Kinase network inhibitors and uses thereof

文档序号：1602156 发布日期：2020-01-07 浏览：16次中文

阅读说明：本技术 激酶网络抑制剂及其用途 (Kinase network inhibitors and uses thereof ) 是由赫尔曼·O·辛蒂姆尼图·达亚尔克莱门特·奥波库·特蒙于 2018-03-29 设计创作，主要内容包括：本发明总体上涉及作为双重激酶-脱甲基酶抑制剂的化合物,用于治疗由激酶和/或组蛋白脱甲基酶介导的疾病,例如炎症、癌症、病毒和细菌感染、神经和免疫疾病。用于治疗这些疾病的药物组合物和方法也在本发明的范围内。(The present invention relates generally to compounds that are dual kinase-demethylase inhibitors useful for treating diseases mediated by kinases and/or histone demethylases, such as inflammation, cancer, viral and bacterial infections, neurological and immune diseases. Pharmaceutical compositions and methods for treating these diseases are also within the scope of the invention.)

1. a compound having the structural formula or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R¹is amino, hydroxy and derivatives thereof, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

R²and R³Each independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, thiol, carboxyl, ester, amide, and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety; and

R⁴represents four substituents, each substituent being independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkeneAryl and arylalkynyl, each of which is optionally substituted; or any two adjacent substituents of said four substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following structural formula:

wherein n is 1-5; the bond between A and B, the bond between B and D may be a double bond or a single bond, but not both; A. b and D independently represent C, O, N and S, wherein at least one of A, B and D is a heteroatom;

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

R⁴represents two substituents, each substituent being independently selected from hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynylA heteroaryl group, a cycloalkenyl group, a cycloheteroalkyl group, a cycloheteroalkenyl group, an aryl group, a heteroaryl group, an arylalkyl group, an arylalkenyl group, and an arylalkynyl group, each of which is optionally substituted; or said two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety; and

elements according to A, B and D, R⁵Represents two or three substituents, each independently selected from hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl and arylalkynyl, each of which is optionally substituted.

3. The compound of claim 2, wherein R¹Is composed of

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following structural formula:

R¹is amino, hydroxyl and derivatives thereof, alkylA group, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

R⁴represents two substituents, each independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or said two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

elements according to A, B and D, R⁵Represents two or three substituents, each substituent being independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl and arylalkynyl, each of which is optionally substituted; and

according to the value of n, R⁶Represents 2 to 6 substituents, each independently selected from hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl and arylalkynyl, each of which is optionally substituted.

5. The compound of claim 4Wherein R is¹Is composed of

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following structural formula:

wherein, 1-5;

R⁴represents two substituents, each independently selected from hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl and arylalkynyl, each of which is optionally substitutedSubstitution; or said two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

elements of A and B according to the definition below, R⁵Represents one or two substituents, each substituent being independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl and arylalkynyl, each of which is optionally substituted;

a and B independently represent CR⁸N or NR⁹Wherein R is⁸And R⁹Independently represent hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

according to the value of n, R⁶Represents 2 to 6 substituents, each independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; and

R⁷is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

7. The compound of claim 6, wherein R¹Is composed of

8. The compound of claim 7, wherein R¹Is composed of

9. The compound of claim 6, wherein n-3; r¹Is composed of

10. The compound of claim 6, wherein R³Is composed of

11. The compound of claim 6, wherein R¹Is composed of

R³is composed of

12. The compound of claim 1, wherein the compound is

13. The compound of claim 1, wherein the compound is

14. A pharmaceutical composition comprising one or more compounds as claimed in claims 1 to 13 or a pharmaceutically acceptable salt thereof, together with one or more diluents, excipients or carriers.

15. The compound of claims 1 to 13 is a histone demethylase inhibitor.

16. The compound of claims 1 to 13 is a kinase inhibitor.

17. The kinase inhibitor according to claim 16, wherein the kinase is selected from FLT3, MNK1/2, JAK1/2/3, Limk1/2, various CDKs, Haspin, ROCK1/2, TOPK, LRRK2, GSK3a/3B, RSK1-4, ERK, P70S6K, AKT, PI3K, P38, PKC, PKA, FGFR1-4, VEGFR1-3, ALK, AXL, Limk1/2, Aurora a/B, ABL1, AKT, CSF1R, CSNK1D, DCAMKL1, CSNK1G2, EPHA2, ERBB2, IKK-IKK, IKK- β, JNK1/2/3, MARK3, PIM1/2, MET, MLK1, PAK/1, PAK1, pdgk 1, prkk 1/1, prkk 1, and another receptor (receptor for protein kinase/1).

18. A method for treating diseases mediated by kinases and/or histone demethylases, including inflammation, cancer, viral and bacterial infections, gastrointestinal diseases, ocular diseases, neurological diseases, cardiovascular diseases and immune diseases, comprising the steps of: administering to a patient in need of remission from said cancer a therapeutically effective amount of one or more compounds as claimed in claims 1 to 13, together with one or more carriers, diluents or excipients.

19. A method for treating diseases mediated by kinases and histone demethylases, including inflammation, cancer, viral and bacterial infections, gastrointestinal diseases, ocular diseases, neurological diseases, cardiovascular diseases and immune diseases, comprising the steps of: administering to a patient in need of remission from said cancer a therapeutically effective amount of a compound of claims 1 to 13 in combination with one or more other compounds having the same or different effect and one or more carriers, diluents or excipients.

20. A drug conjugate, which is a small molecule or bioconjugate, comprising one or more compounds of claims 1 to 13, wherein the conjugate confers cell type or tissue type targeting, or the conjugate targets another pathway that synergizes the effect of the compounds of claims 1 to 13.

21. A drug conjugate, which is a small molecule or bioconjugate, comprising one or more compounds of claims 1 to 13, wherein the conjugate confers water solubility or low clearance.

22. A drug conjugate comprising one or more compounds of claims 1 to 13, and a moiety that aids in the degradation of a target protein by a system including, but not limited to, ubiquitin ligase/proteasome degradation systems.

23. A pharmaceutical composition comprising one or more compounds as claimed in claims 1 to 13 in the form of nanoparticles, together with one or more diluents, excipients or carriers.

24. A prodrug comprising one or more compounds of claims 1 to 13, wherein the prodrug moiety is removed at a specific location, for example in the gastrointestinal tract or in the blood or tissue or a location specific for cancer.

25. An analogue of the compound as claimed in claims 1 to 13, wherein a specific metabolic hotspot is modified by a group such as deuterium or fluorine.

26. Use of a compound of claims 1-13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

Technical Field

The present invention relates generally to compounds that are kinase inhibitors and methods of treating diseases mediated by kinases, such as inflammation, cancer, viral and bacterial infections, neurological and immune diseases.

Background

This section introduces several aspects that may help facilitate a better understanding of the present disclosure. Accordingly, these statements are to be read in this light, and not as admissions of prior art or non-prior art.

The cells contain more than 500 kinases that regulate various processes, e.g., regulating cell cycle, growth, migration, immune response¹. Several deregulated kinases (i.e., kinases that have acquired gain-of-function mutations or overexpression) can drive cancer spread¹. Small molecule inhibitors of cancer driver kinases (e.g., BCR-ABL1 fusion protein, FLT3-ITD, mutated or overexpressed ALK, EGFR, PDGFR, Kit, VEGFR, B-Raf, BTK, PI3K delta, ErbB2) have been shown to be clinically successful². Recently, efforts have been made to target other kinases, such as cell cycle kinases (CDKs) or kinases that target histones, cytoskeleton or other processes important to the cell, to prevent the growth of cancer. Most of the kinase inhibitors entering the clinic are initially functional, but over time drug resistant clones may appear leading to drug ineffectiveness³. Various mechanisms account for the resistance of cancer cells to kinase inhibitors. For example, copy number doubling, other kinase mutations (e.g., in the tyrosine kinase domain of FLT3-ITD kinaseSecondary mutations generated) or activation of other kinase pathways and/or downstream targets may bypass the inhibitory effect of a particular kinase target⁴. Inhibition of cancer driver kinases and downstream targets (kinases and non-kinase targets, e.g., histone demethylases) kinase inhibitors and/or kinases that act synergistically with driver kinases may enhance drug efficacy and reduce the likelihood of resistance to the kinase inhibitors⁵. However, the challenge with such multi-bolus is to avoid confounding binding that can lead to toxicity.

