluoro-2-methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.12mmol) as a pale orange solid. UPLC-MS (ES) ⁺Short acidic): 1.68 min, M/z 465.9[ M + H]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-(2,2,2- Trifluoroethyl) pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl)]-2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.12mmol) to give the title compound (22mg, 0.05mmol, 39% yield) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 484.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.44 min, M/z 484.0[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.82(t,J＝5.9Hz,1H),7.51(dd,J＝9.7,3.7Hz,1H),7.47-7.40(m,1H),7.37-7.27(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.63(s,2H),4.95(q,J＝9.3Hz,2H),4.57(d,J＝6.5Hz,2H),3.90(s,3H)。

Example 129: 5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl group]-2-fluoro-phenyl]Methyl radical]-2- Methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoroethyl) pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.27mmol) gave the title compound (0.07mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 448.0[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoroethyl) ethane Yl) pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoroethyl) pyrazol-3-yl ] was reacted]-2-fluoro-phenyl]Methyl radical]-2-methoxy-benzamide (27mg, 0.06mmol) gave the title compound (0.03mmol, 54% yield) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.45 min, M/z 466.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.32 min, M/z 466.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.7,1.8Hz,1H),7.51-7.42(m,2H),7.35-7.28(m,2H),7.16(d,J＝7.7Hz,1H),7.07-7.01(m,1H),6.61(s,2H),5.00-4.90(m,2H),4.57(d,J＝6.0Hz,2H),3.90(s,3H)。

Example 130: 5-amino-1-cyclopentyl-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromo-2-fluoro-phenyl) -1-Cyclopentyl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (0.71mmol) and cyclopentylhydrazine hydrochloride (0.85mmol) gave the title compound as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.95 min, M/z 350.8[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.37mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group ]Methyl radical]Potassium borane (0.41mmol) gave the title compound (0.32mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.70 min, M/z 434.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [ 2-fluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4- Carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-2-methoxy-benzamide (0.32mmol) gave the title compound (0.07mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 452.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.52 min, M/z 452.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.79(t,J＝6.0Hz,1H),7.74(dd,J＝7.7,1.8Hz,1H),7.52-7.46(m,1H),7.43-7.37(m,1H),7.26-7.21(m,2H),7.19-7.14(m,1H),7.04(td,J＝11.2,0.9Hz,1H),6.29(s,2H),4.66-4.59(m,1H),4.56(d,J＝6.1Hz,2H),3.91(s,3H),2.02-1.73(m,6H),1.64-1.56(m,2H)。

Example 131: 5-amino-1- (1-cyclopropylethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ 1-Cyclopropylethylideneamino]Carbamic acid tert-butyl ester

Following general procedure E, using cyclopropylmethyl ketone (0.60mL, 6.06mmol) and tert-butyl carbazate (880mg, 6.66mmol) gave the title compound (6.06mmol) as a white solid.¹H NMR(400MHz,CDCl₃,δ):7.35(br s,1H),1.80-1.71(m,1H),1.63(s,3H),1.50(s,9H),0.77(s,2H),0.75(s,2H)。

5-amino-3- (4-bromophenyl) -1- (1-cyclopropylethyl) pyrazole-4-carbonitrile

To N- [ 1-cyclopropylethylamino ] -N]To a solution of tert-butyl carbamate (6.05mmol) in THF (20mL) was added a solution of borane dimethylsulfide complex (2M in THF, 10.3 mmol). The reaction was stirred at room temperature for 2 hours, then the volatiles were removed under reduced pressure. The residue was dissolved in MeOH (20mL) and concentrated HCl (30.3mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was dissolved in EtOH (10mL) and 2- [ (4-bromophenyl) -methoxy-methylene) was added ]Malononitrile (100mg, 0.38mmol) and triethylamine (1.9 mmol). The reaction mixture was heated to reflux and stirred for 16 hours. All volatiles were then removed under reduced pressure and the residue was purified to give the title compound (0.33mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.95 min, M/z 332.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-cyclopropylethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzene Carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (1-cyclopropylethyl) pyrazole-4-carbonitrile (0.33mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.48mmol) gave the title compound (0.12mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 416.1[ M + H]⁺。

5-amino-1- (1-cyclopropylethyl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (1-cyclopropylethyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.12mmol) gave the title compound (0.06mmol) as a solid. UPLC-MS (ES)⁺Short acidic): 1.47 min, M/z 434.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.35 min, M/z 434.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.4Hz,1H),7.75(dd,J＝7.7,1.7Hz,1H),7.50-7.40(m,5H),7.15(d,J＝8.2Hz,1H),7.06-7.02(m,1H),6.26(s,2H),4.54(d,J＝6.2Hz,2H),3.90(s,3H),3.71-3.64(m,1H),1.41(d,J＝6.6Hz,3H),1.33-1.23(m,1H),0.58-0.51(m,1H),0.40-0.34(m,2H),0.28-0.22(m,1H)。

Example 132: 5-amino-3- [3, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Modified general procedure H, at RT, with 2- (4-chloro-3, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (0.98mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.18mmol) gave the crude title compound (0.98 mmol). UPLC-MS (ES)⁺Short acidic): 1.82 min, M/z 339.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]-2- Methoxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (1.09mmol) and 5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.49mmol) gave the title compound (0.13 mmol). UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [3, 5-bisFluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran- 4-Yl-pyrazole-4-carboxamides

Following general procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 6-difluoro-phenyl ] -was allowed to stand ]Methyl radical]-2-methoxy-benzamide (0.13mmol) gave the title compound (0.01mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.18 min, M/z 486.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.57(t,J＝5.5Hz,1H),7.73(dd,J＝7.8,1.8Hz,1H),7.51-7.44(m,1H),7.26-7.19(m,2H),7.14(d,J＝8.5Hz,1H),7.05-7.01(m,1H),6.27(br s,2H),4.58(d,J＝5.6Hz,2H),4.43-4.32(m,1H),4.00-3.93(m,2H),3.88(s,3H),3.43(t,J＝11.9Hz,2H),2.04-1.94(m,2H),1.79-1.75(m,2H)。

Example 133: 5-amino-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]-5- Fluoro-2-methoxy-benzamides

General procedure K, using trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (0.99mmol) and 5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.49mmol) gave the crude title compound (0.49 mmol). UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 486.0[ M + H ]]⁺。

5-amino-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-4-ylpyrazole-4-carboxamides

General procedure M, purification, Synthesis of N- [ [4- (5-amino-4-cyano-1-tetrahydropyran)-4-ylpyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.49mmol) gave the title compound (0.09mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.45 min, M/z 504.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.31 min, M/z 504.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.67(t,J＝5.6Hz,1H),7.48(dd,J＝9.0,3.3Hz,1H),7.36-7.30(m,1H),7.26-7.13(m,3H),6.27(br s,2H),4.58(d,J＝5.5Hz,2H),4.43-4.33(m,1H),3.99-3.94(m,2H),3.87(s,3H),3.43(t,J＝11.1Hz,2H),2.03-1.93(m,2H),1.79-1.74(m,2H)。

Example 134: 5-amino-1-cyclopentyl-3- [6- [ [ (2-methoxybenzoyl) amino ] methyl ] -3-pyridinyl ] pyrazole-4-carboxamide

N- [ (5-bromo-2-pyridyl) methyl group]-2-methoxy-benzamide

To a solution of (5-bromo-2-pyridyl) methylamine (1.60mmol) in DMF (4mL) at 0 deg.C was added N, N-diisopropylethylamine (4.81 mmol). After stirring for 10 min, 2-methoxybenzoyl chloride (3.21mmol) was added slowly. The reaction mixture was warmed to RT and stirred under nitrogen for 18 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purification gave the title compound (0.92mmol) as a pale yellow oil. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 322.8[ M +2 ]]⁺。

[6- [ [ (2-methoxybenzoyl) amino group]Methyl radical]-3-pyridyl]Boric acid

At-78 deg.C to N- [ (5-bromo-2-pyridyl) methyl group]Triisopropylborate (0.35mL, 1.50mmol) was added slowly to a solution of-2-methoxy-benzamide (240mg, 0.75mmol) in THF (10 mL). A solution of n-butyllithium (2.5M in hexanes, 0.90mL, 2.24mmol) was added dropwise, and the mixture was stirred Stir at-78 ℃ for 1h, then return to-20 ℃ for 1.5 h. The reaction mixture was quenched with hydrochloric acid (2M), neutralized with saturated aqueous sodium bicarbonate and partitioned with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure to give the title compound (0.86mmol), which was used as such in the next step. UPLC-MS (ES)⁺Short acidic): 0.99 min, M/z 287.0[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [6- [ [ (2-methoxybenzoyl) amino]Methyl radical]-3-pyridyl]Pyrazole-4- Carboxamides

Following general procedure D, after purification, [6- [ [ (2-methoxybenzoyl) amino ] was reacted]Methyl radical]-3-pyridyl]Boronic acid (0.86mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide gave the title compound (0.09mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 435.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.07 min, M/z 435.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.99(t,J＝6.1Hz,1H),8.64(m,1H),7.88(dd,J＝8.1,2.2Hz,1H),7.84(dd,J＝7.7,1.8Hz,1H),7.50-7.47(m,1H),7.42(d,J＝8.5Hz,1H),7.18(dd,J＝8.6,0.9Hz,1H),7.01(td,J＝7.6,1.2Hz,1H),6.23(s,2H),4.68-4.59(m,3H),3.95(s,3H),2.02-1.86(m,4H),1.85-1.76(m,2H),1.65-1.55(m,2H)。

Example 135: 5-amino-1- (2-hydroxy-1-methyl-ethyl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (2-hydroxy-1-methylethylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, using tert-butyl carbazate (7.57mmol) and hydroxyacetone (9.08mmol) gave the title compound (7.57mmol) as a yellow oil. UPLC-MS (ES) ⁺Short acidic): 1.07 min, M/z 188.9[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1- (2-hydroxy-1-methyl-ethyl) pyrazole-4-carbonitrile

General procedure O, purification, N- [ (2-hydroxy-1-methylethylidene) amino]Carbamic acid tert-butyl ester (7.39mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) gave the title compound (0.28mmol) as an off-white solid. UPLC (ES)⁺Short acidic): 1.59 min, 322.9M/z [ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-hydroxy-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methyl Oxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.72mmol) and 5-amino-3- (4-bromophenyl) -1- (2-hydroxy-1-methyl-ethyl) pyrazole-4-carbonitrile (0.28mmol) gave the title compound (0.22mmol) as an orange solid. UPLC-MS (ES)⁺Short acidic): 1.42 min, 406.1M/z [ M + H ]]⁺。

5-amino-1- (2-hydroxy-1-methyl-ethyl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2-hydroxy-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.22mmol) gave the title compound (0.07mmol) as a light brown solid. UPLC-MS (ES) ⁺Short acidic): 1.25 min, 424.1M/z [ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.78 min, 424.1M/z [ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.74(t,J＝6.0Hz,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.50-7.40(m,5H),7.16(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.24(s,2H),4.89(t,J＝5.4Hz,1H),4.55(d,J＝5.9Hz,2H),4.36-4.27(m,1H),3.90(s,3H),3.70-3.62(m,2H),1.29(d,J＝6.7Hz,3H)。

Example 136: 5-amino-1-cyclopentyl-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.28mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (89mg, 0.31mmol) gave the title compound (126mg, 0.28mmol, 99%) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.75 min, M/z 452.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3-fluoro-phenyl ] -was allowed to stand]Methyl radical]-5-fluoro-2-methoxy-benzamide to give the title compound (66mg, 0.14mmol, 47% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 470.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.63 min, M/z 470.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.88(t,J＝6.0Hz,1H),7.50(dd,J＝7.6,1.7Hz,1H),7.42-7.32(m,2H),7.25-7.17(m,3H),6.28(s,2H),4.66-4.59(m,1H),4.55(d,J＝6.0Hz,2H),3.91(s,3H),2.03-1.73(m,6H),1.63-1.53(m,2H)。

Example 137: 5-amino-1-cyclopentyl-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]-5-fluoro-2- Methoxy-benzamides

General procedure K, after recrystallization from methanol, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.39mmol) and trifluoro- [ [ (5-fluoro-2-methyl-benzoyl) amino group]Methyl radical]Potassium borane (0.58mmol) gave the title compound (0.23 mmol). UPLC-MS (ES)⁺Short acidic): 1.83 min, M/z 470.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 5-difluoro-phenyl ] -was reacted]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.22mmol) gave the title compound (0.13mmol) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, M/z 488.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.80 min, M/z 488.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.0Hz,1H),7.49(dd,J＝9.2,3.3Hz,1H),7.37-7.32(m,1H),7.27-7.17(m,3H),6.23(s,2H),4.66-4.58(m,1H),4.55(d,J＝6.9Hz,2H),3.90(s,3H),2.02-1.92(m,2H),1.91-1.83(m,2H),1.82-1.72(m,2H),1.63-1.52(m,2H)。

Example 138: 5-amino-1-cyclopentyl-3- [3, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

General procedure H, after purification at RT, cyclopentylhydrazine hydrochloride (0.47mmol) and 2- [ (4-chloro-3, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (0.39mmol) gave the title compound (0.31mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.13 min, M/z 323.0[ M]⁺。

N- [ [4- (5-amino-4-cyano)-1-cyclopentyl-pyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.16mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.31mmol) gave the title compound (0.11mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.86 min, M/z 452.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [3, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 6-difluoro-phenyl ] -was reacted]Methyl radical]-2-methoxy-benzamide (0.11mmol) gave the title compound (0.08mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.64 min, M/z 470.1[ M + H ] ]⁺。UPLC-MS(ES⁺Long acidic): 3.80 min, M/z 470.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.56(t,J＝5.5Hz,1H),7.73(dd,J＝7.7,1.7Hz,1H),7.50-7.43(m,1H),7.25-7.17(m,2H),7.13(d,J＝8.3Hz,1H),7.05-6.99(m,1H),6.20(s,2H),4.68-4.54(m,3H),3.87(s,3H),2.05-1.73(m,6H),1.65-1.51(m,2H)。

Example 139: 5-amino-1-cyclopentyl-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]-5-fluoro-2- Methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.16mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.39mmol) to yieldThe title compound (20mg, 0.04mmol, 27% yield) was an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 470.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 6-difluoro-phenyl ] -was reacted]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.04mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 488.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.92 min, M/z 488.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.66(t,J＝5.6Hz,1H),7.47(dd,J＝9.2,3.3Hz,1H),7.37-7.28(m,1H),7.25-7.12(m,3H),6.20(s,2H),4.67-4.52(m,3H),3.86(s,3H),2.05-1.73(m,6H),1.65-1.52(m,2H)。

Example 140: 5-amino-1-cyclopentyl-3- [2, 6-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromo-2, 6-difluoro-phenyl) -1H-pyrazole-4-carbonitrile

General procedure H, in the absence of triethylamine, with hydrazine hydrate (55-60% in water, 1.43mmol) and 2- [ (4-bromo-2, 6-difluoro-phenyl) -methoxy-methylene]Malononitrile (1.19mmol) gave the crude title compound (1.17mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z300.8[ M +2 ]]⁺。

5-amino-3- (4-bromo-2, 6-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure N, after purification, 5-amino-3- (4-bromo-2, 6-difluoro-phenyl) -1H-pyrazole-4-carbonitrile (350mg, 1.17mmol) and bromocyclopentane (1.76mmol) were obtainedA mixture of 5-amino-3- (4-bromo-2, 6-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile and the title compound (3:2 ratio) (0.80mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.86 and 1.92 minutes, M/z 368.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3, 5-difluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-bromo-2, 6-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile and 3-amino-5- (4-bromo-2, 6-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (0.33mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Potassium borane (0.36mmol) gave the title compound (0.12mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.72 min, M/z 452.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [2, 6-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

General procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -3, 5-difluoro-phenyl ] -was reacted]Methyl radical]-2-methoxy-benzamide (0.12mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 470.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.60 min, M/z 470.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.81(t,J＝6.2Hz,1H),7.72(dd,J＝7.6,1.9Hz,1H),7.52-7.45(m,1H),7.17-7.13(m,3H),7.06-7.00(m,1H),6.28(br s,2H),4.67-4.60(m,1H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),2.03-1.92(m,2H),1.90-1.72(m,4H),1.62-1.52(m,2H)。

Example 141: 5-amino-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene]Malononitrile (200mg, 0.79mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (144mg, 0.94mmol) gave the title compound (0.65 mmol). UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 339.0[ M ]]+。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 3-difluoro-phenyl ]Methyl radical]-2- Methoxy-benzamides

General procedure K, after purification, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.32mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.65mmol) gave the title compound (0.24mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran- 4-Yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 3-difluoro-phenyl ] -was allowed to stand]Methyl radical]-2-methoxy-benzamide (112mg, 0.24mmol) to give the title compound (78mg, 0.16mmol, 67% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.40 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.12 min, M/z 486.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.0Hz,1H),7.78-7.72(m,1H),7.53-7.45(m,1H),7.29-7.19(m,2H),7.16(d,J＝7.8Hz,1H),7.07-7.01(m,1H),6.31(s,2H),4.60(d,J＝6.0Hz,2H),4.43-4.32(m,1H),4.00-3.93(m,2H),3.91(s,3H),3.45-3.39(m,2H),2.01-1.90(m,2H),1.82-1.73(m,2H)。

Example 142: 5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]-5- Fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (106mg, 0.31mmol) and trifluoro- [ (5-fluoro-2-methoxy-benzoyl) amino group ]Methyl radical]Borohydride (181mg, 0.63mmol) gave the title compound (124mg, 0.26mmol, 82% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, M/z 486.1[ M + H]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-4-ylpyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 3-difluoro-phenyl ] -N]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.25mmol) gave the title compound (0.12mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.44 min, M/z 504.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.24 min, M/z 504.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.87(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.38-7.33(m,1H),7.24-7.18(m,3H),6.31(s,2H),4.60(d,J＝6.2Hz,2H),4.42-4.34(m,1H),3.98-3.94(m,2H),3.90(s,3H),3.46-3.39(m,2H),2.00-1.90(m,2H),1.78-1.76(m,2H)。

Example 143: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- (2-methoxy-1-methyl-ethyl) pyrazole-4-carboxamide

N- [ (2-methoxy-1-methylethylidene) amino group]Carbamic acid tert-butyl ester

General procedure E, using tert-butyl carbazate (3.78mmol) and methoxyacetone (2.27mmol) gave the title compound (2.27mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 202.9[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1- (2-methoxy-1-methyl-ethyl) pyrazole-4-carbonitrile

After purification according to general procedure O, N- [ (2-methoxy-1-methylethylidene) amino group]Carbamic acid tert-butyl ester (830mg, 4.11mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) gave the title compound (0.18 mmol). UPLC-MS (short acidity): 1.82 min, 337M/z [ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2-methoxy-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2- Methoxy-benzamides

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.31mmol) and 5-amino-3- (4-bromophenyl) -1- (2-methoxy-1-methyl-ethyl) pyrazole-4-carbonitrile (0.18mmol) gave the title compound (0.13mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.57 min, 420.1M/z [ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2-methoxy-1-methyl-ethyl) Yl) pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2-methoxy-1-methyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.13mmol) gave the title compound (0.03mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.38 min, 438.1M/z [ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.10 min, 438.1M/z [ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.51–7.38(m,5H),7.15(d,J＝8.2Hz,1H),7.04(t,J＝7.4Hz,1H),6.31(s,2H),4.54(d,J＝6.0Hz,2H),4.48–4.51(m,1H),3.90(s,3H),3.69–3.62(m,1H),3.49(dd,J＝9.8,5.4Hz,1H),3.23(s,3H),1.28(d,J＝6.6Hz,3H)。

Example 144: 5-amino-1- (4, 4-difluoropyrrolidin-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

2, 2-Difluorovinyl 4-methylbenzenesulfonate

A solution of 2,2, 2-trifluoroethyl tosylate (33.4mmol) in dry THF (111mL) and a solution of n-butyllithium (11M in hexanes, 66.9mmol) were stirred at-78 deg.C for 20 minutes, then quenched with a mixture of water (20mL) and THF (20mL) while maintaining the internal temperature at-60 deg.C, then warmed to RT and extracted with EtOAc. The combined organic extracts were washed with saturated brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification gave the title compound (26.9mmol) as a colorless oil.¹H NMR(400MHz,DMSO-d₆,δ):7.86(d,J＝8.4Hz,2H),7.54(d,J＝8.6Hz,2H),6.85(dd,J＝15.6,3.9Hz,1H),2.45(s,3H)。

(1-benzyl-4, 4-difluoro-pyrrolidin-3-yl) 4-methylbenzenesulfonate

A mixture of 2, 2-difluorovinyl 4-methylbenzenesulfonate (26.6mmol) and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (106mmol) was heated at 130 ℃ for 5 minutes under nitrogen. Trifluoroacetic acid (2.66mmol) was added dropwise and stirred at 130 ℃ for 30 min, cooled to room temperature, concentrated under reduced pressure and triethylamine (2.66mmol) was added. The residue was then purified to give the title compound (23.0mmol) as a pale yellow oil. UPLC-MS (ES) ⁺Short acidic): 1.98 min, M/z 368.0[ M + H ]]⁺。

1-benzyl-4, 4-difluoro-pyrrolidin-3-ol

Magnesium turnings (1.7g, 64.6mmol) were added to (1-benzyl) at 0 ℃ under nitrogen-4, 4-difluoro-pyrrolidin-3-yl) 4-methylbenzenesulfonate (12.9mmol) in MeOH (40 mL). The reaction was stirred at room temperature for 1 hour, water (4mL) was added slowly, followed by hydrochloric acid (5M, 20 mL). The volatiles were removed under reduced pressure, basified with aqueous KOH to pH 8, and extracted with DCM (× 3). The organic extracts were combined, dried over a hydrophobic frit, and concentrated under reduced pressure. The residue was diluted with EtOAc and stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The resulting residue was purified to give the title compound (9.15mmol) as a yellow oil.¹H NMR(400MHz,DMSO-d₆,δ):7.39-7.23(m,5H),5.69(d,J＝5.8Hz,1H),4.13-4.01(m,1H),3.66-3.53(m,2H),3.15-3.00(m,2H),2.73-2.59(m,1H),2.32-2.26(m,1H)。

3, 3-difluoro-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1-benzyl-4, 4-difluoro-pyrrolidin-3-ol (6.78mmol) in EtOH (60mL) under nitrogen was added di-tert-butyl dicarbonate (8.14mmol) followed by palladium hydroxide (20 wt% on carbon, 1.14 mmol). The reaction was flushed several times with hydrogen and stirred at RT for 16 h. Then useThe reaction was filtered through a pad, and the filtrate was concentrated under reduced pressure. Further purification gave the title compound (4.95mmol) as a yellow oil. ¹H NMR(400MHz,DMSO-d₆,δ):6.08(d,J＝5.2Hz,1H),4.20(s,1H),3.66-3.55(m,3H),3.22-3.20(m,1H),1.41(s,9H)。

3, 3-difluoro-4- (trifluoromethylsulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3, 3-difluoro-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.04mmol) in anhydrous DCM (20mL) was added dropwise trifluoromethanesulfonic anhydride (1M in DCM, 7.57mmol) at-20 ℃ under nitrogen. The reaction was stirred at-20 to-10 ℃ for 40 minutes, quenched with aqueous citric acid (0.5M), basified with saturated aqueous sodium bicarbonate to reach a pH of about 4.5 and extracted with DCM. The organic extracts were combined, dried over a hydrophobic frit and concentrated under reduced pressure to give the crude title compound (2.51mmol) as a brown oil.¹H NMR(400MHz,DMSO-d₆,δ):5.98-5.93(m,1H),3.97-3.68(m,3H),3.71-3.67(m,1H),1.43(s,9H)。

5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile

General procedure H, without triethylamine, purification followed by isolation of 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.76mmol) and hydrazine hydrate (55-60% in water, 1.9mmol) gave the title compound as a white solid. UPLC-MS (ES)⁺Short acidic): 1.44 min, M/z 265.9[ M +2 ]]⁺。

4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 3, 3-difluoro-4- (trifluoromethylsulfonyloxy) pyrrolidine-1-carboxylate (578mg, 1.59mmol), 5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile (300mg, 1.14mmol), and cesium carbonate (743mg, 2.28mmol) in DMF (12mL) was heated to 90 ℃ for 2.5H. The reaction was cooled to RT, diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification gave the title compound (105mg, 0.22mmol) as an orange solid. UPLC-MS (ES) ⁺Short acidic): 2.06 min, M/z 468.0[ M]⁺。

4- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]- 3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

General procedure K, after purification, 4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.37mmol) gave the title compound (0.15mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.82 min, M/z 553.2[ M + H ]]⁺。

5-amino-1- (4, 4-difluoropyridin-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical] Pyrazole-4-carboxamides

General procedure M, pureAfter the reaction, 4- [ 5-amino-4-cyano-3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, 0.14mmol) gave the title compound (20mg, 0.04mmol, 29% yield) as a light yellow solid. UPLC-MS (ES)⁺Short acidic): 1.14 min, M/z 471.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.42 min, M/z 471.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.74(dd,J＝7.6,1.7Hz,1H),7.50-7.40(m,5H),7.15(d,J＝8.3Hz,1H),7.05-7.01(m,1H),6.54(br s,2H),5.04-4.96(m,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),3.54-3.45(m,2H),3.26-3.07(m,2H)。

Example 145: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [1- (3-pyridinyl) ethyl ] pyrazole-4-carboxamide

1- (3-pyridinyl) ethanol

A solution of magnesium (methyl) bromide (2.7M in ether, 0.31mmol) and 3-pyridinecarboxaldehyde (1.60mmol) in THF (3.2mL) at-78 deg.C was stirred at RT for 1h under a nitrogen atmosphere, quenched with MeOH and concentrated under reduced pressure. Purification gave the title compound (1.47mmol) as a clear oil.¹H NMR(400MHz,CDCl₃,δ):8.65-8.58(m,1H),8.56-8.50(m,1H),7.80-7.75(m,1H),7.35-7.29(m,1H),4.99(q,J＝6.5Hz,1H),1.56(d,J＝6.5Hz,3H)。

3-acetylpyridine

Pyridine (0.04mL, 0.49mmol) was added to a solution of pyridinium chlorochromate (2.20mmol) and 1- (3-pyridyl) ethanol (1.47mmol) in DCM (3mL) at 0 deg.C. The reaction was stirred at room temperature for 2 hours, washed with DCM and the resulting black residue washed with more DCM (× 3). Then passing the combined organic matterPadding and removing the solvent under reduced pressure to obtainCrude 3-acetylpyridine (0.66mmol) was obtained as dark oil, which was used directly in the next step.¹H NMR(400MHz,CDCl₃,δ):9.27-9.15(m,1H),8.88-8.76(m,1H),8.29(d,J＝7.8Hz,1H),7.53-7.44(m,1H),2.68(s,3H)。

N- [1- (3-pyridinyl) ethylideneamino]Carbamic acid tert-butyl ester

Following general procedure E, after purification, 3-acetylpyridine (0.66mmol) gave the title compound (97mg, 0.41mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.05 min, M/z236.0[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1- [1- (3-pyridyl) ethyl]Pyrazole-4-carbonitriles

Improved general procedure O, purification at RT, N- [1- (3-pyridyl) ethylideneamino ]Carbamic acid tert-butyl ester (97mg, 0.41mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.34mmol) gave the title compound (0.33mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 369.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [1- (3-pyridinyl) ethyl ] ethyl]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [1- (3-pyridyl) ethyl]Pyrazole-4-carbonitrile (0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.54mmol) gave the title compound (0.16mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 453.2[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [1- (3-pyridinyl) ethyl] Pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [1- (3-pyridinyl) ethyl ] ester]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.16mmol) to give the title compound (47mg, 0.10mmol, 62% yield) as a pale yellow solid. UPLC-MS(ES⁺Short acidic): 1.20 min, M/z 471.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.62 min, M/z 471.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),8.53(d,J＝1.6Hz,1H),8.47(dd,J＝4.7,1.4Hz,1H),7.75(dd,J＝7.6,1.6Hz,1H),7.72-7.66(m,1H),7.51-7.34(m,6H),7.15(d,J＝8.3Hz,1H),7.07-7.00(m,1H),6.47(br s,2H),5.66(q,J＝6.9Hz,1H),4.54(d,J＝6.0Hz,2H),3.90(s,3H),1.76(d,J＝6.9Hz,3H)。

Example 146: 5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-4-ylpyrazole-4-carboxamides

General procedures K and M, after purification, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.38mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.77mmol) gave the title compound (43mg, 0.09mmol, 24% yield). UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 504.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.24 min, M/z 504.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.0Hz,1H),7.49(dd,J＝9.1,3.3Hz,1H),7.38-7.31(m,1H),7.28-7.22(m,2H),7.20(dd,J＝9.1,4.3Hz,1H),6.28(s,2H),4.56(d,J＝6.0Hz,2H),4.42-4.33(m,1H),3.96(dd,J＝11.9,4.1Hz,2H),3.90(s,3H),3.42(t,J＝12.0Hz,2H),2.01-1.96(m,2H),1.77(d,J＝12.0Hz,2H)。

Example 147: 5-amino-1- (5, 5-dimethyltetrahydrofuran-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

2-methylpent-4-en-2-ol

Anhydrous acetone (136.19mmol) was added dropwise to a solution of allylmagnesium bromide (1M in ether, 272.4mmol) at 0 ℃. After stirring at 0 ℃ for 15 minutes, the reaction mixture was stirred at room temperature for 2 hours. Adding saturated NH₄The Cl solution was separated into layers. The aqueous layer was extracted with ether, washed with water and saturated brine solution, dried over sodium sulfate and carefully removed all volatiles under reduced pressure to give 2-methylpent-4-en-2-ol (49.64mmol) as a colourless oil. ¹H NMR(400MHz,CDCl₃,δ):5.98-5.83(m,1H),5.23-5.09(m,2H),2.26(d,J＝7.6Hz,2H),1.29-1.26(m,1H),1.25(s,6H)。

4-methylpentane-1, 2, 4-triol

2-methylpent-4-en-2-ol (20.0mmol) was dissolved in tert-butanol (88mL) and water (88mL) and AD-mix-. beta.was added (16 g). The reaction mixture was stirred at room temperature for 72 hours. EtOAc (25mL) and sodium sulfite (12g) were added and the reaction was stirred for 1 hour until two phases separated significantly. The aqueous phase was extracted with EtOAc, dried over sodium sulfate and all volatiles were removed under reduced pressure to give crude 4-methylpentane-1, 2, 4-triol (8.34mmol) as a colorless oil.¹H NMR(400MHz,CDCl₃,δ):4.19-4.07(m,1H),3.75-3.60(m,2H),3.55-3.44(m,1H),2.41(br s,1H),2.16-2.00(m,1H),1.78(dd,J＝14.5,10.8Hz,1H),1.50(dd,J＝14.5,2.3Hz,1H),1.37(s,3H),1.33(s,3H)。

5, 5-Dimethyltetrahydrofuran-3-ol

4-methylpentane-1, 2, 4-triol (8.35mmol) is dissolved in DCM (40mL), the reaction mixture is purged with nitrogen and then p-toluenesulfonyl chloride (12.52mmol) and triethylamine (25.04mmol) are added. The reaction mixture was heated to reflux and stirred for 48 hours. Adding saturated NH₄The Cl solution was separated and the organic layer was extracted with DCM, washed with saturated brine solution, dried over sodium sulfate and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica, eluting with 0-100% EtOAc in heptane,5, 5-dimethyltetrahydrofuran-3-ol (3.56mmol) was obtained as a colorless oil.¹H NMR(400MHz,CDCl₃,δ):4.57-4.46(m,1H),3.97(dd,J＝9.9,4.5Hz,1H),3.82(ddd,J＝9.9,2.5,1.2Hz,1H),2.04(dd,J＝13.5,6.5Hz,1H),1.82(ddd,J＝13.5,2.5,1.2Hz,1H),1.78-1.69(m,1H),1.41(s,3H),1.25(s,3H)。

5, 5-dimethyltetrahydrofuran-3-one

To a solution of 5, 5-dimethyltetrahydrofuran-3-ol (1.93mmol) in DCM (10mL) under nitrogen at RT was added dessimutane oxidant (2.12mmol) and stirred for 72 h. With saturated sodium thiosulfate solution and then saturated NaHCO ₃The mixture was quenched by the solution. The phases were separated and the organic phase was dried over sodium sulfate and filtered. The solvent was concentrated under reduced pressure to give the crude title compound (1.93mmol), which was used immediately in the next step.¹H NMR(400MHz,CDCl₃,δ):4.06(s,2H),2.38(s,2H),1.42(s,6H)。

N- [ (5, 5-dimethyltetrahydrofuran-3-ylidene) amino]Carbamic acid tert-butyl ester

General procedure E, using tert-butyl carbazate (1.97mmol) and 5, 5-dimethyltetrahydrofuran-3-one (1.93mmol) gave the crude title compound (mixture of isomers, 1.93mmol) as a yellow oil.¹H NMR(400MHz,CDCl₃Delta, isomers 1 and 2) isomers 1:5.94(s,1H),4.49-4.45(m,2H),2.36-2.30(m,2H),1.48(s,9H),1.36(s,6H) and isomers 2:5.94(s,1H),4.38-4.32(m,2H),2.64-2.58(m,2H),1.48(s,9H),1.33(s, 6H).

5-amino-3- (4-bromophenyl) -1- (5, 5-dimethyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile

To N- [ (5, 5-dimethyltetrahydrofuran-3-ylidene) amino group]To a solution of tert-butyl carbamate (1.93mmol) in THF (10mL) was added a solution of borane dimethylsulfide complex (2M in THF, 3.43 mmol). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in MeOH (10mL) and hydrochloric acid (12M, 20.15mmol), then heated under reflux for 14h, cooled and concentrated under reduced pressure. The residue was dissolved in EtOH (10mL) and 2- [ (4-bromophenyl) -methoxy-methylene) was added ]Malononitrile (0)38mmol) and triethylamine (1.9mmol) were heated under reflux for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with 0-100% EtOAc in heptane to give the title compound (0.12mmol) as a yellow oil. UPLC-MS (ES)^-Short acidic): 1.86 min, M/z 360.9[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (5, 5-dimethyltetrahydrofuran-3-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

General procedure K, purification by flash column chromatography on silica gel eluting with 20-100% EtOAc in heptane, was performed by reacting 5-amino-3- (4-bromophenyl) -1- (5, 5-dimethyltetrahydrofuran-3-yl) pyrazole-4-carbonitrile (0.14mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (0.19mmol) gave the title compound (0.1mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 446.0[ M + H ]]⁺。

5-amino-1- (5, 5-dimethyltetrahydrofuran-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

General procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (5, 5-dimethyltetrahydrofuran-3-yl) pyrazol-3-yl ] was]Phenyl radical]Methyl radical]-2-methoxy-benzamide (0.10mmol) gave the title compound (0.03mmol) as an off-white solid. UPL-CMS (ES) ⁺Short acidic): 1.44 min, M/z 464.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.32 min, M/z 464.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆):8.66(t,J＝6.0Hz,1H),7.68(dd,J＝7.6,1.7Hz,1H),7.42-7.33(m,5H),7.07(d,J＝8.3Hz,1H),6.96(t,J＝7.1Hz,1H),6.34(s,2H),4.99-4.92(m,1H),4.45(d,J＝6.1Hz,2H),3.98(t,J＝8.1Hz,1H),3.82(s,3H),3.80-3.78(m,1H),2.10(dd,J＝3.5,2.6Hz,2H),1.24(s,3H),1.16(s,3H)。

Example 148: 5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H, purification by flash chromatography on silica eluting with 15-75% EtOAc in heptane, was performed to give 2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (1.57mmol) gave the title compound (0.77mmol) as a solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 339.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]-2- Methoxy-benzamides

General procedure K, starting from 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (130mg, 0.38mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (208mg, 0.77mmol) gave the title compound (136mg, 0.29mmol, 76% yield) as a solid, which was used without further purification. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]-1-tetrahydropyran- 4-Yl-pyrazole-4-carboxamides

Following general procedure L, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl) -2, 5-difluoro-phenyl ] -was allowed to stand]Methyl radical]-2-methoxy-benzamide (136mg, 0.29mmol) gave the title compound (0.04mmol) as a solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.12 min, M/z 486.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.0Hz,1H),7.72(dd,J＝7.6,1.8Hz,1H),7.51-7-47(m,1H),7.28-7.22(m,2H),7.18-7.15(m,1H),7.04(td,J＝7.6,0.9Hz,1H),6.28(s,2H),4.56(d,J＝6.0Hz,2H),4.42-4.34(m,1H),3.96(dd,J＝11.5,4.1Hz,2H),3.91(s,3H),3.45-3.39(m,2H),2.01-1.91(m,2H),1.80-1.75(m,2H)。

Example 149: 5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H, after purification, 2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (0.79mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (240mg, 1.57mmol) gave the title compound (0.34mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 339.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]- 5-fluoro-2-methoxy-benzamides

General procedure K, using 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.16mmol) and trifluoro- [ [ (5-chloro- (4-fluoro-2-methoxy-benzoyl) amino group ]Methyl radical]Potassium borane (0.32mmol) gave the title compound (0.16mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 486.1[ M + H]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-3-yl-pyrazole-4-carboxamides

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl ] -was reacted]Methyl radical]-5-fluoro-2-methoxy-benzamide (0.16mmol) gave the title compound (0.05mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 504.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.43 min, M/z 504.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.0Hz,1H),7.48(dd,J＝9.1,3.3Hz,1H),7.39-7.31(m,1H),7.28-7.16(m,3H),6.31(s,2H),4.55(d,J＝6.0Hz,2H),4.33-4.21(m,1H),3.92-3.73(m,5H),3.52(t,J＝10.5Hz,1H),3.35-3.26(m,1H),2.03-1.94(m,2H),1.79-1.58(m,2H)。

Example 150: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-sec-butyl-pyrazole-4-carboxamide

N- [ 1-Methylpropyleneamino group]Carbamic acid tert-butyl ester

Following general procedure E, using tert-butyl carbazate (7.57mmol) and 2-butanone (9.08mmol) gave the title compound (7.57mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.36 min, M/z 186.9[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1-sec-butylpyrazole-4-carbonitrile

General procedure O, purification, N- [ 1-Methylpropyleneamino group]Carbamic acid tert-butyl ester (7.39mmol) and 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (0.76mmol) gave the title compound (0.38mmol) as an off-white solid. UPLC (ES)⁺Short acidic): 1.95 min, 321.0M/z [ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-sec-butylpyrazol-3-yl) phenyl]Methyl radical]-2-methoxy-benzamide

General procedure K, purification, isolation of trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.69mmol) and 5-amino-3- (4-bromophenyl) -1-sec-butylpyrazole-4-carbonitrile (0.40mmol) gave the title compound (0.26mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, 404.1M/z [ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-sec-butylpyrazole-4-carboxamide

General procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-sec-butylpyrazol-3-yl) phenyl)]Methyl radical]-2-methoxy-benzamide (0.06mmol) gave the title compound (0.04mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.49 min, 422.2M/z [ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.34 min, 422.2M/z [ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.51-7.45(m,5H),7.15(d,J＝8.3Hz,1H),7.04(t,J＝7.5Hz,1H),6.31(s,2H),4.54(d,J＝6.0Hz,2H),4.28-4.16(m,1H),3.90(s,3H),1.88-1.72(m,1H),1.72-1.56(m,1H),1.31(d,J＝6.5Hz,3H),0.76(t,J＝7.3Hz,3H)。