Kinase inhibitors have also proven effective in treating immune disorders (e.g., JAK kinases)⁶) Hypertension and erectile dysfunction (ROCK1/2 kinase)⁷) And glaucoma (ROCK and LIMK kinases)⁸). Other kinase targets (e.g., LRRK2) have also been shown to be important in CNS-related diseases, such as Alzheimer's disease or Parkinson's disease⁹. The unique chemical scaffold can be tailored to selectively inhibit disease-associated kinases or to inhibit a group of kinases located in a particular pathway or network, which can facilitate the treatment of a variety of disease states.

Disclosure of Invention

The present invention relates generally to compounds that inhibit kinase and/or histone demethylase networks, as useful compounds for treating diseases mediated by kinases, such as inflammation, cancer, viral and bacterial infections, neurological and immune diseases. Pharmaceutical compositions and methods for treating these diseases are within the scope of the present invention.

In some illustrative embodiments, the present invention relates to a compound having the structural formula or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R¹is amino, hydroxyl and derivatives thereof, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl or arylalkynyl, among othersEach is optionally substituted;

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety; and

R⁴represents four substituents, each independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or any two adjacent substituents of said four substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety.

In some illustrative embodiments, the present invention relates to a compound having the structural formula or a pharmaceutically acceptable salt thereof,

R¹is amino, hydroxyl and derivatives thereof, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkeneA group, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

In some illustrative embodiments, the present invention relates to a composition having a structureA compound of formula (II) wherein R¹Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (III), or a pharmaceutically acceptable salt thereof,

elements according to A, B and D, R⁵Represents two or three substituents, each substituent being independently selected from hydrogen, deuterium, halogen, azido, cyano,Nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; and

In some illustrative embodiments, the present invention relates to a compound having structural formula (III), wherein R¹Comprises the following steps:

in some illustrative embodiments, the present invention relates to a compound having structural formula (IV), or a pharmaceutically acceptable salt thereof,

wherein, 1-5;

R¹is amino, hydroxyl and derivatives thereof, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkeneAryl or arylalkynyl, each of which is optionally substituted;

a and B independently represent CR⁸N or NR⁹Wherein R is⁸And R⁹Independently represent hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloAlkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R¹Is composed of

A is carbon (C); b is nitrogen (N); r⁵、R⁶And R⁷All represent hydrogen, R⁴Represents two substituents, each substituent being independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, nitro, amino, thiol, carboxyl, ester, amide, and derivatives thereof,Cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or the two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety.

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R³Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R¹Is composed of

And R³Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (I), wherein the compound is

In some illustrative embodiments, the present invention relates to a pharmaceutical composition comprising one or more compounds as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more diluents, excipients, or carriers.

In some illustrative embodiments, the present invention relates to a kinase inhibitor, wherein the kinase is selected from the group consisting of: FLT3, MNK1/2, JAK1/2/3, Limk1/2, various CDKs, Haspin, ROCK1/2, TOPK, LRRK2, GSK3a/3B, RSK1-4, ERK, P70S6K, AKT, PI3K, P38, PKC, PKA, FGFR1-4, VEGFR1-3, ALK, AXL, LIMK1/2, Aurora A/B, ABL1, AKT, CSF1R, CSNK1D, DCAMKL1, CSNK1G2, EPHA2, ERBB2, PDGK-alpha, IKK-beta, JNK 1/IKAN 2/3, MARK3, MEK1/2, MET, MLK1, PAK 1/1, FRKA/PIM, PDGK 1, PLKA/72, PRK 1/1, TRK 1, TRK3672/1, TRK 1, and TRK3672/1 receptor (receptor interaction).

In some illustrative embodiments, the present invention relates to a method for treating a disease mediated by kinases and/or histone demethylases, including inflammation, cancer, viral and bacterial infections, gastrointestinal tract diseases, ocular diseases, neurological diseases, cardiovascular diseases and immune diseases, comprising the steps of: administering to a patient in need of remission from said cancer a therapeutically effective amount of one or more compounds as disclosed herein, and one or more carriers, diluents, or excipients.

In some illustrative embodiments, the present invention relates to a method for treating diseases mediated by kinases and histone demethylases, including inflammation, cancer, viral and bacterial infections, gastrointestinal diseases, ocular diseases, neurological diseases, cardiovascular diseases and immune diseases, comprising the steps of: administering to a patient in need of remission from said cancer a therapeutically effective amount of a compound as disclosed herein in combination with one or more other compounds having the same or different effect, and one or more carriers, diluents or excipients.

These and other features, aspects, and advantages of the present invention will become better understood with reference to the following detailed description and claims.

Detailed Description

While the description herein shows and describes in detail the concepts of the present disclosure, the results in the description are to be regarded as illustrative rather than restrictive in nature. It being understood that only exemplary embodiments have been shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

The present invention relates generally to compounds that are kinase inhibitors and that are useful in the treatment of diseases mediated by kinases, such as inflammation, cancer, viral and bacterial infections, neurological and immune diseases. Pharmaceutical compositions and methods for treating these diseases are within the scope of the present invention.

As used herein, the following terms and phrases shall have the meanings as set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

As used herein, the term "about" can allow for a degree of variability in the value or range, e.g., within 10%, within 5%, or within 1% of the limit of the stated value or range. In the present disclosure, the term "substantially" may allow for a degree of variability in the value or range, for example, within 90%, 95%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of the limits of the stated value or range.

As used herein, the terms "a" and "an" or "the" are intended to include one or more than one, unless the context clearly indicates otherwise. The term "or" is used to mean a non-exclusive "or" unless otherwise stated. Also, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid in reading text and should not be construed as limiting. In addition, information related to the section title may appear within or outside of that particular section. In addition, all publications, patents, and patent documents cited herein are incorporated by reference in their entirety as if individually incorporated by reference. Where usage is inconsistent between this text and those incorporated by reference, usage in the incorporated references should be considered supplementary to this text; for inconsistent inconsistencies, the usage in this text controls.

As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms contained in a functional group with one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that may be substituted or has been substituted by a molecule. Examples of substituents or functional groups include, but are not limited to, halogen (e.g., F, Cl, Br, and I); such as the oxygen atoms in the following groups: hydroxy, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) group, carboxylic acid, carboxylate salt, and carboxyl group of carboxylic acid ester; such as the sulfur atom in the following groups: thiol groups, alkyl and arylthio groups, sulfoxide groups, sulfonic acid groups, sulfonyl groups and sulfonamide groups; such as the nitrogen atoms in the following groups: amines, azides, hydroxylamines, cyano, nitro, N-oxides, hydrazides, and enamines; and heteroatoms in various other groups.

The term "alkyl" as used herein means having from 1 to about 20 carbon atoms (C)₁-C₂₀) 1 to 12 carbon (C)₁-C₁₂) 1 to 8 carbon atoms (C)₁-C₈) Substituted or unsubstituted straight and branched alkyl and cycloalkyl groups of (a) or, in some embodiments, having 1 to 6 carbon atoms (C)₁-C₆). Examples of the straight-chain alkyl group include alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl, and 2, 2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-, iso-and trans-iso-alkyl groups as well as other branched forms of alkyl groups. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, mercapto, alkoxy, and halo.

The term "alkenyl" as used herein refers to a group having 2 to 20 carbon atoms (C)₂-C₂₀) 2 to 12 carbon atoms (C)₂-C₁₂) 2 to 8 carbon atoms (C)₂-C₈) And at least one carbon-carbon double bond, or in some embodiments, from 2 to 4 carbon atoms (C)₂-C₄) And at least one carbon-carbon double bond. Straight chainExamples of alkenyl groups include straight-chain alkenyl groups having 2 to 8 carbon atoms, such as-CH ═ CH-, -CH ═ CHCH₂-and the like. Examples of branched alkenyl groups include, but are not limited to, -CH ═ C (CH)₃) -and the like.

An alkynyl group is a fragment that contains an open point of attachment at a carbon atom, which would result if the hydrogen atom attached to the triple bonded carbon atom were removed from the alkyne molecule. The term "hydroxyalkyl" as used herein refers to an alkyl group as defined herein substituted with at least one hydroxyl group (-OH).

The term "cycloalkyl" as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups may have 3 to about 8-12 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 4,5, 6, or 7. In some embodiments, cycloalkyl groups may have 3 to 6 carbon atoms (C)₃-C₆). Cycloalkyl also includes polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, deoxyphenyl (camphenly), isodeoxyphenyl (isocamphenyl), and carenyl (carenylgroups), as well as fused rings such as, but not limited to, decahydronaphthyl and the like.

The term "acyl" as used herein refers to a group containing a carbonyl moiety, wherein the group is bonded through the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the like. In the particular case where the carbonyl carbon atom is bonded to hydrogen, the group is "formyl" and the term "acyl" is as defined herein. The acyl group may include from 0 to about 12-40, 6-10, 1-5, or 2-5 additional carbon atoms bonded to the carbonyl group. Acryloyl is an example of acyl. Acyl groups within the meaning of this text may also comprise heteroatoms. Nicotinoyl (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, and the like. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl". An example is trifluoroacetyl.

The term "aryl" as used herein refers to a substituted or unsubstituted cyclic aromatic hydrocarbon that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, oxazolyl (azulenyl), heptenyl (heptalenyl), biphenyl (biphenyl), indenylenyl (indacenyl), fluorenyl (fluoroenyl), phenanthrenyl (phenanthrenyl), terphenyl (triphenylenyl), pyrenyl (pyrenyl), naphthoenyl (naphthoenyl), turf (chrysenyl), biphenyl (biphenylenyl), anthracenyl (anthrenyl), and naphthyl. In some embodiments, about 6 to about 14 carbons (C) are included in the ring portion of the aryl group₆-C₁₄) Or 6 to 10 carbon atoms (C)₆-C₁₀). As defined herein, an aryl group can be unsubstituted or substituted. Representative substituted aryl groups may be mono-or poly-substituted, such as but not limited to 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl, which may be substituted with carbon or non-carbon groups such as those listed herein.

The terms "aralkyl" and "arylalkyl" as used herein refer to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenethyl, as well as fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl. Aralkenyl is alkenyl as defined herein, wherein a hydrogen or carbon bond of an alkyl group is replaced by a bond to an aryl group as defined herein.

The term "heterocyclyl" as used herein, refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, one or more of which is a heteroatom, such as, but not limited to B, N, O and S. Thus, a heterocyclyl group may be a cycloheteroalkyl or heteroaryl group, or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl includes 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl includes compounds containing 3 to 8 carbon atoms (C)₃-C₈) 3 to 6 carbon atoms (C)₃-C₆) Or 6 to 8 carbon atoms (C)₆-C₈) The heterocyclic group of (1).

Heteroaryl rings are a specific example of a heterocyclyl group. The phrase "heterocyclyl" includes fused rings, including those rings that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, indolyl, isoindolyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thienyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzoxazolinyl, benzothiazolinyl, benzimidazolyl and benzimidazolyl.

The term "heterocyclylalkyl" as used herein refers to an alkyl group, as defined herein, wherein a hydrogen or carbon bond of an alkyl group, as defined herein, is replaced by a bond of a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indol-2-ylpropyl.

The term "heteroarylalkyl" as used herein refers to an alkyl group, as defined herein, wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group, as defined herein.

The term "alkoxy" as used herein means that an oxygen atom is attached to an alkyl group, including to a cycloalkyl group as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like. The alkoxy group may further comprise a double bond or a triple bond, and may further comprise a heteroatom. For example, allyloxy is an alkoxy group within the meaning of this document. Within the meaning of the present text, methoxyethoxy is also alkoxy, as is the case when two adjacent atoms in the methylenedioxy structure are substituted by it.

The term "amine" as used herein refers to a compound having, for example, the formula N (group)₃Wherein each group can be independently H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to, R-NH₂For example, alkylamines, arylamines, alkylarylamines; r₂NH, wherein each R is independently selected, such as dialkylamines, diarylamines, arylalkylamines, heterocyclylamines, and the like; r₃N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

The term "amino" as used herein refers to-NH₂、-NHR、-NR₂、-NR₃ ⁺(iii) substituents of the form in which each R is independently selected, and the protonated form of each substituent, but-NR₃ ⁺Cannot be protonated. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein may be a primary, secondary, tertiary or quaternary amino group. "alkylamino" includes monoalkylamino, dialkylamino and trialkylamino.

As used herein, unless otherwise specified, the term "halo", "halogen" or "halogenated" group can refer to a fluorine, chlorine, bromine or iodine atom, either as a substituent per se or as part of another substituent.

As used herein, the term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, wherein all halogen atoms may be the same or different, and perhaloalkyl, wherein all hydrogen atoms are substituted with halogen atoms, such as fluorine. Examples of haloalkyl groups include trifluoromethyl, 1-dichloroethyl, 1, 2-dichloroethyl, 1, 3-dibromo-3, 3-difluoropropyl, perfluorobutyl, -CF (CH)₃)₂And the like.

The terms "optionally substituted" or "optionally substituted" as used herein mean that the group in question is unsubstituted or substituted with one or more of the specified substituents. When a group in question is substituted with multiple substituents, these substituents may be the same or different. When the terms "independently," "independently is," and "independently selected from" are used, the groups in question may be the same or different. Certain terms defined herein may appear multiple times in a structure, and once they appear, each term should be defined independently.

The compounds described herein may contain one or more chiral centers, or may otherwise exist as multiple stereoisomers. It will be appreciated that in one embodiment, the invention described herein is not limited to any particular stereochemical requirement, but rather that the compounds, compositions, methods, uses and medicaments comprising them may be optically pure or may be any mixture comprising the following stereoisomers: racemic and other compounds of enantiomers, other mixtures of diastereomers, and the like. It is also understood that mixtures of such stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configurations at one or more other chiral centers.

Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, but rather the compounds, compositions, methods, uses and medicaments comprising them may be pure or may be any mixture of various geometric isomers. It is also understood that mixtures of such geometric isomers may include single configurations at one or more double bonds, while including mixtures of geometric shapes at one or more other double bonds.

As used herein, the terms "salt" and "pharmaceutically acceptable salt" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and acidic groups such as alkali metal or organic salts of carboxylic acids. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acids and the like.

Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In some cases, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th edition, Mack publishing company, Iston, Pa., 1985, the disclosure of which is incorporated herein by reference.

The term "solvate" refers to a compound or salt thereof that also includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

The term "prodrug" refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of the present invention, which include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable urates, and biohydrolyzable phosphate analogs. A particular prodrug of a compound having a carboxyl functionality is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs can generally be prepared using well known methods, such as those described in hamburger Medicinal Chemistry and drug discovery (Burger's Medicinal Chemistry and drug discovery) 6 th edition (Donald j. abraham editions, 2001, Wiley) and Design and application of Prodrugs (Design and applications of Prodrugs) (h. bundgaard editions, 1985, harwood university Publishers GmbH).

Furthermore, in each of the foregoing and following embodiments, it is understood that the structural formula includes and represents not only all pharmaceutically acceptable salts of the compounds, but also any and all hydrates and/or solvates of the compound structural formula or salts thereof. It is understood that certain functional groups, such as hydroxyl, amino, and the like, form complexes and/or coordination compounds with water and/or various solvents in various physical forms. Accordingly, the above structural formulae should be understood to include and represent those various hydrates and/or solvates. In each of the foregoing and following embodiments, it is also to be understood that the structural formula includes and represents each of the possible isomers, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the structural formulae include and represent any and all crystalline forms, partially crystalline forms, and amorphous and/or amorphous forms of the compounds.

The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in or transports any subject composition or component thereof. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) radix astragali powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (nine) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) a ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) other non-toxic compatible substances used in pharmaceutical formulations.

The term "administering" as used herein includes all manner of administering the compounds and compositions described herein to a patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

Illustrative forms for oral administration include tablets, capsules, elixirs, syrups and the like. Exemplary routes of parenteral administration include intravenous, intraarterial, intraperitoneal, epidural, intraurethral, intrasternal, intramuscular, and subcutaneous, as well as any other art-recognized route of parenteral administration.