Example 151: 5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl ]Methyl radical]- 2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.16mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (0.32mmol) gave the title compound (0.15mmol, 93% yield) as a yellow solid. UPLC-MS: (ES)⁺Short acidic): 1.63 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran- 3-yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl) -was allowed to stand]Methyl radical]-2-methoxy-benzamide (65mg, 0.14mmol) to give the title compound (10mg, 0.02mmol, 15% yield) as an off-white solid.UPLC-MS：(ES⁺Short acidic): 1.49 min, M/z 486.1[ M + H]⁺。UPLC-MS：(ES⁺Long acidic): 3.32 min, M/z 468.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝5.9Hz,1H),7.71(dd,J＝7.7,1.7Hz,1H),7.51-7.47(m,1H),7.26-7.22(m,2H),7.16(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.32(s,2H),4.55(d,J＝6.0Hz,2H),4.31-4.24(m,1H),3.91-3.81(m,5H),3.55-3.50(m,1H),3.37-3.26(m,1H),2.02-1.96(m,2H),1.76-1.64(m,2H)。

Example 152: 5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene ]Malononitrile (250mg, 0.98mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (163mg, 1.18mmol) gave the title compound (70mg, 0.22 mmol). UPLC-MS (ES +, short acidic): 1.66 min, M/z 325.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]- 2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (70mg, 0.22mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (117mg, 0.43mmol) gave the title compound (0.14mmol, 63% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 454.1[ M + H]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydrofuran- 3-yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl ] -was reacted]Methyl radical]-2-methoxy-benzamide (60mg, 0.13mmol) to give the title compound (18mg, 0.04mmol, 29% yield) as a solid. UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 472.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.16 min, M/z 472.1[ M + H ] ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.1Hz,1H),7.72(dd,J＝7.6,1.7Hz,1H),7.51-7.47(m,1H),7.29-7.22(m,2H),7.16(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.30(s,2H),4.98-4.91(m,1H),4.55(d,J＝6.0Hz,2H),4.01-3.92(m,2H),3.91(s,3H),3.83-3.76(m,2H),2.30-2.20(m,2H)。

Example 153: 5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (60mg, 0.18mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (134mg, 0.46mmol) gave the title compound (40mg, 0.08mmol, 46% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 472.1[ M + H ]]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Furan-3-yl-pyrazole-4-carboxamides

Purification according to general procedure M, followed by isolation of N- [ [4- (5-Ammonia)Yl-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (39mg, 0.08mmol) gave the title compound (18mg, 0.04mmol, 43% yield). UPLC-MS (ES)⁺Short acidic): 1.51 min, M/z 490.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.29 min, M/z 490.1[ M + H ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.3Hz,1H),7.49(dd,J＝9.1,3.3Hz,1H),7.38-7.31(m,1H),7.29-7.17(m,3H),6.30(s,2H),4.98-4.91(m,1H),4.55(d,J＝5.9Hz,2H),4.01-3.92(m,2H),3.90(s,3H),3.84-3.76(m,2H),2.30-2.21(m,2H)。

Example 154: 5-amino-1-cyclopentyl-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-cyclopentyl-1H-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene ] malononitrile (250mg, 0.98mmol) and cyclopentylhydrazine hydrochloride (174mg, 1.28mmol) gave the title compound (173mg, 0.54mmol, 55% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.97 min, M/z 322.9[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]-5-fluoro-2- Methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (79mg, 0.25mmol) and potassium trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] borane (120mg, 0.42mmol) gave the title compound (91mg, 0.19mmol, 79% yield) as a white solid.

UPLC-MS(ES⁺Is short and shortAcidic): 1.81 min, M/z 470.1[ M + H]⁺。

5-amino-1-cyclopentyl-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Benzene and its derivatives Base of]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 3-difluoro-phenyl) -was allowed to stand ]Methyl radical]-5-fluoro-2-methoxy-benzamide (90mg, 0.19mmol) to give the title compound (65mg, 0.13mmol, 70% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, M/z 488.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.86 min, M/z 488.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.87(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.38-7.33(m,1H),7.25-7.18(m,3H),6.26(br s,2H),4.67-4.59(m,1H),4.60(d,J＝5.9Hz,2H),3.90(s,3H),2.01-1.94(m,2H),1.92-1.83(m,2H),1.82-1.73(m,2H),1.63-1.56(m,2H)。

Example 155: 5-amino-1-cyclopentyl-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

Following general procedure K, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (86mg, 0.27mmol) and potassium trifluoro- [ [ (2-methoxybenzoyl) amino ] methyl ] borane (123mg, 0.45mmol) gave the title compound (111mg, 0.25mmol, 92% yield) as a white solid.

UPLC-MS(ES^-Short acidic): 1.77 min, M/z 450.1[ M-H]^-。

5-amino-1-cyclopentyl-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 3-difluoro-phenyl) -was allowed to stand]Methyl radical]-2-methoxy-benzamide (110mg, 0.24mmol) gave the title compound (74mg, 0.16mmol, 65% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.65 min, M/z 470.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.75 min, M/z 470.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.0Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.52-7.49(m,1H),7.26-7.20(m,2H),7.17(d,J＝8.2Hz,1H),7.06-7.03(m,1H),6.26(br s,2H),4.67-4.60(m,1H),4.60(d,J＝6.0Hz,2H),3.91(s,3H),2.03-1.93(m,2H),1.92-1.83(m,2H),1.82-1.73(m,2H),1.63-1.54(m,2H)。

Example 156: 5-amino-1-cyclopentyl-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (250mg, 0.98mmol) and cyclopentylhydrazine hydrochloride (161mg, 1.18mmol) gave the title compound (250mg, 0.77mmol, 79% yield). UPLC-MS (ES)⁺Short acidity) for 1.98 min, M/z323.0[ M]⁺。

N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]-2-methoxy group Phenyl-carboxamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1-cyclopentyl-pyrazole-4-carbonitrile (125mg, 0.39mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Potassium borane (158mg, 0.58mmol) gave the title compoundThe title compound (75mg, 0.17mmol, 43% yield) was a white solid. UPLC-MS (ES)⁺Short acidity) 1.78 min, M/z 452.1[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino ]Methyl radical]Phenyl radical]Pyridine (II) Azole-4-carboxamides

Purification by flash column chromatography on silica gel eluting with 50-100% EtOAc in heptane and then after passage through an SCX-SPE column, according to general procedure M, afforded N- [ [4- (5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl) -2, 5-difluoro-phenyl]Methyl radical]-2-methoxy-benzamide (135mg, 0.30mmol) to give 5-amino-1-cyclopentyl-3- [2, 5-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (63mg, 0.13mmol, 45% yield) as a light brown solid. UPLC-MS (ES)⁺Short acidic): 1.65 min, M/z 470.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.78 min, M/z 470.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.77(t,J＝6.0Hz,1H),7.72(dd,J＝7.7,1.7Hz,1H),7.51-7.47(m,1H),7.27-7.22(m,2H),7.17(d,J＝8.3Hz,1H),7.06-7.02(m,1H),6.22(s,2H),4.67-4.57(m,1H),,4.55(d,J＝6.0Hz,2H),3.91(s,3H),2.03-1.83(m,4H),1.79-1.77(m,2H),1.60-1.57(m,2H)。

Example 157: 5-amino-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Tetrahydropyran-3-ylhydrazine hydrochloride

To a solution of 3-hydroxytetrahydropyran (1.8mL, 19.58mmol) in toluene (30mL) under nitrogen was added triphenylphosphine (7.7g, 29.37mmol) and di-tert-butyl azodicarboxylate (5.4g, 23.50 mmol). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was concentrated and then suspended in MeOH (55mL), then a solution of hydrogen chloride (4M in dioxane, 39.17mL, 156.7mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. EtOAc was then added to the resulting residue, which was then filtered. The collected solid was washed with EtOAc to give the title compound (2.99g, 19.58mmol, assuming quantitative yield) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆,δ):3.91-3.82(m,1H),3.76-3.58(m,1H),3.45-3.29(m,2H),3.04-2.94(m,1H),2.00-1.90(m,1H),1.77-1.65(m,1H),1.62-1.37(m,2H)。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]- 2-methoxy-benzamides

Following general procedure K, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (50mg, 0.15mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (81mg, 0.30mmol) gave the crude title compound (0.15mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 468.1[ M + H ]]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydropyran- 3-yl-pyrazole-4-carboxamides

Purification by flash column chromatography on silica gel, eluting with 0-5% MeOH in DCM, and isolation of N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl ] -according to general procedure M]Methyl radical]-2-methoxy-benzamide (98mg, 0.21mmol) to give the title compound (13mg, 0.02mmol, 12% yield) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z 486.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.41 min, M/z 486.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.78(t,J＝6.0Hz,1H),7.75(dd,J＝7.6,1.7Hz,1H),7.52-7.47(m,1H),7.26-7.16(m,3H),7.07-7.03(m,1H),6.35(s,2H),4.60(d,J＝5.9Hz,2H),4.32-4.25(m,1H),3.91-3.83(m,5H),3.52(t,J＝10.5Hz,1H),3.32-3.28(m,1H),2.04-1.93(m,2H),1.77-1.65(m,2H)。

Example 158: 5-amino-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-3, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (166mg, 0.65mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (150mg, 0.98mmol) gave the title compound (32mg, 0.09mmol, 14% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.94 min, M/z 339.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 6-difluoro-phenyl]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-3, 5-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.09mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.23mmol) gave the title compound (0.10mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 486.1[ M + H]⁺。

5-amino-3- [3, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-3-yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 6-difluoro-phenyl) -was allowed to stand]Methyl radical ]-5-fluoro-2-methoxy-benzamide (47mg, 0.10mmol) to give the title compound (22mg, 0.04mmol, 39% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.58 min, M/z 504.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.63 min, M/z 504.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.66(t,J＝6.0Hz,1H),7.47(dd,J＝9.2,3.3Hz,1H),7.36-7.31(m,1H),7.22-7.16(m,3H),6.30(s,2H),4.60(d,J＝5.5Hz,2H),4.31-4.24(m,1H),3.87-3.85(m,5H),3.54(t,J＝10.5Hz,1H),3.39-3.25(m,1H),2.04-1.98(m,2H),1.78-1.63(m,2H)。

Example 159: 5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene]Malononitrile (150mg, 0.59mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (225mg, 1.47mmol) gave the title compound (60mg, 0.18mmol, 30% yield) as a brown solid. UPLC-MS (ES)⁺Short acidic): 1.79 min, M/z 339.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile (0.18mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.53mmol) gave the title compound (0.22mmol, assuming the present quantitative yield) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.69 min, M/z 486.1[ M + H]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Pyran-3-yl-pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- (5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl) -was allowed to stand]Methyl radical]-5-fluoro-2-methoxy-benzamide (108mg, 0.22mmol) to give the title compound (25mg, 0.04mmol, 20% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 504.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.54 min, M/z 504.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.87(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.39-7.33(m,1H),7.26-7.18(m,3H),6.35(s,2H),4.60(d,J＝5.9Hz,2H),4.33-4.26(m,1H),3.90-3.84(m,5H),3.52(t,J＝10.5Hz,1H),3.32-3.28(m,1H),2.00-1.96(m,2H),1.77-1.61(m,2H)。

Example 160: 5-amino-1- (4, 4-difluoropyrrolidin-3-yl) -3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1H-pyrazole-4-carbonitrile

To a solution of 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene ] malononitrile (2.23g, 7.94mmol) in EtOH (90mL) was added hydrazine hydrate (55-60% in water, 2.71mL, 27.8 mmol). The reaction mixture was heated at 90 ℃ for 1 hour. The reaction was cooled to room temperature and the solvent was removed under reduced pressure to give the crude title compound (1.88g, 6.70mmol, 84% yield) as a yellow solid.

UPLC-MS(ES⁺Short acidic): 1.57 min, M/z 282.9[ M +2 ] ]⁺。

4- [ 5-amino-3- (4-bromo-3-fluoro-phenyl) -4-cyano-pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid Tert-butyl ester

3, 3-difluoro-4- (trifluoromethylsulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (626mg, 1.73mmol), 5-amino-3- (4-bromo-3-fluoro-phenyl) -1H-pyrazole-4-carbonitrile (370mg, 1.32mmol) and carbonic acidCesium (858mg, 2.63mmol) was suspended in DMF (8mL) and heated at 90 ℃ for 2.5 h. The reaction was cooled to RT and diluted with water. Work-up and purification gave the title compound (0.22mmol, 16% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.11 min, M/z 488.0[ M +2 ]]⁺。

4- [ 5-amino-4-cyano-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] carbonyl]Methyl radical]Phenyl radical]Pyrazole-1- Base of]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

Following general procedure K, after purification, 4- [ 5-amino-3- (4-bromo-3-fluoro-phenyl) -4-cyano-pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (120mg, 0.25mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (114mg, 0.42mmol) gave the title compound (102mg, 0.17mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 571.2[ M + H ]]⁺。

5-amino-1- (4, 4-difluoropyridin-3-yl) -3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ]Methyl radical] Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, 4- [ 5-amino-4-cyano-3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] carbonyl]Methyl radical]Phenyl radical]Pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (96mg, 0.17mmol) gave the title compound (57mg, 0.12mmol, 69% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.24 min, M/z 489.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.56 min, M/z 489.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.51-7.43(m,2H),7.36-7.30(m,2H),7.17(d,J＝8.3Hz,1H),7.07-7.03(m,1H),6.48(br s,2H),5.04-4.97(m,1H),4.58(d,J＝6.0Hz,2H),3.91(s,3H),3.54-3.44(m,2H),3.24-3.08(m,2H)。

Example 161: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (1-tetrahydropyran-4-ylethyl) carboxamide

1-tetrahydropyran-4-yl ethanone hydrazone

To a solution of 1-tetrahydro-2H-pyran-4-yl-ethanone (166mg, 1.30mmol) in MeOH (7.5mL) was added hydrazine hydrate (55-60% in water, 0.90mL, 17.61 mmol). The reaction mixture was heated under reflux for 16 h, cooled and concentrated under reduced pressure to give crude 1-tetrahydropyran-4-yl ethanone hydrazone (171mg, 1.20mmol, 93% yield) as a colorless oil.¹H NMR(400MHz,CDCl₃,δ):4.92(s,2H),4.03-3.98(m,2H),3.45-3.40(m,2H),2.38-2.30(m,1H),1.73(s,3H),1.65-1.63(m,4H)。

5-amino-3- (4-bromophenyl) -1- (1-tetrahydropyran-4-ylethyl) pyrazole-4-carbonitrile

A solution of borane tetrahydrofuran complex (1M in THF, 3.00mL, 3.00mmol) was added to a solution of 1-tetrahydropyran-4-yl ethanone hydrazone (171mg, 1.20mmol) in THF (7mL) at 0 deg.C. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Dissolve the residue with EtOH (10mL) and add 2- [ (4-bromophenyl) -methoxy-methylene) ]Malononitrile (200mg, 0.76 mmol). The reaction mixture was heated at reflux for 16 h to give the title compound (60mg, 0.16mmol, 21% yield) as a brown oil. UPLC-MS: (ES)⁺Short acidic): 1.90 min, M/z 377.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-tetrahydropyran-4-ylethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5- Fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (1-tetrahydropyran-4-ylethyl) pyrazole-4-carbonitrile (0.16mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (0.80mmol) gave the title compound (0.16mmol) as a yellow oil. UPLC-MS: (ES)⁺Short acidic): 1.67 min, M/z 478.1[ M + H]⁺。

5-Ammonia3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino-yl ] -phenyl]Methyl radical]Phenyl radical]-1- (1-tetrahydropyran- 4-ylethyl) pyrazole-4-carboxamide

Following general procedure L, after purification, N- [ [4- [ 5-amino-4-cyano-1- (1-tetrahydropyran-4-ylethyl) pyrazol-3-yl ] is]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (76mg, 0.16mmol) to give the title compound (10mg, 0.02mmol, 13% yield) as an off-white solid. UPLC-MS: (ES)⁺Short acidic): 1.51 min, M/z 496.2[ M + H ] ]⁺。UPLC-MS：(ES⁺Long acidic): 3.28 min, M/z 496.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.82(t,J＝6.0Hz,1H),7.50(dd,J＝9.2,3.1Hz,1H),7.45-7.39(m,4H),7.36-7.31(m,1H),7.18(dd,J＝9.0,4.3Hz,1H),6.34(s,2H),4.54(d,J＝5.9Hz,2H),4.10-4.03(m,1H),3.93-3.83(m,4H),3.82-3.74(m,1H),3.29-3.22(m,1H),3.19-3.12(m,1H),2.03-1.90(m,1H),1.71-1.65(m,1H),1.37(d,J＝6.5Hz,3H),1.28-1.16(m,2H),1.07-1.03(m,1H)。

Example 162: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [ (3S) -tetrahydrofuran-3-yl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carbonitriles

Modified general procedure H, at RT, with 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (2mmol) and [ (3S) -tetrahydrofuran-3-yl]Hydrazine hydrochloride (3.65mmol) gave the crude title compound (2 mmol). UPLC-MS (ES)⁺Short acidic): 1.75 min, M/z 335.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ (3S) -tetrahydrofuran-3-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro- 2-methoxy-benzamides

Following general procedure K, using trifluoro- [ [ (5)-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (1229mg, 4.25mmol) and 5-amino-3- (4-bromophenyl) -1- [ (3S) -tetrahydrofuran-3-yl]Pyrazole-4-carbonitrile (644mg, 1.93mmol) gave crude title compound (840mg, 1.93mmol, assuming quantitative yield). LC-MS (ES)⁺Short acidic): 1.59 min, M/z 436.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [ (3S) -tetrahydrofuran Pyran-3-yl radicals]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ (3S) -tetrahydrofuran-3-yl ] was allowed to stand ]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (840mg, 1.93mmol) to give the title compound (293mg, 0.65mmol, 34% yield) as a white solid. UPLC-MS (ES)⁺Long acidic): 3.09 min, M/z 454.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.2Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.47-7.39(m,4H),7.37.7.31(m,1H),7.22-7.16(m,1H),6.39(br s,2H),4.97-4.89(m,1H),4.54(d,J＝6.1Hz,2H),4.02-3.91(m,2H),3.89(s,3H),3.83-3.77(m,2H),2.31-2.21(m,2H)。

Example 163 a: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide-isomer 1; and example 163b isomer 2

Purification of 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group by preparative SFC (SFC-B)]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide (150mg, 0.31mmol) to give, after evaporation and freeze-drying, 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide (isomer 1, 44mg, 0.09mmol, 29% yield) and 5-amino-3- [4- [ [ (5-fluoro-2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide (isomer 2, 48mg, 0.10mmol, 32% yield) as a white solid. UPLC-MS (ES)⁺Short acidic, isomer 1): 1.53 min, M/z 480.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic, isomer 1): 3.55 min, M/z 480.1[ M + H ] ]⁺. SFC (SFC-A, isomer 1): 1.95 minutes.

¹H NMR(DMSO-d₆δ, isomer 1):8.83(t, J ═ 6.1Hz,1H),7.51(dd, J ═ 9.3,3.3Hz,1H),7.48 to 7.39(m,4H),7.33(ddd, J ═ 9.0,7.9,3.3Hz,1H),7.18(dd, J ═ 9.0,4.3Hz,1H),6.67(s,2H),5.35 to 5.22(m,1H),4.55(d, J ═ 6.1Hz,2H),3.89(s,3H),1.61(d, J ═ 6.7Hz, 3H).

UPLC-MS(ES⁺Short acidic, isomer 2): 1.53 min, M/z 480.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic, isomer 2): 3.55 min, M/z 480.1[ M + H ]]⁺. SFC (SFC-A, isomer 2): 2.26 minutes.

¹H NMR(DMSO-d₆δ, isomer 2):8.84(t, J ═ 6.1Hz,1H),7.52(dd, J ═ 9.3,3.3Hz,1H),7.49-7.40(m,4H),7.38-7.31(m,1H),7.19(dd, J ═ 9.0,4.3Hz,1H),6.68(s,2H),5.34-5.24(m,1H),4.56(d, J ═ 6.1Hz,2H),3.90(s,3H),1.62(d, J ═ 6.7Hz, 3H).