Illustrative means of parenteral administration include needle (including microneedle) syringes, needle-less syringes and infusion techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably having a pH in the range of from about 3 to about 9), but for some applications they may be more suitably formulated as sterile, anhydrous solutions or in dry form for use with a suitable vehicle, for example sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. Parenteral administration of the compounds is illustratively carried out as a salt solution or by incorporating the compounds into liposomes. In the case where the compound itself does not have sufficient solubility to be soluble, a solubilizing agent such as ethanol may be used.

The dosage of each compound of the claimed combination depends on several factors, including: the method of administration, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight and health of the person being treated. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetics, pharmacodynamics or efficacy profile of the therapeutic) information about a particular patient can affect the dosage used.

It will be appreciated that in the methods described herein, the components which are co-administered or administered in combination may be administered simultaneously, concurrently, sequentially, separately or in a single pharmaceutical formulation in any suitable manner. When the co-administered compounds or compositions are administered in different dosage forms, the number of doses of each compound administered per day may be the same or different. The compounds or compositions may be administered by the same or different routes of administration. The compounds or compositions may be administered simultaneously, in separate or single forms, at the same or different times during the course of therapy, according to a simultaneous or alternating regimen.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate a disease or disease symptom at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily amount of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and factors well known to researchers, veterinarians, physicians, or other ordinary skill.

Depending on the route of administration, a wide range of permissible doses is contemplated herein, including doses falling within the range of about 1 μ g/kg to about 1 g/kg. The doses may be single or divided, and may be administered according to a variety of regimens including q.d. (once a day), b.i.d. (twice a day), t.i.d. (3 times a day), even once every other day, weekly, monthly, quarterly, etc. In each of these cases, it is understood that the therapeutically effective amount described herein corresponds to the example of administration, or alternatively to the total dose per day, week, month, or quarter as determined by the dosing regimen.

In addition to the exemplary dosages and dosing regimens described herein, it will be understood that an effective amount of any one or mixture of the compounds described herein can be determined by the attending physician or physician using known techniques and/or procedures and/or by observing results obtained under analogous circumstances. The attending physician or physician, in determining an effective amount or dose, will consider a number of factors including, but not limited to, the species of mammal, including human, its size, age, and general health, the particular disease or condition involved, the intervention or severity of the disease or condition, the patient's response, the particular compound used, the mode of administration used, the bioavailability characteristics of the formulation used, the selected dosage regimen, the use of co-administered drugs, and other relevant circumstances.

The term "patient" includes both human and non-human animals, such as companion animals (dogs and cats, etc.) and livestock. Livestock are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being.

In some illustrative embodiments, the present invention relates to compounds having the structural formula or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety; and

In some illustrative embodiments, the present invention relates to a compound having the structural formula or a pharmaceutically acceptable salt thereof,

R²And R³Together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

elements according to A, B and D, R⁵Represents two or three substituents, each substituent being independently selected from hydrogen, deuterium, halogen, azido, and,Cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted.

In some illustrative embodiments, the present invention relates to a compound having structural formula (II), wherein R¹Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (III), or a pharmaceutically acceptable salt thereof,

R⁴represents two substituents, each independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkenylAlkynyls, each of which is optionally substituted; or said two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety;

In some illustrative embodiments, the present invention relates to a compound having structural formula (III), wherein R¹Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), or a pharmaceutically acceptable salt thereof,

wherein, 1-5;

R¹is amino, hydroxyl and derivatives thereof, alkyl, alkenyl, alkynyl, heteroalkylA group, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted;

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R¹Is composed of

A is carbon (C); b is nitrogen (N); r⁵、R⁶And R⁷All represent hydrogen, R⁴RepresentsTwo substituents, each substituent independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, ester, amide and derivatives thereof, and acyl, sulfo, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or the two substituents together with the attached carbon form an optionally substituted cyclic or heterocyclic moiety.

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R³Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (IV), wherein R¹Is composed of

And R³Is composed of

In some illustrative embodiments, the present invention relates to a compound having structural formula (I), wherein the compound is

In some illustrative embodiments, the present invention relates to a kinase inhibitor, wherein, the kinase is selected from the group consisting of FLT, MNK/2, JAK/, Limk/2, various CDKs, Haspin, ROCK/2, TOPK, LRRK, GSK 3/3B, RSK-4, ERK, P70S6, AKT, PI3, P, PKC, PKA, FGFR-4, VEGFR-3, ALK, AXL, LIMK/2, Aurora A/, AKT, CSF1, CSNK1, DCAMKL, CSNK1G, EPHA, ERBB, IKK-alpha, IKK-beta, JNK/, MARK, MEK/2, MET, MLK, PAK/, PDGFRa/B, PIM, PLK/, PRKCE, PRKX, RET, TAOK/B/and receptor interacting protein kinase 4 (RIPK).

In some other illustrative embodiments, the invention relates to a drug conjugate, which is a small molecule or bioconjugate, comprising one or more compounds disclosed herein, wherein the conjugate confers cell-type targeting or tissue-type targeting, or the conjugate targets another pathway that synergizes the effect of the compounds.

In some illustrative embodiments, the invention relates to a drug conjugate, which is a small molecule or bioconjugate, comprising one or more compounds disclosed herein, wherein the conjugate confers water solubility or low clearance.

In some illustrative embodiments, the present invention relates to a drug conjugate comprising one or more compounds disclosed herein, and a moiety that aids in the degradation of a target protein by a system including, but not limited to, a ubiquitin ligase/proteasome degradation system.

In some illustrative embodiments, the present invention relates to a pharmaceutical composition comprising one or more of the compounds disclosed herein in nanoparticle form, and one or more diluents, excipients, or carriers.

In some illustrative embodiments, the present invention relates to a prodrug comprising one or more of the compounds disclosed herein, wherein the prodrug moiety is removed at a specific location, for example, in the gastrointestinal tract or in the blood or tissue or a location specific for cancer.

In some illustrative embodiments, the invention relates to analogs of the compounds disclosed herein, wherein a particular metabolic hotspot is modified with a group such as deuterium or fluorine.

In addition, it is understood herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of cancer, such as compounds that are administered to alleviate pain, nausea, vomiting, and the like.

The following non-limiting exemplary embodiments are included herein to further illustrate the invention. These exemplary embodiments are not intended to, and should not be construed as, limiting the scope of the invention in any way. It should also be understood that numerous variations of these exemplary embodiments are contemplated herein.

Experimental part and characterization:

general procedure for the multicomponent reaction:¹⁰

the method A comprises the following steps: a mixture of amine (1mmol) and aldehyde (1mmol) in 3mL of anhydrous ethanol was refluxed for 2 hours, and then cyclic ketone or acetaldehyde (2.1mmol) was added to the reaction mixture. A catalytically metered amount of concentrated hydrochloric acid was added and the reaction was continued under reflux for 6-12 hours. The reaction mixture was concentrated and dissolved in DCM (50mL) and washed with brine solution (20mL X2). The organic layer was dried (Na)₂SO₄) Concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane: methanol (99: 01 to 80: 20)) to give the desired cyclized compound.

The method B comprises the following steps: a mixture of amine (1mmol) and aldehyde (1mmol) in 3mL acetonitrile was refluxed for 2 hours. The reaction mixture was cooled to room temperature and then the olefin (2mmol) and Y (OTf) were added₃(30 mol%). The reaction was continued to reflux overnight. The reaction mixture was concentrated and purified by silica gel chromatography, eluting with dichloromethane: methanol (99: 01) to afford the desired cyclized compound.

The method C comprises the following steps: a mixture of amine (1mmol), aldehyde (1mmol) and cyclic ketone (2mmol) in 6mL tetrahydrofuran in the presence of iodine (10 mol%) was refluxed for 6-12 h. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel chromatography: ethyl acetate: hexane (80: 20) or dichloromethane: methanol (99: 01) to afford the desired cyclized compound. (note: sometimes the product may precipitate out, which is filtered, washed with absolute ethanol and further purified by column chromatography).

Kinase assay: the HotSpot kinase screening assay (reaction biology) was used to measure kinase/inhibitor interactions. Kinase and substrate were incubated in a medium containing 20mM HEPES pH 7.5, 10mM MgCl₂、1mM EGTA、0.02％Brij35、0.02mg/mL BSA、0.1mM Na₃VO₄2mM DTT and 1% DMSO. Then will beA single dose of compound (500nM) was added to each reaction mixture. After 20 min incubation, ATP (Sigma) and [ gamma-³³P]ATP (Perkin Elmer) was then left at room temperature for 2 hours and then spotted on P81 ion-exchange cellulose chromatography paper (Whatman, Inc.). The filter paper was washed with 0.75% phosphoric acid to remove unbound ATP. The remaining percentage of kinase activity of the vehicle (DMSO) containing the kinase reactant was calculated for each kinase/inhibitor pair using Prism 5 (GraphPad).

LSD1 analysis:

the LSD1 test kit was used to measure LSD1 activity of the purified LSD1 enzyme. LSD1 buffer, 10uM histone H3(1-21) K4me2 peptide and test compound or DMSO control were added to 96-well plates. The reaction was initiated with the LSD1 enzyme. After incubation at room temperature for 30 min, peroxidase and Ampiex Red reagent were added and after 5 min fluorescence was measured using a microplate reader (λ ex 530 ± 13nm, λ em 590 ± 18 nm). Percent inhibition was calculated as the fluorescence intensity in the presence of inhibitor divided by the DMSO control multiplied by 100%.

IC50 proliferation assay

In the afternoon before treatment, cell lines and primary cells were seeded into 96-well plates. After about 18 hours, the compounds were semi-serially diluted in Dimethylsulfoxide (DMSO), then diluted in growth medium, and then added to the cells. Plates were incubated for 72 hours before addition of Alamar Blue (life technologies, Carlsbad, CA, usa). After an additional incubation at 37 ℃ for 4 hours, plates were read using a Bio-Tek Synergy HT plate reader (Bio-Tek, Winooski, VT) from Baote, Wenouski, Fomont, USA). Data were analyzed and plotted using GraphPad Prism software (GraphPad, La Jolla, CA, usa).

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

H]⁺HRMS (ESI) m/z calculated 315.1497, found 315.1499.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

316.1458。

4- (8, 9-dihydro-3H-cyclobut [ c ] pyrrolo [3,2-f ] quinolin-7-yl) phenol

287.1184, found 287.1184.

4- (3,8,9, 10-tetrahydrocyclopenta [ c ] pyrrolo [3,2-f ] quinolin-7-yl) phenol

35.16,31.66,24.38；C₂₀H₁₇N_2O[M+H]⁺HRMS (ESI) m/z calculated 301.1340, found 301.340.

4- (9-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

129.45,126.06,123.12,122.70,120.75,120.16,115.52,112.48,106.36,36.01,31.36,29.62,27.78,20.23；C₂₂H₂₁N₂O[M+H]⁺HRMS (ESI) m/z calculated 329.1653, found 329.1653.

2, 6-dibromo-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

7- (4-bromophenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

Calculating a value of 377.0653, measuringValue 377.0653.

4- (9-methyl-3H-pyrrolo [3,2-f ] quinolin-7-yl) phenol

7- (3,4, 5-trimethoxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

Measured value 389.1861.

4- (9, 9-dimethyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

34.69,28.29,27.71,26.60；C₂₃H₂₃N₂O[M+H]⁺HRMS (ESI) m/z calculated 343.1810, found 343.1808.

5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzene-1, 2, 3-triol

347.1395, found 347.1390.

4- (6,7,8, 9-tetrahydro-1H-pyrrolo [2,3-c ] phenanthridin-5-yl) phenol

7- (2, 2-Difluorobenzo [ d ] [1,3] Dioxazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

C₂₁H₁₆F₂N₃O₂[M+H]⁺380.1211, found 380.1216.

7- (1-methyl-1H-imidazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

Calculated m/z value C₁₉H₁₉N₄[M+H]⁺303.1609, found 303.1599.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzene-1, 3-diol

C₂₁H₁₉N₂O₂[M+H]⁺HRMS (ESI) m/z calculated 331.1446, found 331.1440.

4- (3,8,9,10,11, 12-hexahydrocyclohepta [ c ] pyrrolo [3,2-f ] quinolin-7-yl) phenol

Method A an off-white solid (187mg, 57%).¹H NMR(500MHz,DMSO-d₆)δ11.67(s,1H),9.52(s,1H),7.72(s,1H),7.56(d,J＝8.9Hz,1H),7.45(d,J＝2.8Hz,1H),7.29(d,J＝8.1Hz,2H),7.07(d,J＝3.1Hz,1H),6.85

329.1653, found 329.1652.

4- (8,9,10, 11-tetrahydro-3H- [1,2,3] triazolo [4,5-a ] phenanthridin-7-yl) phenol

HRMS (ESI) m/z calculated 317.1402, found 317.1408.

4- (2,3,4, 8-tetrahydro-1H-pyrrolo [3,2-b ] phenanthridin-5-yl) phenol

130.00,128.49,127.57,125.52,124.19,123.50,119.83,117.04,114.57,102.65,29.32,28.61,22.41,22.04；C₂₁H₁₉N₂O[M+H]⁺HRMS (ESI) m/z calculated 315.1497, found 315.1495.

4- (2,3,4, 8-tetrahydro-1H-pyrrolo [3,2-b ] phenanthridin-5-yl) phenol

133.37,129.18,127.97,124.12,124.09,122.80,120.25,116.84,106.43,55.22,29.96,28.70,22.75,22.49；C₂₀H₁₉N₄O[M+H]⁺HRMS (ESI) m/z calculated 331.1558, found 331.1553.

2,2' - ((4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenyl) azepinyl) diethanol

Found 402.2179.

2-fluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

127.33,123.16,120.36,118.65,118.49,118.29,114.87,30.92,28.11,21.80,21.69；C₂₀H₁₇FN₃O[M+H]⁺HRMS (ESI) m/z calculated 334.1355, found 334.1352.

7- (pyridin-4-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

28.67,22.76,22.39；C₂₀H₁₈N₃[M+H]⁺HRMS (ESI) m/z calculated 300.1500, found 300.1508.

4- (2,3,4, 9-tetrahydro-1H-indolo [3,2-a ] phenanthridin-5-yl) phenol

139.23,132.51,131.70,130.16,128.83,125.54,125.33,125.13,123.01,120.08,116.30,115.84,113.14,112.73,110.76,33.12,26.84,21.64,21.36；C₂₅H₂₁N₂O[M+H]⁺HRMS (ESI) m/z calculated 365.1653, found 365.1647.

4- (3-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

118.64,115.50,112.77,105.58,32.40,31.23,27.96,21.60,21.28；C₂₂H₂₁N₂O[M+H]⁺HRMS (ESI) m/z calculated 329.1653, found 329.1645.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyridin-2-ol

C₁₉H₁₇N₄O[M+H]⁺HRMS (ESI) m/z calculated 317.1402, found 317.1403.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) aniline

m/z calculated 315.1609, found 315.1619.

5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) pyridin-2-ol

C₂₀H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 316.1449, found 316.1455.

4- (8,9,10, 11-tetrahydrofuro [3,2-a ] phenanthridin-7-yl) phenol

131.37,122.86,121.34,119.47,116.00,110.37,30.67,28.32,21.74,21.57；C₂₁H₁₈NO₂[M+H]⁺HRMS (ESI) m/z calculated 316.1337, found 316.1343.

4- (8,9,10, 11-tetrahydrothieno [3,2-a ] phenanthridin-7-yl) phenol

131.22,130.02,128.68,127.46,125.78,123.88,115.49,31.70,29.13,22.58,21.88；C₂₁H₁₈NOS[M+H]⁺HRMS (ESI) m/z calculated 332.1109, found 332.1118.

2, 6-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) aniline

31.13,28.60,22.25,21.94；C₂₁H₂₀N₃[M+H]⁺HRMS (ESI) m/z calculated 314.1657, found 314.1651.

2, 6-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

+H]⁺HRMS (ESI) m/z calculated 351.1308, found 351.1302.

2-methyl-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

129.19,127.02,124.97,122.99,122.46,121.27,119.85,115.10,113.79,106.76,31.34,28.25,22.01,21.65,16.42；C₂₂H₂₁N₂O[M+H]⁺HRMS (ESI) m/z calculated 329.1653, found 329.1645.