Example 164: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [ (3R) -tetrahydrofuran-3-yl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- [ (3R) -tetrahydrofuran-3-yl]Pyrazole-4-carbonitriles

Following general procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (300mg, 1.14mmol) and [ (3R) -tetrahydrofuran-3-yl ] hydrazine hydrochloride (190mg, 1.37mmol) gave the title compound (210mg, 0.63mmol, 55% yield).

UPLC(ES⁺Short acidic): 1.77 min, M/z 335.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydrofuran-3-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro- 2-methoxy-benzamides

Following general procedure K, after purification, potassium trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] borane (334mg, 1.15mmol) and 5-amino-3- (4-bromophenyl) -1- [ (3R) -tetrahydrofuran-3-yl ] pyrazole-4-carbonitrile (150mg, 0.45mmol) gave the title compound (48mg, 0.11mmol, 25% yield) as a light yellow solid.

UPLC-MS(ES⁺Short acidic): 1.63 min, M/z 436.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [ (3R) -tetrahydrofuran Pyran-3-yl radicals]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydrofuran-3-yl ] was allowed to stand]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (48mg, 0.11mmol) to give the title compound (25mg, 0.05mmol, 50% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.45 min, 454.1M/z [ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.08 min, 454.1M/z [ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.1Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.2Hz,2H),7.41(d,J＝8.2Hz,2H),7.39-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.40(s,2H),4.98-4.89(m,1H),4.55(d,J＝6.1Hz,2H),4.03-3.92(m,2H),3.90(s,3H),3.85-3.76(m,2H),2.30-2.22(m,2H)。

Example 165: 5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromo-2, 3-difluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromo-2, 3-difluoro-phenyl) -methoxy-methylene ] malononitrile (140mg, 0.47mmol) and (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (100mg, 0.61mmol) gave the title compound (129mg, 0.33mmol, 70% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.86 min, M/z 397.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]-2, 3-difluoro-benzene Base of]Methyl radical]-5-fluoro-2-methoxy-benzamide

Purification by flash column chromatography on silica gel according to general procedure K, eluting with 0-10% MeOH in DCM, was followed by 5-amino-3- (4-bromo-2, 3-difluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (124mg, 0.31mmol) and potassium trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] borane (154mg, 0.53mmol) to give N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl ] -2, 3-difluoro-phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide (120mg, 0.24mmol, 77% yield) as a pale yellow solid.

UPLC-MS(ES⁺Short acidic): 1.75 min, M/z 498.1[ M + H ]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-(2, 2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

Purification by flash column chromatography on silica gel, eluting with 0-10% MeOH in DCM, according to general procedure M, was performed by allowing N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl ] -2, 3-difluoro-phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide (110mg, 0.22mmol) to give 5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide (73mg, 0.14mmol, 64% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.62 min, M/z 516.1[ M + H]⁺。

UPLC-MS(ES⁺Long acidic): 3.80 min, M/z 516.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.88(t,J＝5.9Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.38-7.33(m,1H),7.28-7.18(m,3H),6.61(s,2H),5.36-5.27(m,1H),4.61(d,J＝5.9Hz,2H),3.90(s,3H),1.61(d,J＝6.7Hz,3H)。

Example 166: 5-amino-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) -3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (4, 4-difluoro-1-methylpyrrolidin-3-yl) -3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) Amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid carboxamides

Reacting 5-amino-1- (4, 4-difluoropyrrolidin-3-yl) -3- [ 3-fluoro-4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (11mg, 0.02mmol) and cesium carbonate (15mg, 0.05mmol) were suspended in DMF (2 mL). The mixture was cooled to-10 ℃ and purged with nitrogen, then 0.2M iodomethane in DMF (0.1mL, 0.02mmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours. Work-up and purification gave the title compound (4mg, 0.01mmol, 35% yield) as a light yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.25 min, M/z 503.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.73 min, M/z 503.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.76(dd,J＝7.7,1.7Hz,1H),7.51-7.43(m,2H),7.34-7.27(m,2H),7.17(d,J＝8.4Hz,1H),7.06-7.02(m,1H),6.51(s,2H),5.25-5.16(m,1H),4.58(d,J＝6.0Hz,2H),3.91(s,3H),3.29-3.17(m,3H),2.91-2.70(m,1H),2.36(s,3H)。

Example 167: 5-amino-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino] Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Reacting 5-amino-1- (4, 4-difluoropyrrolidine-3-yl) -3- [4- [ [ (2-methoxybenzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (40mg, 0.09mmol) and cesium carbonate (55mg, 0.17mmol) were suspended in DMF (3 mL). The mixture was cooled to-15 deg.C, purged with nitrogen, and then a solution of methyl iodide (0.9M in THF, 0.2mL, 0.18mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. Work-up and purification gave the title compound (5mg, 0.01mmol, 12% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.19 min, M/z 485.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 2.62 min, M/z 485.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.0Hz,1H),7.74(dd,J＝7.6,1.7Hz,1H),7.49-7.40(m,5H),7.15(d,J＝8.3Hz,1H),7.05-7.01(m,1H),6.56(s,2H),5.22-5.13(m,1H),4.54(d,J＝6.0Hz,2H),3.89(s,3H),3.28-3.15(m,3H),2.86-2.73(m,1H),2.34(s,3H)。

Example 168: 5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, with (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (96mg, 0.58mmol) and 2- [ (4-chloro-2, 5-difluoro-phenyl) -methoxy-methylene]Malononitrile (114mg, 0.45mmol) gave crude 5 title compound (156mg, 0.44mmol, assuming quantitative yield). UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 351.0[ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]-2, 5-difluoro-benzene Base of]Methyl radical]-5-fluoro-2-methoxy-benzamide

Following general procedure K, using trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (257mg, 0.89mmol) and 5-amino-3- (4-chloro-2, 5-difluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (156mg, 0.44mmol) gave the title compound (221mg, 0.44mmol, 98% yield). UPLC-MS (ES)⁺Short acidic): 1.76 min, M/z 498.1[ M + H ]]⁺。

5-amino-3- [2, 5-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-(2, 2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl)]-2, 5-difluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (221mg, 0.44mmol) gave the title compound (0.10 mmol). UPLC-MS (ES) ⁺Long acidic): 3.77 min, M/z 516.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.87(t,J＝6.1Hz,1H),7.49(dd,J＝9.2,3.3Hz,1H),7.38-7.31(m,1H),7.29-7.22(m,3H),6.57(br s,2H),5.36-5.27(m,1H),4.56(d,J＝5.9Hz,2H),3.90(s,3H),1.60(d,J＝7.0Hz,3H)。

Example 169: 5-amino-1- (4, 4-difluoropyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]Pyrazole- 1-radical]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical]Potassium borane (128mg, 0.44mmol) and 4- [ 5-amino-3- (4-bromophenyl) -4-cyano-pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (81mg, 0.17mmol) gave the title compound (50mg, 0.09mmol, 51% yield) as a light yellow solid. UPLC-MS (ES)^-Short acidic): 1.86 min, 569.2M/z [ M-H]^-。

5-amino-1- (4, 4-difluoropyridin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, 4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]Pyrazol-1-yl]-3, 3-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (50mg, 0.09mmol) gave the title compound (13mg, 0.05mmol) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.20 min, 489.1M/z [ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.61 min, 489.2M/z [ M + H]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.47(d,J＝8.3Hz,2H),7.42(d,J＝8.3Hz,2H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.54(s,2H),5.08-4.94(m,1H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.59-3.43(m,2H),3.26-3.07(m,2H)。

Example 170: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [1- (trifluoromethyl) propyl ] pyrazole-4-carboxamide

N- [1- (trifluoromethyl) propyleneamino]Benzamide derivatives

Following general procedure S, crude title compound was obtained using 1,1, 1-trifluoro-2-butanone (0.45mL, 3.30mmol) and benzoyl hydrazine (2.20mmol)Compound (487mg, 2.0mmol, 91% yield) was a white solid. UPLC-MS (ES)⁺Short acidic): 1.70 min, M/z 245.0[ M + H ]]⁺。

N' - [1- (trifluoromethyl) propyl]Benzoyl hydrazine

Following general procedure T, using N- [1- (trifluoromethyl) propyleneamino]Benzamide (487mg, 2.0mmol) gave the crude title compound (487mg, 1.98mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 247.0[ M + H ]]⁺。

1- (trifluoromethyl) propylhydrazine hydrochloride

Following general procedure U, using N' - [1- (trifluoromethyl) propyl ] benzoyl hydrazine (487mg, 1.98mmol) gave crude title compound (1.98mmol, assuming quantitative yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,δ):3.64-3.59(m,1H),1.76-1.53(m,2H),1.02(t,J＝7.4Hz,3H)。

5-amino-3- (4-bromophenyl) -1- [1- (trifluoromethyl) propyl]Pyrazole-4-carbonitriles

Modified general procedure H, purification at RT, to obtain 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (100mg, 0.38mmol) and 1- (trifluoromethyl) propylhydrazine hydrochloride (102mg, 0.57mmol) gave the title compound (135mg, 0.36mmol, 95% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.03 min, M/z 373.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy group Phenyl-carboxamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [1- (trifluoromethyl) propyl]Pyrazole-4-carbonitrile (135mg, 0.36mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (196mg, 0.72mmol) gave the title compound (219mg, 0.48mmol) as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.78 min, M/z 458.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [1- (trifluoromethyl) propyl] Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (219mg, 0.48mmol) to give the title compound (77mg, 0.16mmol, 34% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 476.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.69 min, M/z 476.1[ M + H ] ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.73(t,J＝6.1Hz,1H),7.74(dd,J＝7.7,1.7Hz,1H),7.49-7.39(m,5H),7.14(d,J＝8.2Hz,1H),7.06-7.00(m,1H),6.69(s,2H),5.12-5.00(m,1H),4.54(d,J＝6.1Hz,2H),3.89(s,3H),2.27-2.16(m,1H),1.99-1.88(m,1H),0.79(t,J＝7.3Hz,3H)。

Example 171: 5-amino-3- [4- [ [ (2-methoxybenzoyl) amino ] methyl ] phenyl ] -1- [ 2-methyl-1- (trifluoromethyl) propyl ] pyrazole-4-carboxamide

N- [ [ 2-methyl-1- (trifluoromethyl) propylidene ] s]Amino group]Benzamide derivatives

Following general procedure S, using 1,1, 1-trifluoro-3-methyl-2-butanone (3.31mmol) and benzoyl hydrazine (2.20mmol) gave the title compound (1.30mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 259.0[ M + H ]]⁺。

N' - [ 2-methyl-1- (trifluoromethyl) propyl]Benzoyl hydrazine

Following general procedure T, using N- [ [ 2-methyl-1- (trifluoromethyl) propylene]Amino group]Benzamide (335mg, 1.30mmol) gave the crude title compound (341mg, 1.31mmol, quantitative yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, M/z 261.0[ M + H ]]⁺。

[ 2-methyl-1- (trifluoromethyl) propyl group]Hydrazine hydrochloride

According to the general procedure U, N' - [ 2-methyl-1- (trifluoromethyl) propyl]Benzoyl hydrazine (341mg, 1.31mmol) gave the crude title compound (243mg, 1.26mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.63-3.52(m,1H),2.14-2.04(m,1H),1.04(d,J＝6.9Hz,3H),0.97(d,J＝6.9Hz,3H)。

5-amino-3- (4-bromophenyl) -1- [ 2-methyl-1- (trifluoromethyl) propyl]Pyrazole-4-carbonitriles

Modified general procedure H, purification at RT, to obtain 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (100mg, 0.38mmol) and [ 2-methyl-1- (trifluoromethyl) propyl ]]Hydrazine hydrochloride (110mg, 0.57 gave the title compound (99mg, 0.26mmol, 67% yield) as a white solid UPLC-MS (ES)⁺Short acidic): 2.10 min, M/z 387.0[ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]- 2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [ 2-methyl-1- (trifluoromethyl) propyl]Pyrazole-4-carbonitrile (99mg, 0.26mmol) and trifluoro- [ [ (2-methoxybenzoyl) amino]Methyl radical]Potassium borane (139mg, 0.51mmol) gave the title compound (179mg, 0.38mmol, assuming quantitative yield) as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.82 min, M/z 472.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]-1- [ 2-methyl-1- (trifluoromethyl) Yl) propyl group]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-2-methoxy-benzamide (179mg, 0.38mmol) gave the title compound (66mg, 0.12mmol, 32% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic):1.69 min, M/z 490.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.89 min, M/z 490.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆,δ):8.72(t,J＝6.0Hz,1H),7.74(dd,J＝7.7,1.7Hz,1H),7.49-7.39(m,5H),7.14(d,J＝8.2Hz,1H),7.05-7.00(m,1H),6.68(s,2H),4.90-4.80(m,1H),4.54(d,J＝6.0Hz,2H),3.89(s,3H),2.61-2.50(m,1H),1.09(d,J＝6.4Hz,3H),0.77(d,J＝6.6Hz,3H)。

Example 172: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (1-tetrahydrofuran-3-ylethyl) carboxamide

N-methoxy-N-methyltetrahydrofuran-3-carboxamide

Tetrahydro-3-furoic acid (0.25mL, 2.61mmol), triethylamine (0.7mL, 5.23mmol), a solution of propylphosphonic anhydride (50 wt% in EtOAc, 2.3mL, 3.92mmol) and a solution of N, O-dimethylhydroxylamine hydrochloride (382mg, 3.92mmol) in DCM (10mL) were stirred at room temperature for 16 h to give (after treatment) the title compound (416mg, 2.61mmol, assuming quantitative yield) as a colorless oil.¹H NMR(400MHz,CDCl₃,δ):4.10-4.03(m,1H),3.95-3.78(m,3H),3.72(s,3H),3.50-3.37(m,1H),3.22(s,3H)2.30-2.19(m,1H),2.15-2.03(m,1H)。

1-tetrahydrofuran-3-yl ethanones

To a solution of N-methoxy-N-methyl-tetrahydrofuran-3-carboxamide (276mg, 1.73mmol) in THF (8mL) at 0 deg.C was added magnesium (methyl) bromide (3.4M in 2-MeTHF, 0.7mL, 2.25 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with HCl (1M aqueous solution), the residue diluted with ether, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude 1-tetrahydrofuran-3-yl ethanone (127mg, 1.11mmol, yield 64%) as a clear oil. ¹H NMR(400MHz,CDCl₃,δ):4.00-3.70(m,4H),3.27-3.18(m,1H),2.23(s,3H),2.17-2.09(m,2H)。

N- [ 1-tetrahydrofuran-3-ylethyleneamino]Carbamic acid tert-butyl ester

Following general procedure E, purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane, the title compound was obtained as a white solid from 1-tetrahydrofuran-3-yl ethanone (127mg, 1.11 mmol). UPLC-MS (ES)⁺Short acidic): 1.26 min, M/z 229.0[ M + H ]]⁺。

5-amino-3- (4-bromophenyl) -1- (1-tetrahydrofuran-3-ylethyl) pyrazole-4-carbonitrile

Purification by reverse phase chromatography at RT according to modified general procedure O, eluting with an aqueous solution of equal 30% MeCN containing 0.1% formic acid, N- [ 1-tetrahydrofuran-3-ylethyleneamino]Carbamic acid tert-butyl ester (0.38mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (95mg, 0.36mmol) gave the title compound (33mg, 0.09mmol, 26% yield) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.81 min, M/z 361.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-tetrahydrofuran-3-ylethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5- Fluoro-2-methoxy-benzamides

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure K gave 5-amino-3- (4-bromophenyl) -1- (1-tetrahydrofuran-3-ylethyl) pyrazole-4-carbonitrile (33mg, 0.09mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group ]Methyl radical]Potassium borane (59mg, 0.20mmol) gave the title compound (37mg, 0.08mmol, 87% yield) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 464.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (1-tetrahydrofuran-) 3-ylethyl) pyrazole-4-carboxamide

Purification by flash column chromatography on silica gel eluting with 2-5% MeOH in DCM according to general procedure M gave N- [ [4- [ 5-amino-4-cyano-1- (1-tetrahydrofuran-3-ylethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (37mg, 0.08mmol) to give 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (1-tetrahydrofuran-3-ylethyl) pyrazole-4-carboxamide (12mg, 0.02mmol, 30% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.43 min, M/z 482.2[ M + H ]]⁺3.28 min, M/z 482.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆δ, mixture of diastereomers 8.83(t, J ═ 6.0Hz,1H),7.51(dd, J ═ 9.2,3.3Hz,1H),7.48 to 7.43(m,2H),7.41(d, J ═ 8.2Hz,2H),7.37 to 7.30(m,1H),7.18(dd, J ═ 9.1,4.3Hz,1H),6.38(s,1.34H),6.36(s,0.66H),4.54(d, J ═ 6.0Hz,2H),4.30 to 4.18(m,1H),3.89(s,3H),3.86 to 3.40(m,3.67H),3.28 to 3.30(m,0.33H),2.82 to 2.63(m,1H), 10.91 (m, 1.34H), 3.54 (d, 1.34H), 1.54 (d, 1.34H), 1.7 (d, 1.31H), 1.6.6.6.6.6H).

Example 173: 5-amino-1- (2, 2-difluoro-1-methyl-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- (2, 2-difluoro-1-methyl-ethyl) pyrazol-3-yl ] phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2, 2-difluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (91mg, 0.27mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (170mg, 0.59mmol) gave the title compound (119mg, 0.27mmol, quantitative yield) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.70 min, M/z 444.1[ M + H ]]⁺。

5-amino-1- (2, 2-difluoro-1-methyl-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino] Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

According to the general procedureM, after purification, the N- [ [4- [ 5-amino-4-cyano-1- (2, 2-difluoro-1-methyl-ethyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (119mg, 0.27mmol) to give the title compound (85mg, 0.18mmol, 69% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 462.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.49 min, M/z 462.1[ M + H ] ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.1Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.2Hz,2H),7.41(d,J＝8.2Hz,2H),7.38-7.30(m,1H),7.18(dd,J＝9.1,4.3Hz,1H),6.53(s,2H),6.21(dt,J＝55.8,5.4Hz,1H),4.85-4.70(m,1H),4.55(d,J＝6.0Hz,2H),3.89(s,3H),1.44(d,J＝6.7Hz,3H)。

Example 174: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (3,3, 3-trifluoropropyl) carboxamide

N- [3,3, 3-Trifluoropropyleneamino]Benzamide derivatives

Following general procedure S, 3, 3-trifluoropropionaldehyde (0.15mL, 1.78mmol) gave N- [3,3, 3-trifluoropropyleneamino]A cis-trans mixture of benzamide (290mg, 1.26mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.32 min, M/z 230.9[ M + H ]]⁺。

N' - (3,3, 3-trifluoropropyl) benzoyl hydrazine

According to general procedure T, using N- [3,3, 3-trifluoropropyleneamino]Benzamide (290mg, 1.26mmol) gave crude N' - (3,3, 3-trifluoropropyl) benzoyl hydrazine (201mg, 0.87mmol, 69% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.37 min, M/z 233.1[ M + H]⁺。

3,3, 3-Trifluoropropylhydrazine hydrochloride

According to the general procedure U, N' - (3,3, 3-trifluoropropyl) benzoylHydrazine (201mg, 0.87mmol) gave crude 3,3, 3-trifluoropropylhydrazine hydrochloride (140mg, 0.85mmol, assuming quantitative yield) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.07(t,J＝14.9Hz,2H),2.58-2.56(m,2H)。

5-amino-3- (4-bromophenyl) -1- (3,3, 3-trifluoropropyl) pyrazole-4-carbonitrile

Following general procedure H, purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane, 3,3, 3-trifluoropropylhydrazine hydrochloride (140mg, 0.85mmol) and 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (224mg, 0.85mmol) gave the title compound (227mg, 0.63mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 361.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3,3, 3-trifluoropropyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-5-fluoro-2-carboxylic acid methyl ester Oxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (3,3, 3-trifluoropropyl) pyrazole-4-carbonitrile (227mg, 0.63mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (909mg, 3.15mmol) gave the title compound (270mg, 0.59 mmol). UPLC-MS (ES)⁺Short acidic): 1.74 min, M/z 462.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (3,3, 3-trifluoropropan) Yl) pyrazole-4-carboxamides

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure M gave N- [ [4- [ 5-amino-4-cyano-1- (3,3, 3-trifluoropropyl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (270mg, 0.59mmol) to give the title compound (66mg, 0.14mmol, 24% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.48 min, M/z 480.1[ M + H ]]⁺。

UPLC-MS(ES⁺Long acidic): 3.42 min, M/z 480.1[ M + H ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.4Hz,1H),7.50(dd,J＝9.2,3.6Hz,1H),7.44(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.36-7.28(m,1H),7.17(dd,J＝9.2,4.4Hz,1H),6.45(s,2H),4.53(d,J＝6.1Hz,2H),4.18(t,J＝7.2Hz,2H),3.87(s,3H),2.83-2.69(m,2H)。

Example 175: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-tetrahydrofuran-2-yl) -3-yl-ethyl) pyrazole-4-carboxamide

Tetrahydrofuran-3-carboxylic acid benzyl ester

A solution of tetrahydro-3-furoic acid (0.25mL, 2.61mmol), potassium carbonate (433mg, 3.14mmol) and benzyl bromide (0.3mL, 2.74mmol) in MeCN (5.5mL) was stirred at room temperature for 16 h. Work-up and purification gave the title compound (398mg, 1.93mmol, 74% yield) as a colorless oil.