2-chloro-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

154.51,153.28,143.38,142.36,133.59,133.20,130.91,129.36,127.54,124.08,123.92,122.39,120.33,119.60,116.47,116.41,106.27,29.99,29.17,22.87,22.60；C₂₁H₁₈ClN₂O[M+H]⁺HRMS (ESI) m/z calculated 349.1107, found 349.1112.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine-9-carbonitrile

114.00,106.64,30.73,29.32,24.59,23.97；C₂₂H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 340.1449, found 340.1445.

4- (1,2,4, 9-tetrahydropyrano [3,4-c ] pyrrolo [3,2-f ] quinolin-5-yl) phenol

29.76；C₂₀H₁₇N₂O₂[M+H]⁺HRMS (ESI) m/z calculated 317.1290, found 317.1290.

6- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) pyridin-3-ol

C₂₀H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 316.1450, found 316.1453.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzoic acid

119.96,117.15,105.96,47.93,30.20,28.28,22.22,21.85；C₂₂H₁₉N₂O₂[M+H]⁺HRMS (ESI) m/z calculated 343.1446, found 343.1438。

5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzene-1, 3-diol

(ESI) m/z calculated 331.1446, found 331.1450.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyridin-2-amine

122.70,119.27,115.60,111.95,29.80,28.11,21.86,21.86；C₁₉Η₁₈Ν₅[M+H]⁺HRMS (ESI) m/z calculated 316.1562, found 316.1555.

7- (pyrimidin-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

H]⁺HRMS (ESI) m/z calculated 301.1453, found 301.1457.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) thiazol-2-amine

2-fluoro-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

Value 333.1403.

5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) thiazol-2-amine

2-hydroxy-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzoic acid

2-hydroxy-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzoic acid methyl ester

124.82,122.96,121.86,118.10,117.86,115.02,114.60,53.03,30.66,28.23,21.85,21.79；C₂₂H₂₀N₃O₃[M+H]⁺HRMS (ESI) m/z calculated 374.1505, found 374.1508.

3- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) pyridin-2 (1H) -one

30.01,28.91,22.83,22.63；C₂₀H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 316.1450, found 316.1459.

2-hydroxy-5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzoic acid methyl ester

(126MHz,MeOD)δ170.24,161.08,154.60,143.93,142.64,136.22,133.26,132.11,130.33,127.42,122.82,121.91,120.24,116.86,116.03,111.93,105.77,51.58,48.10,29.95,28.67,22.45,22.16；C₂₃H₂₁N₂O₃[M+H]⁺HRMS (ESI) m/z calculated 373.1552, found 373.1557.

2- (7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-9-yl) isoindoline-1, 3-dione 12.11

Found 460.1665.

Benzyl (7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-9-yl) carbamate

137.46,133.91,133.75,131.95,128.79,128.27,127.75,127.12,122.61,122.34,121.41,119.89,116.02,113.72,106.77,65.77,45.47,33.92,29.80,27.29；C₂₉H₂₆N₃O₃[M+H]⁺HRMS (ESI) m/z calcd for 4,64.1974 found 464.1970.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-9-ol

119.84,115.99,113.73,106.74,63.25,36.67,29.46,29.03；C₂₁H₁₉N₂O₂[M+H]⁺HRMS (ESI) m/z calculated 331.1447, found 331.1452.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) -2- (trifluoromethyl) phenol

121.29,119.80,118.25,114.31,106.81,,31.29,28.01,21.96,21.63；C₂₂H₁₈F₃N₂O[M+H]⁺HRMS (ESI) m/z calculated 399.1320, found 399.1321.

3- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

Method A yellow solid (188mg, 60%).¹H NMR(500MHz,DMSO-d₆)δ10.28(s,1H),8.17(d,J＝8.9Hz,1H),7.97(d,J＝8.9Hz,1H),7.77(t,J＝2.9Hz,1H),7.43(t,J＝7.9Hz,1H),7.27-

315.1499。

5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) pyrimidin-2-amine

C₁₉H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 316.1562, found 316.1565.

2- ((dimethylamino) methyl) -4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

2, 6-diiodo-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

3- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

117.83,116.79,114.86,30.73,28.07,21.77,21.59；C₁₉H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 316.1562, found 316.1555.

3- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyridin-2 (1H) -one

(ESI) m/z calculated 317.1402, found 317.1411.

Benzyl (7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) carbamate

119.33,118.00,115.47,114.97,66.04,48.13,48.08,47.96,47.79,47.62,47.45,47.28,47.11,45.66,33.71,29.28,26.87；C₂₈H₂₅N₄O₃[M+H]⁺HRMS (ESI) m/z calculated 465.1927, found 465.1927.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-ol

115.38,64.42,37.63,30.18,28.16；C₂₀H₁₈N₃O₂[M+H]⁺HRMS (ESI) m/z calculated 332.1399, found 332.1402.

2- (7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) isoindoline-1, 3-dione

461.1619。

2-chloro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

21.65,21.61；C₂₀H₁₇ClN₃O[M+H]⁺HRMS (ESI) m/z calculated 350.1060, found 350.1066.

4- (1-bromo-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

114.56,36.01,27.02,20.91,20.80.¹³C NMR(126MHz,MeOD)δ160.37,155.96,154.60,151.79,141.55,135.37,132.94,130.83,127.59,123.46,121.93,120.38,119.25,115.60,114.56,36.01,27.02,20.91,20.80；C₂₀H₁₇BrN₃O[M+H]⁺HRMS (ESI) m/z calculated 394.0555, found 394.0556.

7- (6-Chloropyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -2- (trifluoromethyl) phenol

J＝30.24Hz),114.39,29.69,29.00,22.55；C₂₁H₁₇F₃N₃O[M+H]⁺HRMS (ESI) m/z calculated 384.1324, found 384.1329.

2-methoxy-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

346.1556, found 346.1562.

3-fluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

119.35,116.25,112.08,102.89,102.70,29.48,27.50,22.64,22.24；C₂₀H₁₇FN₃O[M+H]⁺HRMS (ESI) m/z calculated 334.1356, found 334.1360.

4- (9-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

134.75,132.00,130.90,124.14,123.00,123.00,122.62,121.61,119.36,119.08,116.55,115.54,115.03,35.98,30.99,29.34,27.83,20.20；C₂₁H₂₀N₃O[M+H]⁺HRMS (ESI) m/z calculated 330.1606, found 330.1609.

4- (3,8,9, 10-tetrahydrocyclopenta [ c ] pyrazolo [4,3-f ] quinolin-7-yl) phenol

Value 302.1295.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-9-carbonitrile

25.08,24.57；C₂₁H₁₇N₄O[M+H]⁺HRMS (ESI) m/z calculated 341.1402, found 341.1410.

2- ((dimethylamino) methyl) -4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

7- (6-Fluoropyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

C₁₉H₁₆FN₄[M+H]⁺HRMS (ESI) m/z calculated 319.1359, found 319.1366.

2-iodo-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

27.82,21.28,21.20；C₂₀H₁₇IN₃O[M+H]HRMS (ESI) m/z calculated 442.0416, found 442.0416.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzoic acid

124.86,122.74,118.09,115.38,30.20,28.32,22.04,21.92；C₂₁H₁₈N₃O₂[M+H]⁺HRMS (ESI) m/z calculated 344.1399, found 344.1401.

4- (8, 9-dihydro-3H-cyclobut [ c ] pyrazolo [4,3-f ] quinolin-7-yl) phenol

Value 288.1137, found 288.1139.

4- (3, 8-dihydro-2H-furo [3,2-c ] pyrazolo [4,3-f ] quinolin-4-yl) phenol

7- (1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

C₂₁H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 340.1562, found 340.1565.

7- (1H-indazol-6-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

133.74,131.74,129.55,129.36,125.92,122.00,116.36,114.53,111.49,110.02,29.64,28.80,22.52,22.44；C₂₁H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 340.1562, found 340.1565.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -1H-benzo [ d ] imidazol-2 (3H) -one

108.18,29.70,29.28,22.65,22.62；C₂₂H₁₇N₄O₂[M+H]⁺HRMS (ESI) m/z calculated 369.1352, found 369.1352.