¹H NMR(400MHz,CDCl₃,δ):7.43-7.32(m,5H),5.17(s,2H),4.04-3.80(m,4H),3.21-3.11(m,1H),2.30-2.10(m,2H)。

N- [ (2,2, 2-trifluoro-1-tetrahydrofuran-3-ylethylene) amino]Carbamic acid tert-butyl ester

To a solution of benzyl tetrahydrofuran-3-carboxylate (398mg, 1.93mmol) in THF (3.8mL) at 0 deg.C was added trimethyl (trifluoromethyl) silane (0.34mL, 2.32mmol) and tetrabutylammonium fluoride (1M in THF, 0.48mL, 0.48 mmol). The reaction mixture was stirred at room temperature for 16 h, then tert-butyl carbazate (255mg, 1.93mmol) and acetic acid (3.8mL) were added. The mixture was heated to 90 ℃ for 3 hours and cooled to room temperature. Work-up and purification gave the title compound (409mg, 1.45mmol, 75% yield) as a clear oil. UPLC-MS (ES)^-Short acidic): 1.79 min, M/z 281.0[ M-H]^-。

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-tetrahydrofuran-3-yl-ethyl) pyrazole-4-carboxylic acid methyl ester Nitrile

Purification by flash column chromatography on silica gel eluting with 0-55% EtOAc in heptane according to general procedure O gave N- [ (2,2, 2-trifluoro-1-tetrahydrofuran-3-ylethylene) amino ] carbamic acid tert-butyl ester (409mg, 1.45mmol) and 2- [ (4-bromophenyl) methoxy-methylene ] malononitrile (120mg, 0.46mmol) as 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-tetrahydrofuran-3-yl-ethyl) pyrazole-4-carbonitrile (98mg, 0.24mmol, 52% yield) as a white powder.

UPLC-MS(ES⁺Short acidic): 1.89 min, M/z 414.9[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-tetrahydrofuran-3-yl-ethyl) pyrazol-3-yl]Benzene and its derivatives Base of]Methyl radical]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-tetrahydrofuran-3-yl-ethyl) pyrazole-4-carbonitrile (98mg, 0.24mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (149mg, 0.52mmol) gave the title compound (115mg, 0.22mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.68 min, M/z 518.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro- 1-tetrahydrofuran-3-yl-ethyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-tetrahydrofuran-3-yl-ethyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (115mg, 0.22mmol) to give the title compound (15mg, 0.03mmol, 13% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.51 min, M/z 536.2[ M + H]⁺1.53 min, M/z 536.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.51 min, M/z 536.1[ M + H]⁺3.56 min, M/z 536.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆Delta, diastereoisomers8.82(t, J-5.9 Hz,1H),7.52-7.43(m,3H),7.41(d, J-7.9 Hz,2H),7.36-7.28(m,1H),7.17(dd, J-9.1, 4.3Hz,1H),6.73(s,0.66H),6.71(s,1.34),5.26-5.12(m,1H),4.53(d, J-6.0 Hz,2H),3.94-3.82(m,4H),3.76-3.67(m,1H),3.65-3.57(m,1H),3.57-3.50(m,0.33H),3.25-3.03(m,1.67H),2.18-2.04(m, 0.86H), 1.54-3.33H), 3.25-3.03(m, 1.67H).

Example 176: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (3,3, 3-trifluoro-2-methyl-propyl) pyrazole-4-carboxamide

N- [ (3,3, 3-trifluoro-2-methyl-propylidene) amino group]Benzamide derivatives

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure S gave 3,3, 3-trifluoro-2-methylpropanal (200mg, 1.59mmol) as N- [ (3,3, 3-trifluoro-2-methyl-propylene) amino ]Benzamide (164mg, 0.67mmol, 42% yield) as a mixture of diastereomers. UPLC-MS (ES)⁺Short acidic): 1.45 min, M/z 245.0[ M + H ]]⁺。

N' - (3,3, 3-trifluoro-2-methyl-propyl) benzoyl hydrazine

Following general procedure T, using N- [ (3,3, 3-trifluoro-2-methyl-propylidene) amino]Benzamide (164mg, 0.67mmol) gave crude N' - (3,3, 3-trifluoro-2-methyl-propyl) benzoyl hydrazine (160mg, 0.65mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.51 min, M/z 247.1[ M + H]⁺。

(3,3, 3-trifluoro-2-methylpropyl) hydrazine hydrochloride

Following general procedure U, N' - (3,3, 3-trifluoro-2-methyl-propyl) benzoylhydrazine (160mg, 0.65mmol) gave (3,3, 3-trifluoro-2-methylpropyl) hydrazine hydrochloride (0.65mmol) as a white solid.

¹H NMR(400MHz,DMSO-d₆,δ):3.17-3.14(m,1H),2.82-2.76(m,2H),1.10(d,J＝6.5Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (3,3, 3-trifluoro-2-methyl-propyl) pyrazole-4-carbonitrile

General procedure H, (3,3, 3-trifluoro-2-methylpropyl) hydrazine hydrochloride (0.65mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.65mmol) gave the title compound (0.34mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 2.01 min, M/z 375.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3,3, 3-trifluoro-2-methyl-propyl) pyrazol-3-yl]Phenyl radical]Methyl radical ]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (3,3, 3-trifluoro-2-methyl-propyl) pyrazole-4-carbonitrile (130mg, 0.34mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (490mg, 1.71mmol) gave the title compound (0.26mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.81 min, M/z 476.1[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (3,3, 3-trifluoro- 2-methyl-propyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (3,3, 3-trifluoro-2-methyl-propyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (127mg, 0.27mmol) to give the title compound (31mg, 0.06mmol, 23% yield) as a light yellow solid. UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 494.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.61 min, M/z 494.1[ M + H [)]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.0Hz,1H),7.49(dd,J＝9.2,3.2Hz,1H),7.44(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.36-7.28(m,1H),7.17(dd,J＝9.2,4.4Hz,1H),6.47(s,2H),4.53(d,J＝6.0Hz,2H),4.16(dd,J＝14.2,9.6Hz,1H),4.05(dd,J＝14.2,8.8Hz,1H),3.87(s,3H),3.06-2.92(m,1H),1.02(d,J＝6.8Hz,3H)。

Example 177: 5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromo-3-fluoro-phenyl) -methoxy-methylene]Malononitrile (130mg, 0.46mmol) and (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (100mg, 0.61mmol) gave the title compound (153mg, 0.41mmol, 88% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.01 min, M/z 378.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]-2-fluoro-phenyl] Methyl radical]-5-fluoro-2-methoxy-benzamide

Following general procedure K, with 5-amino-3- (4-bromo-3-fluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (147mg, 0.39mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (225mg, 0.78mmol) gave the crude title compound (0.39mmol) as a pale yellow solid. UPLC-MS (ES)⁺Short acidic): 1.86 min, M/z 480.0[ M + H ]]⁺。

5-amino-3- [ 3-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1-(2,2,2- Trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl)]-2-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (230mg, 0.48mmol) to give the title compound (73mg, 0.15mmol, 31% yield) as a light yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.58 min, M/z 498.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.69 min, M/z 498.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.82(t,J＝6.0Hz,1H),7.49(dd,J＝9.2,3.2Hz,1H),7.45-7.26(m,4H),7.18(dd,J＝9.1,4.3Hz,1H),6.60(s,2H),5.34-5.23(m,1H),4.56(d,J＝6.0Hz,2H),3.88(s,3H),1.60(d,J＝6.9Hz,3H)。

Example 178: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-phenyl-ethyl) pyrazole-4-carboxamide

N- [ (2,2, 2-trifluoro-1-phenyl-ethylene) amino]Benzamide derivatives

Following general procedure S, after purification, 2,2, 2-trifluoroacetophenone (33.0mmol) and benzoyl hydrazine (22.0mmol) gave the title compound (3.44mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.82 min, M/z 293.0[ M + H ]]⁺。

N' - (2,2, 2-trifluoro-1-phenyl-ethyl) benzoylhydrazines

Following general procedure T, using N- [ (2,2, 2-trifluoro-1-phenyl-ethylene) amino]A solution of benzamide (997mg, 3.41mmol) in THF (15mL) gave N' - (2,2, 2-trifluoro-1-phenyl-ethyl) benzoyl hydrazine (1.01g, 3.43mmol) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 295.0[ M + H]⁺。

(2,2, 2-trifluoro-1-phenyl-ethyl) hydrazine hydrochloride

Following general procedure U, using N' - (2,2, 2-trifluoro-1-phenyl-ethyl) benzoylhydrazine (996mg, 3.38mmol) gave the title compound (628mg, 2.77mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):9.67(s,3H),7.53-7.46(m,5H),6.63(d,J＝6.4Hz,1H),5.10-5.02(m,1H)。

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-phenyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene was taken]Malononitrile (200mg, 0.76mmol) and (2,2, 2-trifluoro-1-phenyl-ethyl) hydrazine hydrochloride (621mg, 0.96mmol) gave the title compound (266mg, 0.63mmol, yield 83%) as a white solid. UPLC-MS (ES)⁺Short acidic): 2.06 min, M/z 422.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-phenyl-ethyl) pyrazol-3-yl]Phenyl radical]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-phenyl-ethyl) pyrazole-4-carbonitrile (261mg, 0.62mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (358mg, 1.24mmol) gave the title compound (73mg, 0.14mmol, 23% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.85 min, M/z 524.1[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro- 1-phenyl-ethyl) pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-phenyl-ethyl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (71mg, 0.14mmol) to give the title compound (62mg, 0.12mmol, 84% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.71 min, M/z542.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 4.06 min, M/z542.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.85(t,J＝6.1Hz,1H),7.72-7.70(m,2H),7.52-7.41(m,8H),7.35-7.30(m,1H),7.19-7.16(m,1H),6.79(s,2H),6.51-6.45(m,1H),4.54(d,J＝6.0Hz,2H),3.88(s,3H)。

Example 179: 5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

5-amino-3- (4-bromo-2-fluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, after purification at RT, 2- [ (4-bromo-2-fluoro-phenyl) -methoxy-methylene]Malononitrile (100mg, 0.38mmol) and (2,2, 2-trifluoro-1-methyl-ethyl) hydrazine hydrochloride (88mg, 0.53mmol) gave the title compound (120mg, 0.32mmol, 84% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.84 min, M/z 378.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl]-3-fluoro-phenyl] Methyl radical]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromo-2-fluoro-phenyl) -1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazole-4-carbonitrile (120mg, 0.32mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (184mg, 0.64mmol) gave the title compound (126mg, 0.26mmol, 83% yield) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.69 min, M/z 480.0[ M + H ]]⁺。

5-amino-3- [ 2-fluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-(2,2,2- Trifluoro-1-methyl-ethyl) pyrazole-4-carboxamide

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-methyl-ethyl) pyrazol-3-yl)]-3-fluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (126mg, 0.26mmol) to give the title compound (97mg, 0.17mmol, 66% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 498.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.56 min, M/z 498.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.88(t,J＝6.1Hz,1H),7.48(dd,J＝9.1,3.2Hz,1H),7.41-7.30(m,2H),7.27-7.21(m,2H),7.20-7.16(m,1H),6.62(s,2H),5.34-5.24(m,1H),4.54(d,J＝6.1Hz,2H),3.88(s,3H),1.58(d,J＝6.8Hz,3H)。

Example 180: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [ 2-methyl-1- (trifluoromethyl) propyl ] pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [ 2-methyl-1- (trifluoromethyl) propyl]Pyrazole-4-carbonitrile (102mg, 0.26mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (152mg, 0.53mmol) gave the title compound (69mg, 0.14mmol, 54% yield) as a yellow gum. UPLC-MS (ES) ⁺Short acidic): 1.89 min, M/z 490.1[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [ 2-methyl-1- (tris) Fluoromethyl) propyl group]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ 2-methyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (69mg, 0.14mmol) gave the title compound (22mg, 0.04mmol, 31% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.66 min, M/z508.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.91 min, M/z508.1[ M + H]⁺。

Example 181: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (trifluoromethyl) propyl ] pyrazole-4-carboxamide

N- [ [4- [ 5-amino-4-cyano-1- [1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2- Methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [1- (trifluoromethyl) propyl]Pyrazole-4-carbonitrile (123mg, 0.33mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (190mg, 0.66mmol) gave the title compound (101mg, 0.21mmol, 65% yield) as a yellow gum. UPLC-MS (ES) ⁺Short acidic): 1.83 min, M/z 476.1[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [1- (trifluoromethyl) Propyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (101mg, 0.21mmol) to give the title compound (32mg, 0.06mmol, 28% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.59 min, M/z 494.1[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.71 min, M/z 494.1[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.82(t,J＝6.0Hz,1H),7.53-7.38(m,5H),7.37-7.27(m,1H),7.20-7.14(m,1H),6.69(s,2H),5.12-5.00(m,1H),4.53(d,J＝6.0Hz,2H),3.88(s,3H),2.28-2.14(m,1H),2.01-1.87(m,1H),0.79(t,J＝7.3Hz,3H)。

Example 182: 5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Tetrahydro-alkanesFuran-3-ylhydrazine hydrochloride

To a solution of 3-hydroxytetrahydrofuran (2.8mL, 34.0mmol) in toluene (40mL) under nitrogen was added triphenylphosphine (13.4g, 51.1mmol) and di-tert-butyl azodicarboxylate (9.4g, 40.9 mmol). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was concentrated and then suspended in MeOH (100mL), followed by the addition of hydrogen chloride solution (4M in dioxane, 68.1mL, 272.4 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. EtOAc was then added to the residue, filtered and washed with EtOAc to give the crude title compound (6.7g, 48.1mmol) as a yellow solid. ¹H NMR(400MHz,DMSO-d₆,δ):3.91-3.61(m,5H),2.12-1.86(m,2H)。

5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

Modified general procedure H, purification at RT, to give 2- [ (4-chloro-2, 3-difluoro-phenyl) -methoxy-methylene]Malononitrile (0.59mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.88mmol) gave the title compound (0.18mmol) as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.73 minutes, M/z325.0[ M ]]⁺。

N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]- 5-fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-chloro-2, 3-difluoro-phenyl) -1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (60mg, 0.18mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (159mg, 0.55mmol) gave the title compound (0.18mmol) as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 472.1[ M + H ]]⁺。

5-amino-3- [2, 3-difluoro-4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]-1-tetrahydro Furan-3-yl-pyrazole-4-carboxamides

Following the general procedure M, after purification,reacting N- [ [4- (5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl) -2, 3-difluoro-phenyl]Methyl radical]-5-fluoro-2-methoxy-benzamide (94mg, 0.20mmol) to give the title compound (26mg, 0.05mmol, 24% yield) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.41 min, M/z 490.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.23 min, M/z 490.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.0Hz,1H),7.51-7.47(m,1H),7.38-7.30(m,1H),7.25-7.15(m,3H),6.32(s,2H),4.97-4.90(m,1H),4.58(d,J＝6.0Hz,2H),4.00-3.86(m,5H),3.81-3.75(m,2H),2.28-2.18(m,2H)。

Example 183: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [ (3R) -tetrahydropyran-3-yl ] pyrazole-4-carboxamide

[ (3R) -tetrahydropyran-3-yl]Hydrazine

Triphenylphosphine (1.93g, 7.34mmol) and di-tert-butyl azodicarboxylate (1.35g, 5.87mmol) were added to (S) -tetrahydro-2H-pyran-3-ol (0.46mL, 4.9mmol) in toluene (9 mL). The reaction mixture was stirred at RT under nitrogen for 16 hours. The reaction mixture was concentrated and MeOH (21mL) was added followed by hydrogen chloride solution (4M in dioxane, 9.8mL, 39.17 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then recrystallized from EtOAc and purified by SCX column using NH₃(7M in MeOH) and concentrated under reduced pressure to give crude [ (3R) -tetrahydropyran-3-yl]Hydrazine (0.09g, 0.77mmol, 16% yield) as a yellow oil.

¹H NMR(400MHz,DMSO-d₆,δ):3.90-3.82(m,1H),3.71-3.61(m,1H),3.34-3.22(m,1H),3.13-3.04(m,1H),2.65-2.50(m,1H),1.90-1.77(m,1H),1.69-1.55(m,1H),1.51-1.35(m,1H),1.33-1.20(m,1H)。

5-amino-3- (4-bromophenyl) -1- [ (3R) -tetrahydropyran-3-yl]Pyrazole-4-carbonitriles

Following general procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene was taken ]Malononitrile (166mg, 0.63mmol) and [ (3R) -tetrahydropyran-3-yl]Hydrazine (88mg, 0.76mmol) gave the title compound (110mg, 0.32mmol, 42% yield). UPLC-MS (ES)⁺Short acidic): 1.76 min, 347.0M/z [ M ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydropyran-3-yl ] amino acid]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro- 2-methoxy-benzamides

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical]Potassium borane (210mg, 0.73mmol) and 5-amino-3- (4-bromophenyl) -1- [ (3R) -tetrahydropyran-3-yl]Pyrazole-4-carbonitrile (150mg, 0.43mmol) gave the title compound (0.25mmol) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.60 min, 450.1M/z [ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [ (3R) -tetrahydropyridine Pyran-3-yl radicals]Pyrazole-4-carboxamides

According to general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [ (3R) -tetrahydropyran-3-yl ] is]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (112mg, 0.25mmol) to give the title compound (29mg, 0.06mmol, 25% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.39 min, 468.1M/z [ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.19 min, 468.1M/z [ M + H ]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.1Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.2Hz,2H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.22(s,2H),4.55(d,J＝6.1Hz,2H),4.22-4.14(m,1H),4.00-3.96(m,2H),3.90(s,3H),3.83-3.76(m,1H),3.67-3.60(m,1H),1.99-1.87(m,1H),1.87-1.74(m,2H),1.74-1.61(m,1H)。

Example 184: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-1-tetrahydropyran-4-yl) -4-yl-ethyl) pyrazole-4-carboxamide

N- [ (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethylene) amino]Benzamide derivatives

A mixture of magnesium (1.2g, 45.4mmol) and iodine (23mg, 0.09mmol) in THF (7mL) was heated to 60 ℃. After activation, the mixture was cooled to room temperature and a solution of 4-bromotetrahydro-2H-pyran (1.02mL, 9.09mmol) in THF (2mL) was added dropwise. The mixture was heated to reflux for 1 hour and then cooled to room temperature. The preformed reagent was then added to a solution of N-methoxy-N-methyltrifluoroacetamide (0.82mL, 6.82mmol) in THF (2mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour with saturated NH₄Aqueous Cl was quenched and partitioned with ether. Et for aqueous layer₂And (4) extracting. The combined organic layers were dried over sodium sulfate, filtered and Et was removed under reduced pressure₂O to give a THF solution of 2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethanone (assuming quantitative yield). Further purification by flash column chromatography on silica gel after 48 h according to general procedure S, after elution with 0-100% EtOAc in heptane, a solution of the previously prepared benzoylhydrazine and 2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethanone (0.15mL, 9.09mmol) gives N- [ (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethylene) amino group ]Benzamide (300mg, 1.00mmol, 11% yield).

UPLC-MS(ES⁺Short acidic): 1.60 min, M/z 301.0[ M + H ]]⁺。

N' - (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) benzoyl hydrazine

After purification according to general procedure T, N- [ (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethylene) amino group]Benzamide (403mg, 1.34mmol) gave the title compound (168mg, 0.56mmol, yield 41%). UPLC-MS (ES)⁺Short acidic): 1.56 min, M/z 303.0[ M + H ]]⁺。

(2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) hydrazine hydrochloride

After 48 h according to procedure U, N' - (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) benzoyl hydrazine (168mg, 0.56mmol) gave the title compound (85mg, 0.36mmol, 65% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):3.91-3.83(m,2H),3.72-3.61(m,1H),3.35-3.22(m,2H),2.07-1.95(m,1H),1.67-1.52(m,3H),1.50-1.36(m,1H)。

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (80mg, 0.30mmol) and (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) hydrazine hydrochloride (85mg, 0.36mmol) at RT gave the crude title compound (146mg, 0.34mmol, assuming quantitative yield).

UPLC-MS(ES⁺Short acidity) 1.93 min, M/z 428.9[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) pyrazol-3-yl ]Benzene and its derivatives Base of]Methyl radical]-5-fluoro-2-methoxy-benzamide

Following general procedure K, using 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) pyrazole-4-carbonitrile (130mg, 0.30mmol) and potassium trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] borane (193mg, 0.67mmol) gave the crude title compound (160mg, 0.30mmol, quantitative yield).

UPLC-MS(ES⁺Short acidic): 1.71 min, M/z 532.2[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro- 1-tetrahydropyran-4-yl) -4-yl-ethyl) pyrazole-4-carboxamide

According to general procedure M, purification by flash column chromatography on silica gel, eluting with 0-6% MeOH in DCM, and workup by mass directed semi-preparative HPLCAfter step (b), the N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1-tetrahydropyran-4-yl-ethyl) pyrazol-3-yl group is reacted with a carboxylic acid]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (160mg, 0.30mmol) gave the title compound (0.02 mmol). UPLC-MS (ES)⁺Short acidic): 1.55 min, M/z 550.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.61 min, M/z 550.2[ M + H [)]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.1Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.48-7.40(m,4H),7.37-7.30(m,1H),7.19(dd,J＝9.2,4.3Hz,1H),6.71(br s,2H),5.06-4.98(m,1H),4.55(d,J＝6.1Hz,2H),3.89(s,3H),3.89--3.77(m,2H),3.37-3.22(m,2H),2.68-2.42(m,1H),1.81-1.17(m,1H),1.54-1.43(m,1H),1.34-1.21(m,1H),1.10-1.01(m,1H)。

Example 185: 5-amino-1-cyclopentyl-3- [4- [ 2-hydroxy-1- [ (2-methoxybenzoyl) amino ] ethyl ] -3-methyl-phenyl ] pyrazole-4-carboxamide

2-bromo-1- (4-bromo-2-methyl-phenyl) ethanone

To a solution of 1- (4-bromo-2-methylphenyl) ethanone (2.0g, 9.39mmol) in MeCN (40mL) was added N-bromosuccinimide (1.7g, 9.57mmol) and p-toluenesulfonic acid monohydrate (1.8g, 9.39 mmol). The reaction was stirred at 50 ℃ for 18 h, concentrated and worked up to give the title compound (9.39 mmol). UPLC-MS (ES)⁺Short acidic): 1.91 min, M/z 292.8[ M + H ]]⁺。

1- (4-bromo-2-methyl-phenyl) -2-hydroxy-ethanone

To a solution of 2-bromo-1- (4-bromo-2-methyl-phenyl) ethanone (9.4mmol) in MeOH (30mL) was added cesium formate hydrate (28.2mmol) and the solution was stirred at 80 ℃ for 4 hours. After work-up, the title compound (10.3mmol) was obtained. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 230.8[ M +2 ]]⁺。

1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethanones

To a solution of 1- (4-bromo-2-methyl-phenyl) -2-hydroxy-ethanone (2.15g, 9.39mmol) in DCM (30mL) was added imidazole (959mg, 14.1 mmol). The solution was cooled to 0 deg.C, then tert-butylchlorodimethylsilane (2.00mL, 14.1mmol) in DCM (10mL) was added dropwise. The solution was then stirred at 0 ℃ for 30 minutes and then at room temperature for 18 hours. Work-up and purification gave the title compound (2.22g, 6.47mmol) as a colorless oil. UPLC-MS (ES) ⁺Short acidic): 2.43 min, M/z 345.0[ M +2 ]]⁺。

1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethanol

Sodium borohydride (32.3mmol) was added to a solution of 1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethanone (6.47mmol) in MeOH (20mL) at 0 deg.C. The reaction was stirred at 0 ℃ for 1 hour, then at RT for 3.5 hours. Work up and purify to give the title compound (6.26 mmol).

¹H NMR(400MHz,CDCl₃,δ):7.40-7.38(m,1H),7.33-7.36(m,1H),7.28-7.29(m,1H),4.89-4.95(m,1H),3.75-3.68(m,1H),3.50-3.40(m,1H),2.33-2.27(m,3H),0.92(s,9H),0.07(s,6H)。

2- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]-isoindole Quinoline-1, 3-diones

To a solution of 1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethanol (2.16g, 6.26mmol) in THF (10mL) was added phthalimide (1.06g, 7.20mmol) and triphenylphosphine (1.89g, 7.20 mmol). A solution of diisopropyl azodicarboxylate (1.4mL, 7.20mmol) in THF (10mL) was added dropwise to the reaction. The reaction was stirred at 0 ℃ for 30 minutes and then at RT for 66 hours. Work up and purification by flash column chromatography on silica gel eluting with 0-20% EtOAc in heptane afforded 2- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -isoindoline-1, 3-dione (1.55g, 3.26mmol, 52% yield) and 2- [2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] isoindoline-1, 3-dione (901mg, 1.90mmol, 30% yield).

2- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -isoindoline-1, 3-dione

UPLC-MS(ES^-Short acidic): 2.50 min, M/z 476.0[ M +2 ]]⁺。

2- [2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -isoindoline-1, 3-dione

UPLC-MS(ES⁺Short acidic): 2.48 min, M/z 476.1[ M +2 ]]⁺。

2- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]-isoindole Quinoline-1, 3-diones

Hydrazine hydrate (55-60% in water, 0.26mL, 5.27mmol) was added dropwise to 2- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]Isoindoline-1, 3-dione (500mg, 1.05mmol) in EtOH (5 mL). The reaction was heated to 80 ℃ for 1.5 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by SCX using 1MNH₃Eluted with MeOH to give the title compound (243mg, 0.70mmol, 67% yield).

¹H NMR(400MHz,DMSO-d₆,δ):7.43(d,J＝8.1Hz,1H),7.31-7.36(m,2H),4.11(dd,J＝6.9,5.6Hz,1H),3.44-3.56(m,2H),2.29(s,3H),0.81(s,9H),-0.05(s,3H),-0.06(s,3H)。

N- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]-2-methoxy group Phenyl-carboxamides

To 1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]To a solution of oxy-ethylamine (0.710mmol) in THF (3mL) was added N, N-diisopropylethylamine (2.12 mmol). 2-Methoxybenzoyl chloride (0.78mmol) was added to the reaction at 0 ℃. The reaction was stirred at 0 ℃ for 20 minutes, then at room temperature for 66 hours, and with saturated NH ₄Dissolving Cl in waterAnd (6) quenching the solution. Work up and purify to give the title compound (0.38 mmol). UPLC-MS (ES)⁺Short acidic): 2.44 min, M/z 480.1[ M +2 ]]⁺。

N- [2- [ tert-butyl (dimethyl) silyl]Oxy-1- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-) Dioxaborane-2-yl) phenyl]Ethyl radical]-2-methoxy-benzamide

Following general procedure R, after purification, N- [1- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -2-methoxy-benzamide (183mg, 0.38mmol) gave the title compound (146mg, 0.28mmol, 73% yield).

UPLC-MS(ES⁺Short acidic): 2.51 min, M/z 526.3[ M + H ]]⁺。

5-amino-3- [4- [2- [ tert-butyl (dimethyl) silyl]Oxy-1- [ (2-methoxybenzoyl) ammonia Base of]Ethyl radical]-3-methyl-phenyl]-1-cyclopentylpyrazole-4-carboxamide

After further purification according to general procedure D, N- [2- [ tert-butyl (dimethyl) silyl]Oxy-1- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl radical]-2-methoxy-benzamide (150mg, 0.29mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (74mg, 0.27mmol) to give the title compound (0.27 mmol). UPLC-MS (ES)⁺Short acidic): 2.25 min, M/z 592.3[ M + H ] ]⁺。

5-amino-1-cyclopentyl-3- [4- [ 2-hydroxy-1- [ (2-methoxybenzoyl) amino]Ethyl radical]-3-methyl- Phenyl radical]Pyrazole-4-carboxamides

Tetrabutylammonium fluoride solution (1M in THF, 84. mu.L, 0.291mmol) was added dropwise to 5-amino-3- [4- [2- [ tert-butyl (dimethyl) silyl]Oxy-1- [ (2-methoxybenzoyl) amino]Ethyl radical]-3-methyl-phenyl]-1-cyclopentylpyrazole-4-carboxamide (0.27mmol) in THF (1.5 mL). The reaction was stirred at 0 ℃ for 3 hours and then partitioned between DCM and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Passing through silica gel blockFurther purification by flash chromatography eluting with 0-5% MeOH in DCM followed by mass directed semi-preparative HPLC afforded the title compound (0.06 mmol). UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 478.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.29 min, M/z 478.2[ M + H [)]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.69(d,J＝7.6Hz,1H),7.73(dd,J＝7.6,1.9Hz,1H),7.52-7.46(m,1H),7.42-7.39(m,1H),7.30-7.25(m,2H),7.18(d,J＝8.4Hz,1H),7.08-7.01(m,1H),6.33(s,2H),5.32-5.23(m,1H),5.03(t,J＝5.5Hz,1H),4.65-4.55(m,1H),3.95(s,3H),3.71-3.58(m,2H),2.45(s,3H),2.01-1.84(m,4H),1.83-1.72(m,2H),1.63-1.52(m,2H)。

Example 186: 5-amino-1- (3, 3-difluoro-4-piperidinyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

3, 3-difluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (1.19g, 5.44mmol) is added to a solution of 1-benzyl-3, 3-difluoropiperidin-4-one (995mg, 4.42mmol) in EtOH (60mL) under nitrogen. Palladium hydroxide (palladium 20% on carbon, 148mg, 1.05mmol) was added and the system was evacuated and flushed with hydrogen several times. The mixture was stirred at RT under hydrogen for 20 hours. Removing residual hydrogen and passing the mixture through Filtered and washed with EtOH. Purification gave the title compound (810mg, 3.44mmol, 78% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,δ):3.66-3.52(m,2H),3.39-3.33(m,2H),1.69-1.64(m,2H),1.38(s,9H)。

4- (benzoylhydrazono) -3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

Following general procedure S, after purification, a solution of 3, 3-difluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (650mg, 2.76mmol) in toluene (2mL) and benzoyl hydrazine (300mg, 2.20mmol) gave the title compound (2.00mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.63 min, M/z 354.1[ M + H]⁺。

4- (2-Benzoylhydrazino) -3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

Following general procedure T, tert-butyl 4- (benzoylhydrazono) -3, 3-difluoro-piperidine-1-carboxylate (250mg, 0.71mmol) gave crude b title compound (265mg, 0.75mmol, assuming quantitative yield) as a colorless oil. UPLC-MS (ES)⁺Short acidic): 1.62 min, M/z 356.1[ M + H ]]⁺。

(3, 3-difluoro-4-piperidinyl) hydrazine dihydrochloride

Following general procedure U, after washing with hot EtOAc, tert-butyl 4- (2-benzoylhydrazino) -3, 3-difluoro-piperidine-1-carboxylate (0.73mmol) gave the title compound as a light yellow solid.

¹H NMR(400MHz,DMSO-d₆,δ):5.97(m,1H),3.68-3.45(m,3H),3.23-3.17(m,1H),3.10-3.01(m,1H),2.27-2.20(m,1H),1.90-1.80(m,1H)。

5-amino-3- (4-bromophenyl) -1- (3, 3-difluoro-4-piperidinyl) pyrazole-4-carbonitrile

Following general procedure H, 2- [ (4-bromophenyl) -methoxy-methylene ]Malononitrile (160mg, 0.61mmol) and (3, 3-difluoro-4-piperidinyl) hydrazine dihydrochloride (170mg, 0.76mmol) were stirred at 85 ℃ for 2 hours. Work-up and purification gave the title compound (126mg, 0.33mmol, 54% yield) as a red solid. UPLC-MS (ES)⁺Short acidic): 1.29 min, M/z 383.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (3, 3-difluoro-4-piperidinyl) pyrazol-3-yl group]Phenyl radical]Methyl radical]-5-fluoro- 2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1-(3, 3-difluoro-4-piperidinyl) pyrazole-4-carbonitrile (121mg, 0.32mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (158mg, 0.55mmol) gave the title compound (99mg, 0.20mmol, 65% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.29 min, M/z 485.1[ M + H]⁺。

5-amino-1- (3, 3-difluoro-4-piperidinyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]First of all Base of]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (3, 3-difluoro-4-piperidinyl) pyrazol-3-yl ] was reacted]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (89mg, 0.18mmol) to give the title compound (64mg, 0.13mmol, 69% yield) as a light yellow solid. UPLC-MS (ES) ⁺Short acidic): 1.16 min, M/z 503.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.54 min, M/z 503.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.48-7.41(m,4H),7.37-7.32(m,1H),7.19(dd,J＝9.2,4.3Hz,1H),6.42(s,2H),4.86-4.75(m,1H),4.56(d,J＝6.0Hz,2H),3.90(s,3H),3.30-3.21(m,1H),3.14-3.11(m,1H),2.99-2.88(m,1H),2.69-2.64(m,1H),2.43-2.36(m,1H),1.95-1.89(m,1H)。

Example 187: 5-amino-1-cyclopentyl-3- [4- [ 1-hydroxy-2- [ (2-methoxybenzoyl) amino ] ethyl ] -3-methyl-phenyl ] pyrazole-4-carboxamide

2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethylamine

Hydrazine hydrate (55-60% in water, 0.26mL, 5.27mmol) was added to a solution of 2- [2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] isoindoline-1, 3-dione (500mg, 1.05mmol) in EtOH (5 mL). The reaction was heated to 80 ℃ for 1.5 h, cooled to RT, filtered and concentrated under reduced pressure to give the crude title compound (324mg, 0.94mmol, 89% yield).

¹H NMR(400MHz,DMSO-d₆,δ):7.39-7.33(m,2H),7.28(d,J＝8.3Hz,1H),4.73(dd,J＝7.5,3.9Hz,1H),2.59(dd,J＝13.0,3.9Hz,1H),2.51-2.40(m,1H),2.28(s,3H),0.84(s,9H),0.04(s,3H),-0.13(s,3H)。

N- [2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]-2-methoxy group Phenyl-carboxamides

To 2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]To a solution of oxy-ethylamine (324mg, 0.94mmol) in THF (5mL) was added N, N-diisopropylethylamine (0.5mL, 2.82 mmol). The reaction mixture was cooled to 0 ℃ and then 2-methoxybenzoyl chloride (0.15mL, 1.04mmol) was added. The reaction was stirred at 0 ℃ for 20 minutes and then at room temperature for 66 hours. Work up and purify to give the title compound (0.61 mmol). UPLC-MS (ES) ⁺Short acidic): 2.47 min, M/z 480.1[ M +2 ]]⁺。

N- [2- [ tert-butyl (dimethyl) silyl]Oxy-2- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-) Dioxaborane-2-yl) phenyl]Ethyl radical]-2-methoxy-benzamide

Following general procedure R, after purification, N- [2- (4-bromo-2-methyl-phenyl) -2- [ tert-butyl (dimethyl) silyl]Oxy-ethyl radical]-2-methoxy-benzamide (293mg, 0.61mmol) to give the title compound (286mg, 0.54mmol, 89% yield). UPLC-MS (ES)⁺Short acidic): 2.51 min, M/z 526.3[ M + H ]]⁺。

5-amino-3- [4- [1- [ tert-butyl (dimethyl) silyl]Oxy-2- [ (2-methoxybenzoyl) ammonia Base of]Ethyl radical]-3-methyl-phenyl]-1-cyclopentylpyrazole-4-carboxamide

After purification according to general procedure D, N- [2- [ tert-butyl (dimethyl) silyl]Oxy-2- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl radical]-2-methoxy groupBenzamide (0.54mmol) gave the title compound (0.43mmol, 77% yield). UPLC-MS (ES)⁺Short acidic): 2.24 min, M/z 592.3[ M + H ]]⁺。

5-amino-1-cyclopentyl-3- [4- [ 1-hydroxy-2- [ (2-methoxybenzoyl) amino]Ethyl radical]-3-methyl- Phenyl radical]Pyrazole-4-carboxamides

Tetrabutylammonium fluoride solution (1M in THF, 0.14mL, 0.480mmol) was added dropwise to 5-amino-3- [4- [1- [ tert-butyl (dimethyl) silyl ]Oxy-2- [ (2-methoxybenzoyl) amino]Ethyl radical]-3-methyl-phenyl]-1-cyclopentylpyrazole-4-carboxamide (256mg, 0.43mmol) in THF (2 mL). The reaction was stirred for 3 hours, then warmed to RT and partitioned between DCM and water. Work-up and purification gave the title compound (103mg, 0.22mmol, 50% yield). UPLC-MS (ES)⁺Short acidic): 1.46 min, M/z 478.1[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.39 min, M/z 478.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.34(t,J＝5.7Hz,1H),7.86(dd,J＝7.8,1.7Hz,1H),7.57(d,J＝8.0Hz,1H),7.52-7.45(m,1H),7.31(d,J＝8.0Hz,1H),7.25(s,1H),7.15(d,J＝8.3Hz,1H),7.05(t,J＝7.3Hz,1H),6.33(s,2H),5.55(d,J＝4.3Hz,1H),5.03-4.96(m,1H),4.65-4.55(m,1H),3.89(s,3H),3.69-3.60(m,1H),3.31-3.23(m,1H),2.38(s,3H),2.02-1.84(m,4H),1.84-1.72(m,2H),1.64-1.52(m,2H)。

Example 188: 5-amino-1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [2,2, 2-trifluoroethylidene amino group]Benzamide derivatives

To a solution of 2,2, 2-trifluoro-1-methoxy-ethanol (0.74mL, 7.69mmol) in EtOH (26mL) was added benzoyl hydrazine (1.26g, 9.23mmol) and molecular sieves. The reaction mixture was heated to 80 ℃ for 16 hours. By passingFiltration and purification gave the title compound (1.16g, 5.35mmol, 70% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.39 min, M/z 216.9[ M + H ]]⁺。

N' - (1-cyclopropyl 2,2, 2-trifluoroethyl) benzoyl hydrazine

To N- [2,2, 2-trifluoroethylidene amino group at 0 DEG C]To a solution of benzamide (2.31mmol) in THF (15mL) was added a solution of cyclopropylmagnesium bromide (0.5M in THF, 10 mL). The reaction was stirred at RT for 16 h. A further portion of cyclopropylmagnesium bromide solution (0.5M in THF, 10mL) was added and the reaction was stirred for an additional 5 hours. Saturated NH for reaction ₄Aqueous Cl was quenched and extracted with EtOAc. Work-up and purification gave the title compound (508mg, 1.97mmol, 85% yield) as a yellow oil. LC-MS (ES)⁺Short acidic): 5.17 min, M/z 259.2[ M + H]⁺。

(1-cyclopropyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride

To a solution of hydrochloric acid (12M in water, 5.0mL, 60mmol) was added N' - (1-cyclopropyl 2,2, 2-trifluoroethyl) benzoyl hydrazine (507mg, 1.96 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. The solid was filtered and washed with EtOAc to give crude (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride (149mg, 0.78mmol, 40% yield) as a brown solid.