4- (8,9,10, 11-tetrahydro-1H-pyrazolo [3,4-a ] phenanthridin-7-yl) phenol

28.93,26.48,22.74,22.32；C₂₀H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 316.1449, found 316.1458.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyrimidine-2, 4(1H,3H) -dione

2-methyl-6- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazole e

22.54,20.33；C₂₂H₁₉N₄S[M+H]⁺HRMS (ESI) m/z calculated 371.1330, found 371.1333.

3, 5-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

Method A white solid (168mg, 48%).¹H NMR(500MHz,DMSO-d₆)δ8.52(s,

(ESI) m/z calculated 352.1261, found 352.1266.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-9-carboxylic acid

Measured value 360.1351.

5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

29.18,22.66,22.62；C₂₁H₁₈N₅S[M+H]HRMS (ESI) m/z calculated 372.1283, found 372.1285.

4- (3,8,10, 11-tetrahydropyrano [3,4-c ] pyrazolo [4,3-f ] quinolin-7-yl) phenol

Value 318.1243, found 318.1244.

N- (7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) acetamide

C₂₂H₂₁N₄O₂[M+H]⁺HRMS (ESI) m/z calculated 373.1665, found 373.1670.

4- (6,7,8, 9-tetrahydro-1H-pyrazolo [3,4-c ] phenanthridin-5-yl) phenol

4- (6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-c ] phenanthridin-5-yl) phenol

7- (1H-pyrrolo [2,3-b ] pyridin-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Found 340.1569.

4- (8,9,10, 11-tetrahydro-1H-pyrazolo [3,4-a ] phenanthridin-7-yl) phenol

(ESI) m/z calculated 316.1449, found 316.1458.

3, 5-dimethyl-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) isoxazoles

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-1-carbonitrile

HRMS (ESI) m/z calculated 345.1715, found 345.1720.

Tert-butyl (6- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyridin-2-yl) carbamate

114.29,80.98,30.97,27.41,27.15,21.16,21.06。

4- (5-methoxy-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

150.67,150.36,140.21,132.48,131.68,130.23,125.17,123.07,121.30,115.56,109.83,96.56,56.90,30.79,28.48,21.93,21.80；C₂₁H₂₀N₃O₂[M+H]⁺HRMS (ESI) m/z calculated 346.1556, found 346.1559.

4- (3-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

7- (1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

122.38,121.28,120.41,116.42,109.84,106.27,30.01,29.35,22.91,22.62；C₂₂H₁₉N₄[M+H]⁺HRMS (ESI) m/z calculated 339.1610, found 339.1618.

7- (1H-indol-2-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Found 339.1618.

7- (1H-indol-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Value 339.1610, found 339.1618.

7-cyclopropyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Found 264.1509.

2- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -4H-benzopyran-4-one

7- (bicyclo [2.2.1] hept-5-en-2-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (1H-indazol-5-yl) -1-iodo-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

466.0529, found 466.0535.

1-bromo-7- (1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

N- (7- (1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) acetamide

Measured value 397.1778.

7- (1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-amine

m/z calculated 355.1671, found 355.1673.

(4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenyl) boronic acid

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzonitrile

m/z calculated 325.1453, found 325.1455.

4- (9-amino-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

HRMS (ESI) m/z calculated 331.1559, found 331.1561.

(2-fluoro-3- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenyl) boronic acid

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

HRMS (ESI) m/z calculated 358.1280, found 358.1286.

7- (1H-benzo [ d ] imidazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Found 340.1570.

4- (1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

(ESI) m/z calculated 330.1606, found 330.1606.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine-2-carboxylic acid methyl ester

129.38,126.63,122.76,119.77,118.05,115.31,112.07,30.25,29.02,22.48,22.24；C₂₃H₂₃N₂O₃[M+H]⁺HRMS (ESI) m/z calculated 375.1709, found 375.1711.

7- (4-fluorophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

111.46,101.25,30.79,28.10,21.80,21.67；C₂₀H₂₁FN₃[M+H]⁺¹HRMS (ESI) m/z calculated 322.1720, found 322.1724.

7- (4-fluorophenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

122.53,120.32,116.56,115.24,115.07,106.29,29.96,29.06,22.84,22.53；C₂₁H₂₂FN₂[M+H]+ HRMS (ESI) m/z calculated 321.1767, found 321.1768.

7-phenyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

HRMS (ESI) m/z calculated 300.1501, found 300.1501.

7-phenyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

HRMS (ESI) m/z calculated 301.1705, found 301.1713.

7- (4-hydroxyphenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine-2-carboxylic acid

C₂₂H₂₁N₂O₃[M+H]⁺HRMS (ESI) m/z calculated 361.1552, found 361.1552.

7- (2-bromo-4-fluorophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

m/z calculated 398.0668, found 398.0673.

7- (4-ethynylphenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

131.45,130.16,129.47,129.13,128.86,122.07,121.97,116.19,115.47,83.85,81.41,29.63,28.83,22.52,22.45；C₂₂H₂₀N₃[M+H]⁺HRMS (ESI) m/z calculated 326.1657, found 326.1659.

7- (4-chlorophenyl) -8,9,10, 11-tetrahydro-3H-naphtho [1,2-e ] indazole

C₂₀H₁₉ClN₃[M+H]⁺HRMS (ESI) m/z calculated 336.1268, found 336.1271.

7- (4-chlorophenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

7- (3-fluorophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

22.52,22.43；C₂₀H₁₉FN₃[M+H]⁺HRMS (ESI) m/z calculated 320.1563, found 320.1569.

7- (3-fluorophenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

115.54,114.41,114.24,105.80,29.89,28.41,22.39,22.03；C₂₁H₂₀FN₂[M+H]⁺HRMS (ESI) m/z calculated 319.1611, found 319.1618.

4- (8,9,10, 11-tetrahydro-3H-8, 11-methylpyrazolo [4,3-a ] phenanthridin-7-yl) phenol 1193

C₂₁H₁₈N₃O[M+H]⁺HRMS (ESI) m/z calculated 328.1450, found 328.1450.

4- (2-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

Value 331.1810, found 331.1813.

6- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) pyridin-3-ol

317.1402, found 317.1397.

7- (6-Fluoropyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

116.37,116.32,108.83,108.54,105.95,105.90,29.82,28.39,22.24,21.95；C₂₀H₁₉FN₃[M+H]⁺HRMS (ESI) m/z calculated 320.1563, found 320.1566.

7- (pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (2-bromophenyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

27.36,22.39,21.88；C₂₁H₂₀BrN₂[M+H]⁺HRMS (ESI) m/z calculated 379.0810, found 379.0817.

3-fluoro-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

2-fluoro-4- (2-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

Calculated 349.1716, found 349.1720.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzamidine hydrochloride

N-hydroxy-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzamidine

NH in DMSO (3mL)₂OH.H₂To a solution of O (1.5 equiv.) KOtBut (3 equiv.) is added slowly at 0 ℃ and the suspension is stirred for 30 min. Adding 4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4, 3-a)]Phenanthridin-7-yl) benzonitrile (0.5mmol) and the reaction was continued at room temperature for 4 hours. After completion of the reaction, cold water was added to the reaction mixture, and the resulting precipitate was filtered, washed with water and dried. The solid was recrystallized from ethanol to give the desired product.

Off-white solid (162mg, 90%).¹H NMR(500MHz,DMSO-d₆)δ9.71(s,1H),8.56(s,1H),7.88-7.82(m,2H),7.79-7.76(m,2H),7.59-7.54(m,2H),5.89(s,2H),2.79(t,J＝6.1Hz,2H),2.00(ddt,J＝9.3,6.5,3.1Hz,2H),1.74(tt,J＝8.6,5.4Hz,2H)；¹³C NMR(126MHz,DMSO)δ156.48,151.11,145.66,143.64,142.45,141.74,138.70,136.39,133.15,129.67,129.32,125.43,121.88,116.46,114.44,29.69,28.96,22.60,22.52；C₂₁H₂₂N₅O[M+H]⁺HRMS (ESI) m/z calculated 360.1824, found 360.1827.

N- (4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenyl) acetamide

C₂₂H₂₃N₄O[M+H]⁺HRMS (ESI) m/z calculated 359.1872, found 359.1875.