¹H NMR(400MHz,CDCl₃,δ):3.09-3.02(m,1H),0.94-0.85(m,1H),0.71-0.59(m,3H),0.47-0.40(m,1H)。

5-amino-3- (4-bromophenyl) -1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile

Modified general procedure H, purification at RT, to obtain 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.57mmol) and (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride (0.78mmol) gave the title compound (0.21mmol) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 386.9[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

General procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile (50mg, 0.13mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (83mg, 0.29mmol) gave the title compound (40mg, 0.08mmol, 63% yield) as an off-white solid. LC-MS (ES)⁺Short acidic): 5.79 min, M/z 488.1[ M + H ]]⁺。

5-amino-1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) ammonia Base of]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Purification by flash column chromatography on silica gel, eluting with 0-20% MeOH in DCM, according to general procedure M, and then allowing N- [ [4- [ 5-amino-4-cyano-1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl ] phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide (40mg, 0.08mmol) to give 5-amino-1- (1-cyclopropyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (31mg, 0.06mmol, 76% yield), is a beige solid.

UPLC-MS(ES⁺Short acidic): 1.61 min, M/z 528.2[ M + Na ]]⁺。

UPLC-MS(ES⁺Long acidic): 3.76 min, M/z 506.1[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.0Hz,1H),7.50(dd,J＝9.2,3.3Hz,1H),7.48(d,J＝8.3Hz,2H),7.42(d,J＝8.3Hz,2H),7.36-7.31(m,1H),7.18(dd,J＝9.2,4.2Hz,1H),6.57(s,2H),4.55(d,J＝6.0Hz,2H),4.52-4.46(m,1H),3.89(s,3H),1.70-1.60(m,1H),0.86-0.76(m,1H),0.62-0.52(m,2H),0.41-0.32(m,1H)。

Example 189: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- (2,2, 2-trifluoro-dimethyl-ethyl) pyrazole-4-carboxamide

N- (isopropylidene amino) benzamide

Following general procedure S, anhydrous acetone (0.19mL, 2.58mmol) gave N- (isopropylamino) benzamide (450mg, 2.55mmol, 99% yield) as an off-white solid without further purification.

UPLC-MS(ES⁺Short acidic): 1.06 min, M/z 177.0[ M + H ]]⁺。

N' - (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) benzoyl hydrazine

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane according to general procedure Y gave N- (isopropylamino) benzamide (450mg, 2.55mmol) N' - (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) benzoyl hydrazine (277mg, 1.12mmol, 44% yield) as an off-white solid.

UPLC-MS(ES⁺Short acidic): 1.50 min, M/z 247.0[ M + H ]]⁺。

(2,2, 2-trifluoro-1, 1-dimethyl-ethyl) hydrazine hydrochloride

Following general procedure U, N' - (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) benzoyl hydrazine (1.12mmol) was allowed to react without further purification to give (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) hydrazine hydrochloride (1.43mmol) as an off-white solid.¹H NMR(400MHz,MeOD-d₄,δ):1.42(s,6H)。

5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) pyrazole-4-carbonitrile

Following general procedure H, using (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) hydrazine hydrochloride (200mg, 1.12mmol) and 2- [ (4-bromophenyl) -methoxy-methylene ] malononitrile (295mg, 1.12mmol) gave 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) pyrazole-4-carbonitrile (316mg, 0.85mmol, 76% yield) as a yellow solid.

UPLC-MS(ES⁺Short acidic): 2.02 min, M/z 375.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) pyrazole-4-carbonitrile (216mg, 0.58mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (833mg, 2.88mmol) gave the title compound (250mg, 0.52mmol, 91% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.80 min, M/z 476.1[ M + H]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- (2,2, 2-trifluoro- Dimethyl-ethyl) pyrazole-4-carboxamide

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane and then by SPE SCX cartridge, according to general procedure M, N- [ [4- [ 5-amino-4-cyano-1- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) pyrazol-3-yl ] after elution with MeOH]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (250mg, 0.53mmol) gave the title compound (0.28g, 0.28mmol, 53% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.64 min, M/z 494.1[ M + H ]⁺。UPLC-MS(ES⁺Long acidic): 3.85 min, M/z 494.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.85(t,J＝6.0Hz,1H),7.52(dd,J＝9.3,3.4Hz,1H),7.48-7.41(m,4H),7.38-7.31(m,1H),7.19(dd,J＝9.2,4.3Hz,1H),6.51(br s,2H),4.56(d,J＝6.1Hz,2H),3.90(s,3H),1.88(s,6H)。

Example 190: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [4- (trifluoromethyl) tetrahydropyran-4-yl ] pyrazole-4-carboxamide

N- (tetrahydropyran-4-ylideneamino) benzamides

Benzoyl hydrazine (633mg, 4.65mmol) was added to a solution of tetrahydro-4H-pyran-4-one (0.4mL, 4.65mmol) in MeOH (9 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Purification gave the title compound (920mg, 4.22mmol, 91% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.05 min, M/z 218.9[ M + H]⁺。

N' - [4- (trifluoromethyl) tetrahydropyran-4-yl]Benzoyl hydrazine

Following general procedure Y, in DCM (9mL), after purification, N- (tetrahydropyran-4-ylideneamino) benzamide (250mg, 1.15mmol) was used to give the title compound (329mg, 1.14mmol, quant.) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.40 min, M/z 289.0[ M + H ]]⁺。

[4- (trifluoromethyl) tetrahydropyran-4-yl]Hydrazine hydrochloride

Following the general procedure U, N' - [4- (trifluoromethyl) tetrahydropyran-4-yl]Benzoyl hydrazine (329mg, 1.14mmol) gave the crude title compound (252mg, 1.14mmol, assumed quantitative) as a clear oil. ¹H NMR(400MHz,DMSO-d₆,δ):3.77-3.68(m,2H),3.66-3.55(m,2H),1.87-1.72(m,4H)。

5-amino-3- (4-bromophenyl) -1- [4- (trifluoromethyl) tetrahydropyran-4-yl]Pyrazole-4-carbonitriles

Following general procedure H, at 80 ℃ after purification, [4- (trifluoromethyl) tetrahydropyran-4-yl]Hydrazine hydrochloride (252mg, 1.14mmol) and 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (250mg, 0.95mmol) gave the title compound (122mg, 0.29mmol, 31% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.95 min, M/z 415.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [4- (trifluoromethyl) tetrahydropyran-4-yl]Pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [4- (trifluoromethyl) tetrahydropyran-4-yl]Pyrazole-4-carbonitrile (50mg, 0.12mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (52mg, 0.18mmol) gave the title compound (62mg, 0.12mmol) as an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.74 min, M/z 518.2[ M + H ]]⁺。

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Phenyl radical]-1- [4- (trifluoromethyl) Tetrahydropyran-4-yl]Pyrazole-4-carboxamides

Purification by reverse phase column chromatography using 0-45% MeCN in 0.1% formic acid additive in water and flash column chromatography on silica gel eluting with 0-7% MeOH/DCM according to general procedure M to isolate N- [ [4- [ 5-amino-4-cyano-1- [4- (trifluoromethyl) tetrahydropyran-4-yl ] amine ]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (62mg, 0.12mmol) to give the title compound (5mg, 0.01mmol, 8% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.59 min, M/z 536.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 3.72 min, M/z 536.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.85(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.49-7.41(m,4H),7.38-7.31(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.57(s,2H),4.55(d,J＝6.0Hz,2H),3.95-3.86(m,5H),3.32-3.24(m,2H),3.02-2.93(m,2H),2.07-1.95(m,2H)。

Example 191: 5-amino-1- (3, 3-difluoro-1-methyl-4-piperidinyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-1- (3, 3-difluoro-1-methyl-4-piperidinyl) -3- [4- [ [(s) (e.g. piperidine)5-fluoro-2-methoxy-benzoyl) ammonia Base of]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Reacting 5-amino-1- (3, 3-difluoro-4-piperidinyl) -3- [4- [ [ (5-fluoro-2-methoxybenzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamide (36mg, 0.07mmol) and cesium carbonate (47mg, 0.14mmol) were suspended in DMF (2 mL). The mixture was cooled to 0 ℃ and a solution of iodomethane (0.9M in DMF, 0.1mL, 0.09mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. Work-up and purification gave the title compound (20mg, 0.04mmol, 54% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.18 min, M/z 517.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.56 min, M/z 517.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.52(dd,J＝9.2,3.4Hz,1H),7.47-7.41(m,4H),7.37-7.32(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.44(s,2H),4.74-4.63(m,1H),4.55(d,J＝6.0Hz,2H),3.90(s,3H),3.17-3.10(m,1H),2.96-2.93(m,1H),2.47-2.38(m,2H),2.29(s,3H),2.22-2.16(m,1H),1.94-1.88(m,1H)。

Example 192: 5-amino-1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ (1-cyclohexyl-2, 2, 2-trifluoroethylene) amino group]Benzamide derivatives

Following general procedure S, after purification, 1-cyclohexyl-2, 2, 2-trifluoro-ethanone (5.55mmol) gave the title compound (1.11 mmol). UPLC-MS (ES)⁺Short acidic): 1.92 min, M/z 299.0[ M + H ]]⁺。

N' - (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) benzoylhydrazines

General procedure T, using N- [ (1-cyclohexyl-2, 2, 2-trifluoroethylene) amino]Benzamide (1.11mmol) gave the title compound (0.64mmol), freeA colored oil. UPLC-MS (ES)⁺Short acidic): 1.89 min, M/z 301.0[ M + H ]]⁺。

(1-cyclohexyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride

Following general procedure U, N' - (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) benzoyl hydrazine (0.64mmol) was allowed to proceed without further purification to afford the title compound (0.42mmol) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):5.97(s,1H),1.79-1.66(m,5H),1.65-1.57(m,1H),1.37-1.04(m,5H)。

5-amino-3- (4-bromophenyl) -1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile

Following general procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (0.42mmol) and (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride (0.42mmol) gave the title compound (0.42mmol) as an orange oil. UPLC-MS (ES)⁺Short acidic): 2.25 min, M/z 429.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl ]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

Following general procedure K, using trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (365mg, 1.26mmol) and 5-amino-3- (4-bromophenyl) -1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile (180mg, 0.42mmol) gave the title compound (223mg, 0.42 mmol). UPLC-MS (ES)⁺Short acidic): 1.99 min, M/z 530.2[ M + H]⁺。

5-amino-1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amine Base of]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (1-cyclohexyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl ] was reacted]Phenyl radical]Methyl radical]-2-fluoro-2-methoxy-benzamide (223mg, 0.42mmol) to give the title compound (72mg, 0.13mmol, 31% yield) as a white solid. UPLC-MS (ES)⁺Short acidsProperty): 1.83 min, M/z 548.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.33 min, M/z 548.3[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.83(t,J＝6.1Hz,1H),7.51(dd,J＝9.3,3.3Hz,1H),7.47-7.40(m,4H),7.37-7.30(m,1H),7.18(dd,J＝9.1,4.4Hz,1H),6.69(br s,2H),4.99-4.88(m,1H),4.54(d,J＝6.2Hz,2H),3.89(s,3H),2.39-2.25(m,1H),,1.93-1.85(m,1H),1.79-1.71(m,1H),1.66-1.56(m,2H),1.36-1.11(m,5H),1.04-0.93(m,1H)。

Example 193: 5-amino-1- [1- (difluoromethyl) -3-hydroxy-propyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

3- (tert-Butoxycarbonylhydrazonylidene) -4, 4-difluoro-butyric acid ethyl ester

Following general procedure E, tert-butyl carbazate (505mg, 3.82mmol) and ethyl 4, 4-difluoro-3-oxobutanoate (0.5mL, 3.82mmol) were purified after purification at 60 ℃ to give the title compound (983mg, 3.51mmol, 92% yield) as an off-white solid. UPLC-MS (ES) ^-Short acidic): 1.61 min, M/z 279.0[ M-H]^-。

N- [ [1- (difluoromethyl) -3-hydroxy-propyl ] -methyl ester]Amino group]Carbamic acid tert-butyl ester

To a solution of 3- (tert-butoxycarbonylhydrazono) -4, 4-difluoro-butyric acid ethyl ester (200mg, 0.71mmol) in THF (1.4mL) at 0 deg.C was added borane tetrahydrofuran complex (1M in THF, 3.6mL, 3.60 mmol). The reaction mixture was stirred at RT for 2 hours. MeOH (3.6mL) was then carefully added and the mixture was concentrated to give the crude title compound (171mg, 0.71mmol) as a brown oil.

UPLC-MS(ES^-Short acidic): 1.24 min, M/z 239.1[ M-H ]]^-。

5-amino-3- (4-bromophenyl) -1- [1- (difluoromethyl) -3-hydroxy-propyl]Pyrazole-4-carbonitriles

Hydrogen chloride solution (4M in dioxane, 1.78mL, 7.14mmol) was added to N- [ [1- (difluoromethyl) -3-hydroxy-propyl ] -N- [ [1- (difluoromethyl) -3]Amino group]Tert-butyl carbamate (171mg, 0.71 mmol). After stirring at RT for 1 hour, the mixture was concentrated under reduced pressure. The residue was taken up in EtOH (2.2mL) and then 2- [ (4-bromophenyl) -methoxy-methylene was added]Malononitrile (150mg, 0.57mmol) and then triethylamine (0.2mL, 1.43mmol) were added. The reaction mixture was heated to 80 ℃ for 30 minutes, cooled to RT and concentrated under reduced pressure. Purification gave the title compound (143mg, 0.39mmol, 68% yield) as an off-white solid. UPLC-MS (ES) ⁺Short acidic): 1.67 min, M/z 373.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [1- (difluoromethyl) -3-hydroxy-propyl ] group]Pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [1- (difluoromethyl) -3-hydroxy-propyl]Pyrazole-4-carbonitrile (50mg, 0.13mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (58mg, 0.20mmol) gave the title compound (0.10mmol), an off-white powder. UPLC-MS (ES)⁺Short acidic): 1.54 min, M/z 474.2[ M + H]⁺。

5-amino-1- [1- (difluoromethyl) -3-hydroxy-propyl]-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) ammonia Base of]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [1- (difluoromethyl) -3-hydroxy-propyl ] -was reacted]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (46mg, 0.10mmol) to give the title compound (22mg, 0.05mmol, 47% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.38 min, M/z492.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.14 min, M/z492.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝5.9Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.49-7.39(m,4H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.51(s,2H),6.25(dt,J＝55.5,4.9Hz,1H),4.84-4.66(m,2H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.48-3.36(m,1H),3.28-3.15(m,1H),2.28-2.13(m,1H),2.06-1.87(m,1H)。

Example 194: 5-amino-1- [2, 2-dimethyl-1- (trifluoromethyl) propyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- (2, 2-dimethylpropyleneamino) benzamide

Following general procedure S, after purification, benzoyl hydrazine (300mg, 2.20mmol) and pivalaldehyde (0.40mL, 3.31mmol) gave the title compound (407mg, 1.99mmol, 90% yield) as a white solid.

UPLC-MS(ES⁺Short acidic): 1.40 min, M/z 205.0[ M + H ]]⁺。

N' - [2, 2-dimethyl-1- (trifluoromethyl) propyl]Benzoyl hydrazine

Following general procedure Y, after purification, N- (2, 2-dimethylpropyleneamino) benzamide (407mg, 1.99mmol) was used to give the title compound (492mg, 1.79mmol, 90% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.74 min, M/z 275.0[ M + H]⁺。

[2, 2-dimethyl-1- (trifluoromethyl) propyl group]Hydrazine hydrochloride

According to the general procedure U, N' - [2, 2-dimethyl-1- (trifluoromethyl) propyl]Benzohydrazide (492mg, 1.79mmol) gave the crude title compound (371mg, 1.79mmol, assuming quantitative yield) as a white solid.¹H NMR(400MHz,DMSO-d₆,δ):6.09-5.98(m,1H),1.04(s,9H)。

5-amino-3- (4-bromophenyl) -1- [2, 2-dimethyl-1- (trifluoromethyl) propyl]Pyrazole-4-carbonitriles

Following general procedure H, 2- [ (4-bromophenyl) group) -methoxy-methylene]Malononitrile (100mg, 0.38mmol) and [2, 2-dimethyl-1- (trifluoromethyl) propyl ]]Hydrazine hydrochloride (118mg, 0.57mmol) gave the crude title compound (152mg, 0.38mmol, assuming quantitative yield) as a yellow solid. UPLC-MS (ES) ⁺Short acidic): 2.16 min, M/z 403.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- [2, 2-dimethyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- [2, 2-dimethyl-1- (trifluoromethyl) propyl]Pyrazole-4-carbonitrile (168mg, 0.42mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Potassium borane (243mg, 0.84mmol) gave the title compound (208mg, 0.41mmol, 98% yield) as a yellow gum. UPLC-MS (ES)⁺Short acidic): 1.90 min, M/z 504.1[ M + H ]]⁺。

5-amino-1- [2, 2-dimethyl-1- (trifluoromethyl) propyl]-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) Radical) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- [2, 2-dimethyl-1- (trifluoromethyl) propyl ] group]Pyrazol-3-yl]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (208mg, 0.41mmol) gave (54mg, 0.09mmol, 22% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.77 min, M/z 522.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.19 min, M/z 522.2[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.5-7.4(m,4H),7.38-7.30(m,1H),7.22-7.16(m,1H),6.76(s,2H),5.03-4.94(m,1H),4.55(d,J＝6.1Hz,2H),3.89(s,3H),1.11(s,9H)。

Example 195: 5-amino-1-ethyl-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1-ethyl-pyrazole-4-carbonitrile

Following general procedure H, using 2- [ (4-bromophenyl) -methoxy-methylene]Malononitrile (263mg, 1.0mmol) and oxalic acid ethyl hydrazine (150mg, 1.0mmol) to give the title compound (210mg, 0.7mmol, 72% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.69 min, M/z 292.9[ M +2 ]]⁺。

N- [ [4- (5-amino-4-cyano-1-ethyl-pyrazol-3-yl) phenyl]Methyl radical]-5-fluoro-2-methoxy-benzoyl Amines as pesticides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1-ethyl-pyrazole-4-carbonitrile (0.21g, 0.72mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Potassium borane (1.04g, 3.59mmol) gave the title compound (0.28g, 0.71mmol, 99% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.53 min, M/z 394.2[ M + H]⁺。

5-amino-1-ethyl-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxylic acid methyl ester Amides of carboxylic acids

Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by further purification on SPE SCX cartridge following general procedure M eluting with MeOH afforded N- [ [4- (5-amino-4-cyano-1-ethyl-pyrazol-3-yl) phenyl]Methyl radical ]-5-fluoro-2-methoxy-benzamide (207mg, 0.53mmol) to give the title compound (96mg, 0.23mmol, 44% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.34 min, M/z 412.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.04 min, M/z 412.2[ M + H]⁺。

Example 196: 5-amino-1- (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

N- [ cyclopentyl-methylene-amino group]Benzamide derivatives

To a solution of benzoyl hydrazine (300mg, 2.20mmol) in toluene (4.40mL) was added cyclopentanecarboxaldehyde (0.25mL, 3.31 mmol). The reaction mixture was heated to 110 ℃ for 16 hours, cooled to room temperature and poured into water (20 ml). Work-up gave the crude title compound (420mg, 1.94mmol, 88% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.42 min, M/z 217.0[ M + H ]]⁺。

N' - (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) benzoyl hydrazine

Following general procedure Y, N- [ cyclopentylmethyleneamino group]Benzamide (420mg, 1.94mmol) and trimethyl (trifluoromethyl) silane (0.57mL, 3.88mmol) gave N' - (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) benzoyl hydrazine (556mg, 1.94 mmol). UPLC-MS (ES)⁺Short acidic): 1.81 min, M/z 287.0[ M + H ]⁺。

(1-cyclopentyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride

Following general procedure U, N' - (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) benzoylhydrazine (1.94mmol) gave (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride (1.83mmol) as an off-white solid.¹H NMR(400MHz,CDCl₃,δ):3.81-3.69(m,1H),2.07-2.01(m,1H),1.85-1.70(m,2H),1.64-1.57(m,2H),1.52-1.40(m,4H)。

5-amino-3- (4-bromophenyl) -1- (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile

Following general procedure H, after purification, 2- [ (4-bromophenyl) -methoxy-methylene was taken]Malononitrile (0.70mmol) and (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) hydrazine hydrochloride (0.84mmol) gave the title compound (0.12mmol) as a yellow oil. UPLC (ES)⁺Short acidic): 2.91 min, M/z 415.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1)-cyclopentyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical]Potassium borane (108mg, 0.37mmol) and 5-amino-3- (4-bromophenyl) -1- (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) pyrazole-4-carbonitrile (91mg, 0.22mmol) gave the title compound (112mg, 0.22mmol, 98% yield) as an off-white solid. LC-MS (ES)⁺Short acidic): 5.58 min, M/z 516.1[ M + H]⁺。

5-amino-1- (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) ammonia Base of]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (1-cyclopentyl-2, 2, 2-trifluoro-ethyl) pyrazol-3-yl ] was reacted]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (112mg, 0.22mmol) to give the title compound (18mg, 0.03mmol, 15%) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.71 min, M/z 534.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 4.17 min, M/z 534.2[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.84(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.48-7.39(m,4H),7.38-7.30(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.71(s,2H),5.05-4.93(m,1H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),2.79-2.69(m,1H),1.94-1.81(m,1H),1.80-1.32(m,6H),1.22-1.08(m,1H)。

Example 197: 5-amino-1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

4, 4-difluoro-1-isopropyl-pyrrolidin-3-ol

A mixture of 4, 4-difluoropyrrolidin-3-ol (300mg, 2.44mmol), acetone (0.27mL, 3.66mmol) and glacial acetic acid (0.21mL, 3.66mmol) in THF (9.8mL) was stirred at RT for 30 min. Sodium diacetoxy (acetyl) borate (716mg, 3.66mmol) was then added, and the reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and then treated and purified to give the title compound (178mg, 1.08mmol, 44% yield) as a yellow oil.

¹H NMR(400MHz,CDCl₃,δ):4.25-4.18(m,1H),3.10-3.00(m,3H),2.70-2.65(m,1H),2.59-2.49(m,1H),1.05(d,J＝6.4Hz,3H),1.04(d,J＝6.4Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) pyrazole-4-carbonitrile

A solution of 4, 4-difluoro-1-isopropyl-pyrrolidin-3-ol (178mg, 1.08mmol) in anhydrous DCM (20mL) was cooled to-20 ℃ and purged with nitrogen. Triflic anhydride (1M in DCM, 2.69mL, 2.69mmol) was added and the reaction mixture was stirred for 40 min and then quenched with water. Work-up gave crude (4, 4-difluoro-1-isopropylpyrrolidin-3-yl) trifluoromethanesulfonate (31.08mmol) as a red oil. Following general procedure N, after purification, the crude compound and 5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile (1.06mmol) gave the title compound (0.31mmol) as a light yellow oil. UPLC-MS (ES)⁺Short acidic): 1.61 min, M/z 412.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) pyrazol-3-yl]Phenyl radical] Methyl radical]-5-fluoro-2-methoxy-benzamide

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical]Potassium borane (155mg, 0.54mmol) and 5-amino-3- (4-bromophenyl) -1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) pyrazole-4-carbonitrile (129mg, 0.32mmol) gave the title compound (88mg, 0.17mmol, 54% yield) as a yellow oil. UPLC-MS (ES)^-Short acidic): 1.48 min, M/z 511.2[ M-H ]^-。

5-Ammonia1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) Radical) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluoro-1-isopropyl-pyrrolidin-3-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (88mg, 0.17mmol) to give the title compound (35mg, 0.07mmol, 38%) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.30 min, M/z 531.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.83 min, M/z 531.4[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆,δ):8.86(t,J＝6.1Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.46-7.41(m,4H),7.37-7.33(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.62(s,2H),5.21-5.14(m,1H),4.55(d,J＝6.1,2H),3.90(s,3H),3.26-3.17(m,2H),2.98-2.89(m,1H),2.62-2.57(m,1H),2.53-2.40(m,1H),1.06-1.03(m,6H)。

Example 198: -amino-1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

1-ethyl-4, 4-difluoro-pyrrolidin-3-ol

A mixture of 4, 4-difluoropyrrolidin-3-ol dihydrochloride (1.02mmol), acetaldehyde (1.53mmol), glacial acetic acid (1.53mmol) in THF (6.5mL) was stirred at RT for 1 h. Sodium diacetoxy (acetyl) borate (1.53mmol) was then added and the reaction stirred for 3 hours. Work-up and purification gave the title compound (94mg, 0.62mmol, 61% yield) as a yellow oil.¹H NMR(400MHz,CDCl₃,δ):4.25-4.18(m,1H),3.07-2.91(m,3H),2.64-2.60(m,1H),2.53(q,J＝7.2Hz,2H),1.10(t,J＝7.2Hz,3H)。

(1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) trifluoromethanesulfonate

A solution of 1-ethyl-4, 4-difluoro-pyrrolidin-3-ol (94mg, 0.62mmol) in anhydrous DCM (20mL) was cooled to-20 ℃ and purged with nitrogen. Trifluoromethanesulfonic anhydride (1M in DCM, 1.55mL, 1.55mmol) was then added. The reaction mixture was stirred at the same temperature for 40 minutes. Work-up gave the crude title compound (94mg, 0.33mmol, 53% yield) as a red oil.

¹H NMR(400MHz,CDCl₃,δ):5.08-5.03(m,1H),3.25-3.21(m,1H),3.10-3.04(m,1H),2.98-2.87(m,1H),2.83-2.78(m,1H),2.52(q,J＝7.2Hz,2H),1.04(t,J＝7.2Hz,3H)。

5-amino-3- (4-bromophenyl) -1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) pyrazole-4-carbonitrile

Following general procedure N, after purification, (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) trifluoromethanesulfonate (93mg, 0.33mmol) and 5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile (72mg, 0.27mmol) gave the title compound (60mg, 0.15mmol, 55% yield) as a yellow solid. UPLC-MS (ES)⁺Short acidic): 1.52 min, M/z 398.0[ M +2 ]]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical]Potassium borane (74mg, 0.26mmol) and 5-amino-3- (4-bromophenyl) -1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) pyrazole-4-carbonitrile (60mg, 0.15mmol) gave the title compound (30mg, 0.06mmol, 39% yield) as a colorless oil. UPLC-MS (ES) ^-Short acidic): 1.42 min, 497.2M/z [ M-H [ ]]^-。

5-amino-1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) Radical) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (1-ethyl-4, 4-difluoro-pyrrolidin-3-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (29mg, 0.06mmol) to give the title compound (5mg, 0.01mmol, 16% yield) as an off-white solid. UPLC-MS (ES)⁺Short acidic): 1.26 min, M/z 517.2[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.74 min, M/z 517.2[ M + H]⁺。

¹H NMR(500MHz,DMSO-d₆,δ):8.86(t,J＝6.0Hz,1H),7.51(dd,J＝9.2,3.3Hz,1H),7.46-7.41(m,4H),7.37-7.33(m,1H),7.19(dd,9.1,4.2Hz,1H),6.60(s,2H),5.22-5.15(m,1H),4.55(d,J＝6.1Hz,2H),3.89(s,3H),3.30-3.15(m,2H),2.91-2.77(m,1H),2.69-2.36(m,3H),1.05(t,J＝7.2Hz,3H)。

Example 199: 5-amino-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

4, 4-difluoro-1-methyl-pyrrolidin-3-ol

Paraformaldehyde (64mg, 1.33mmol) and sodium hydroxide (53mg, 1.33mmol) were suspended in THF (12mL) and stirred for 20 min. 4, 4-difluoropyrrolidin-3-ol dihydrochloride (520mg, 2.65mmol) and formic acid (0.25mL, 6.63mmol) were then added and the reaction heated at reflux for 2 hours. The mixture was cooled to 0 ℃, diluted with NaOH (10N, 1mL) and extracted with ether (× 2). The combined organic layers were dried over a hydrophobic frit and concentrated under reduced pressure to give 4, 4-difluoro-1-methyl-pyrrolidin-3-ol (269mg, 1.96mmol, 74% yield) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃,δ):4.27-4.17(m,1H),3.05-3.01(m,1H),3.00-2.91(m,2H),2.63-2.59(m,1H),2.38(s,3H)。

(4, 4-difluoro-1-methyl-pyrrolidin-3-yl) trifluoromethanesulfonate

4, 4-difluoro-1-methyl-pyrrolidin-3-ol (268mg, 1.95mmol) was dissolved in anhydrous DCM (20mL) in a three-necked flask. The solution was cooled to-20 ℃ and flushed with nitrogen (. times.3). Trifluoromethanesulfonic anhydride (1M in DCM, 4.87mL, 4.87mmol) was added slowly. The mixture was stirred at-20- -10 ℃ for 40 minutes. Work-up gave the title compound (429mg, 1.60mmol, 81% yield) as a red oil, which was used without further purification.

¹H NMR(400MHz,CDCl₃,δ):5.07-5.02(m,1H),3.19-3.15(m,1H),3.03-2.88(m,2H),2.80-2.77(m,1H),2.34(s,3H)。

5-amino-3- (4-bromophenyl) -1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) pyrazole-4-carbonitrile

Following general procedure N, after purification, (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) trifluoromethanesulfonate (235mg, 0.87mmol) and 5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile (276mg, 1.05mmol) gave the title compound (177mg, 0.46mmol, 53% yield) as a light yellow solid.

UPLC-MS(ES⁺Short acidic): 1.49 min, M/z 383.8[ M + H]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) pyrazol-3-yl]Phenyl radical]First of all Base of]-5-fluoro-2-methoxy-benzamide

After purification, trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group according to general procedure K]Methyl radical ]Potassium borane (228mg, 0.79mmol) and 5-amino-3- (4-bromophenyl) -1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) pyrazole-4-carbonitrile (177mg, 0.46mmol) gave the title compound (0.06mmol) as a yellow oil. UPLC-MS (ES)⁺Short acidic): 1.41 min, M/z 485.2[ M + H ]]⁺。

5-amino-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) Radical) amino]Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluoro-1-methyl-pyrrolidin-3-yl) pyrazol-3-yl)]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (31mg, 0.06mmol) to give the title compound (6mg, 0.01mmol, 19% yield) asOff-white solid. UPLC-MS (ES)⁺Short acidic): 1.23 min, M/z 503.3[ M + H]⁺。UPLC-MS(ES⁺Long acidic): 2.70 min, M/z 503.2[ M + H]⁺。

¹H NMR(500MHz,DMSO,d₆,δ):8.84(t,J＝6.1Hz,1H),7.52(dd,J＝9.2,3.3Hz,1H),7.46-7.41(m,4H),7.37-7.32(m,1H),7.19(dd,J＝9.1,4.3Hz,1H),6.58(br s,2H),5.21-5.17(m,1H),4.55(d,J＝6.1Hz,2H),3.90(s,3H),3.34-3.15(m,2H),2.91-2.73(m,1H),2.61-2.42(m,1H),2.36(s,3H)。

Example 200: 5-amino-1- (4, 4-difluorotetrahydrofuran-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide

5-amino-3- (4-bromophenyl) -1- (4, 4-difluorotetrahydrofuran-3-yl) pyrazole-4-carbonitrile

To a solution of 4, 4-difluorotetrahydrofuran-3-ol (215mg, 1.73mmol) and pyridine (0.70mL, 8.66mmol) in dry DCM (1mL) at-15 deg.C under nitrogen was added dropwise a solution of trifluoromethanesulfonic anhydride in DCM (1M, 4.30mL, 4.30 mmol). The reaction was stirred for 60 minutes between-15 ℃ and-5 ℃ and quenched with water. And (4) treating to obtain the 5-amino-3- (4-bromophenyl) -1H-pyrazole-4-carbonitrile. A solution of the crude material (90mg, 0.34mmol) and cesium carbonate (223mg, 0.68mmol) in DMF (3mL) was heated to 90 ℃ for 16 h. Work-up and purification gave the title compound (63mg, 0.14mmol, 40% yield) as a white solid. UPLC-MS (ES) ⁺Short acidic): 1.83 min, M/z 369.0[ M]⁺。

N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluorotetrahydrofuran-3-yl) pyrazol-3-yl]Phenyl radical]Methyl radical]-5- Fluoro-2-methoxy-benzamides

Following general procedure K, after purification, 5-amino-3- (4-bromophenyl) -1- (4, 4-difluorotetrahydrofuran-3-yl) pyrazole-4-carbonitrile (63mg, 0.17mmol) and trifluoro- [ [ (5-fluoro-2-methoxy-benzoyl) amino group]Methyl radical]Borane complexesPotassium (94mg, 0.33mmol) gave the title compound (66mg, 0.12mmol, 68% yield) as a white solid. UPLC-MS (ES)⁺Short acidic): 1.67 min, M/z 471.1[ M + H]⁺。

5-amino-1- (4, 4-difluorotetrahydrofuran-3-yl) -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino] Methyl radical]Phenyl radical]Pyrazole-4-carboxamides

Following general procedure M, after purification, N- [ [4- [ 5-amino-4-cyano-1- (4, 4-difluorotetrahydrofuran-3-yl) pyrazol-3-yl ] was reacted]Phenyl radical]Methyl radical]-5-fluoro-2-methoxy-benzamide (62mg, 0.13mmol) to give the title compound (25mg, 0.05mmol, 39% yield) as a light yellow solid. UPLC-MS (ES)⁺Short acidic): 1.50 min, M/z490.2[ M + H ]]⁺。UPLC-MS(ES⁺Long acidic): 3.39 min, M/z490.2[ M + H ]]⁺。

¹H NMR(500MHz,DMSO-d₆,δ):8.84(t,J＝6.1Hz,1H),7.52(dd,J＝9.2,3.4Hz,1H),7.48-7.42(m,4H),7.37-7.32(m,1H),7.19(dd,J＝9.2,4.3Hz,1H),6.60(br s,2H),5.37-5.30(m,1H),4.55(d,J＝6.1Hz,2H),4.47-4.41(m,2H),4.16-4.10(m,1H),4.05-3.96(m,1H),3.90(s,3H)。

Example 201: BTK^WTBinding affinity

Determination of BTK for each test Compound Using time-resolved fluorescence resonance energy transfer (TR-FRET) method ^WTBinding affinity. 2.5nM of recombinant BTK^WTKinase, inhibitor at various concentrations, 2nM lantha Screen^TMEu anti-His antibody and 15nM kinase tracer 236 at 1X LanthaScreen^TMKinase buffer a was incubated for 5 hours. Recombinant BTK kinase and all lanthasScreen^TMIngredients were purchased from Invitrogen. Measurements were performed using half-area 96-well assay plates in a reaction volume of 30 μ Ι _. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340nm and detection wavelengths of 615 and 665 nm. Binding affinity of each compound was determined by measuring TR-FRET signals at different concentrations of compound and plotting relative fluorescence units against inhibitor concentration to assess the binding affinity from log [ inhibition ] using a variable slope model in Graphpad prism from Graphpad softwarePreparation]And responsive IC₅₀(SanDiego, Calif.).

Table 4 shows BTK^WTResults of binding affinity.

Table 4 shows the BTK for the compound of formula (I) determined by the above assay^WTBinding affinity based on BTKIC of a compound₅₀The values are classified as "a", "B", "C", "D", and "E".

IC₅₀：A≤10nM；10nM<B≤100nM；100nM<C≤1μM；1μM<D≤10μM；E>10μM。

Example 202: BTK^C481SBinding affinity

The binding affinity of BTKC481S was determined for each compound tested using the time-resolved fluorescence resonance energy transfer (TR-FRET) method. 5nM recombinant BTKWT kinase, varying concentrations of inhibitor, 2nM LanthaScreenTM Eu anti-His antibody and 30nM kinase tracer 236 were incubated in 1 XLanthaScreen TM kinase buffer A for 5 hours. Recombinant BTKC481S kinase was purchased from SignalChem and all lantha screen TM components were purchased from Invitrogen. Measurements were performed using half-area 96-well assay plates in a reaction volume of 30 μ Ι _. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340nm and detection wavelengths of 615 and 665 nm. Binding affinity of each compound was determined by measuring TR-FRET signals at different concentrations of compound and plotting relative fluorescence units against inhibitor concentration to estimate log [ inhibitor ] from using a variable slope model in Graphpad prism from Graphpad software ]And responsive IC₅₀(SanDiego, Calif.).

Table 4 shows the BTK for the compound of formula (I) determined by the above assay^C481SBinding affinity based on BTK IC of compounds₅₀The values are classified as "a", "B", "C", "D", and "E".

IC₅₀：A≤10nM；10nM<B≤100nM；100nM<C≤1μM；1μM<D≤10μM；E>10μM。

Example 203: EGFR binding affinity

Determination using time-resolved fluorescence resonance energy transfer (TR-FRET) methodEGFR binding affinity. 2.5nM recombinant EGFR, varying concentrations of inhibitor, 2nM LanthaScreen TM Eu anti-GST antibody and 3nM kinase tracer 199 were incubated in 1X LanthaScreen TM kinase buffer A for 5 hours. Recombinant EGFR and all LanthaScreen TM components were purchased from Invitrogen. Measurements were performed using half-area 96-well assay plates in a reaction volume of 30 μ Ι _. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340nm and detection wavelengths of 615 and 665 nm. Binding affinity of each compound was determined by measuring TR-FRET signals at different concentrations of compound and plotting relative fluorescence units against inhibitor concentration to estimate log [ inhibitor ] from using a variable slope model in graphpadpristm from Graphpad software]And responsive IC₅₀(SanDiego, Calif.).

Table 4 shows the EGFR binding affinity for the compounds of formula (I) determined by the above assay, based on the EGFR IC of the compounds₅₀The values are classified as "a", "B", "C", "D", and "E".

IC₅₀：A≤10nM；10nM<B≤100nM；100nM<C≤1μM；1μM<D≤10μM；E>10μM。

Example 204: antiproliferative activity of OCI-Ly10

The effect of compounds on the growth of OCI-Ly10 human DLBCL cells dependent on NF κ B signaling was determined. OCI-Ly10 cells were grown in suspension in T225 flasks, centrifuged and resuspended in media containing 2.5% FBS. Cells were then plated at 7.5x10³Individual cells/well were plated in 96-well plates of varying concentrations of compound and incubated for 72 hours at 37 ℃. Additional cell plates to be used as day 0 readings were seeded without compound addition, Resazurin was added to each well, incubated for 5 hours and fluorescence was measured at 590 nm. After 72 hours of compound treatment, Resazurin was added to each well of the compound-treated plate, incubated for 5 hours, and fluorescence was measured at 590 nm. IC was then calculated by subtracting the average day 0 value from the per well value in the treated plates₅₀Each treatment was then calculated as a percentage of DMSO control and the percentages were plotted against inhibitor concentration to use Graphpadp from Graphpad software Variable slope model estimation in rism from log [ inhibitors ]]And responsive IC₅₀(SanDiego, Calif.).

Table 4 shows the OCI-Ly10 antiproliferative activity for the compounds of formula (I) determined by the above assay, based on the OCI-Ly10 IC of the compound₅₀The values are classified as "a", "B", "C", "D", and "E".

IC₅₀：A≤10nM；10nM<B≤100nM；100nM<C≤1μM；1μM<D≤10μM；E>10μM。

TABLE 4

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, comprise, and/or contain, means "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any novel method or process so disclosed.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.