4- (3, 8-dihydro-2H-furo [3,2-c ] pyrrolo [3,2-f ] quinolin-4-yl) phenol

118.76,116.42,106.27,29.98,29.18,24.55,22.90,22.61；C₂₃H₂₄N₃O[M+H]⁺HRMS (ESI) m/z calculated 358.1919, found 358.1922.

4- (3, 8-dihydro-2H-furo [3,2-c ] pyrrolo [3,2-f ] quinolin-4-yl) phenol

Value 305.1299.

2-fluoro-4- (1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzonitrile

C₂₂H₂₀N₃[M+H]⁺HRMS (ESI) m/z calculated 326.1657, found 326.1662.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzoic acid methyl ester

Found 360.1718.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzamide

345.1719。

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzoic acid methyl ester

+H]⁺HRMS (ESI) m/z calculated 349.1716, found 349.1717.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzoic acid methyl ester

106.71,52.90,30.82,28.26,22.22,21.82；C₂₃H₂₃N₂O₂[M+H]⁺HRMS (ESI) m/z calculated 359.1760, found 359.1767.

N-hydroxy-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzamidine

The synthesis was performed according to the general procedure of 1207. Off-white solid (163mg, 91%);¹H NMR(500MHz,DMSO-d₆)δ11.76(d,J＝2.3Hz,1H),9.69(s,1H),7.78(t,J＝8.9Hz,3H),7.63(d,J＝8.8Hz,1H),7.56-7.52(m,2H),7.49(t,J＝2.8Hz,1H),7.13(d,J＝2.5Hz,1H),5.86(s,2H),3.39(t,J＝6.5Hz,3H),2.77(t,J＝6.2Hz,2H),2.01-1.92(m,2H),1.79-1.69(m,2H).³C NMR(126MHz,DMSO)δ155.44,151.17,143.41,142.38,142.28,133.25,132.92,129.31,127.45,125.38,124.12,123.98,122.52,120.34,116.54,106.31,29.97,29.08,22.87,22.54；C₂₂H₂₃N₄O[M+H]⁺HRMS (ESI) m/z calculated 359.1872, found 359.1872.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzamide

120.33,116.62,106.34,29.97,28.98,22.84,22.50；C₂₂H₂₂N₃O[M+H]⁺HRMS (ESI) m/z calculated 344.1763, found 344.1769.

2, 3-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

C₂₁H₁₉ F₂N₂O[M+H]⁺HRMS (ESI) m/z calculated 353.1465, found 353.1468.

2, 3-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

C₂₀H₁₆F₂N₃O[M+H]⁺HRMS (ESI) m/z calculated 352.1261, found 352.1256.

2-fluoro-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzonitrile

C₂₁H₁₈F N₄[M+H]⁺HRMS (ESI) m/z calculated 345.1515, found 345.1519.

2-fluoro-5- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzonitrile

H]⁺HRMS (ESI) m/z calculated 344.1563, found 344.1565.

3-methoxy-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

116.57,113.84,107.41,99.24,55.49,29.45,27.19,22.74,22.27；C₂₁H₂₂N₃O₂[M+H]⁺HRMS (ESI) m/z calculated 348.1712, found 348.1717.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) -2- (trifluoromethyl) phenol

22.58；C₂₂H₂₀F₃N₂O[M+H]⁺HRMS (ESI) m/z calculated 385.1528, found 385.1530.

2, 5-difluoro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

7- (3-methyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

1-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) -3- (trifluoromethyl) phenol

Found 385.1530.

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -3- (trifluoromethyl) phenol

119.30,116.44,114.27,113.02,112.98,29.41,28.15,22.58,22.19；C₂₁H₁₉F₃N₃O[M+H]⁺HRMS (ESI) m/z calculated 386.1480, found 386.1488.

7- (5- (trifluoromethyl) -1H-pyrazol-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (9- (trifluoromethyl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

HRMS (ESI) m/z calculated 385.1528, found 385.1532.

4- (9- (trifluoromethyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

(ESI) m/z calculated 386.1480, found 386.1484.

4- (9, 9-difluoro-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

m/z calculated 354.1418, found 354.1421.

4- (9, 9-difluoro-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenol

353.1470。

8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-7-carboxylic acid ethyl ester

7- (4-hydroxyphenyl) -8,9,10, ll-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine-1-carbonitrile

[M+H]⁺HRMS (ESI) m/z calculated 342.1606, found 342.1611.

4- (7,8,9, 10-Tetrahydrophenanthridin-6-yl) phenol

4- (6,7,8, 9-tetrahydro-3H-pyrrolo [3,2-c ] phenanthridin-5-yl) phenol

4- (3- (2-hydroxyethyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

Calculated 362.1869, found 362.1871.

7-(3-(δ8.26(s,1H),7.95(d,J＝9.1Hz,1H),7.86(d,J＝9.1Hz,1H),3.55(t,J＝6.3Hz,2H),2.72(t,J＝6.3Hz,2H),1.95-1.86(m,2H),1.84-1.77(m,2H)；¹³C NMR(126MHz,DMSO)δ150.24,144.55,143.03,140.24,139.34,131.66,131.35,130.73,125.49(J＝2704.68Hz),121.28,121.28,119.78,119.14,117.84,116.46,114.90,31.80,28.11,21.99；C₁₉H₁₄F₃N₆[M+H]⁺HRMS (ESI) m/z calculated 383.1232, found 383.1238.

6- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

6- (3,8,9, 10-tetrahydrocyclopenta [ c ] pyrazolo [4,3-f ] quinolin-7-yl) benzo [ d ] thiazol-2-amine

Found 358.1128.

N- (4- (2-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) phenyl) methanesulfonamide

37.63,30.40,26.94,20.76,20.43, 11.29; HRMS (ESI) m/z calculated value C₂₃H₂₈N₃O₂S[M+H]⁺410.1902, found 410.1907.

N- (4- (3,8,9, 10-tetrahydrocyclopenta [ c ] pyrrolo [3,2-f ] quinolin-7-yl) phenyl) methanesulfonamide

149.35,144.61,138.77,136.41,134.23,132.57,129.96,124.46,123.67,120.85,120.10,119.48,116.78,104.29,33.87,33.12,25.08；C₂₁H₂₂N₃O₂S[M+H]⁺HRMS (ESI) m/z calculated 380.1433, found 380.1440.

7- (2-aminobenzo [ d ] thiazol-6-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine-1-carbonitrile

6- (1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

7- (3, 5-dimethyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (1H-indazol-5-yl) -1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

22.08,21.72；C₂₂H₂₄N₅[M+H]⁺HRMS (ESI) m/z calculated 358.2032, found 358.2033.

7- (1H-indazol-5-yl) -1, 2-dimethyl-8, 9,10, 11-tetrahydro-2H-pyrazolo [4,3-a ] phenanthridine

29.10,22.71,22.60,9.69；C₂₃H₂₄N₅[M+H]⁺HRMS (ESI) m/z calculated 370.2032, found 370.2039.

7- (1H-indazol-5-yl) -2-methyl-8, 9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

357.2079, found 357.2079.

7- (1H-indazol-5-yl) -1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

354.1719, found 354.1722.

7- (1H-pyrrolo [3,2-c ] pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

340.1562, found 340.1566.

7- (4-chloro-1H-pyrrolo [2,3-6] pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridine

116.27,114.39,106.19,30.22,28.95,22.89,22.82；C₂₂H₁₉N₄[M+H]⁺HRMS (ESI) m/z calculated 339.1610, found 339.1615。

7- (5H-pyrrolo [3,2-d ] pyrimidin-7-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (6-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

374.1172, found 374.1178.

7- (1H-pyrrolo [3,2-b ] pyridin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzenesulfonamide

115.57,31.16,29.66,28.81,22.54,22.43；C₂₀H₁₉N₄O₂S[M+H]⁺HRMS (ESI) m/z calculated 379.1229, found 379.1234.

4- (8,9,10, 11-tetrahydro-3H-pyrrolo [3,2-a ] phenanthridin-7-yl) benzenesulfonamide

142.65,133.35,130.06,127.32,125.76,124.09,122.72,120.30,116.75,106.36,29.96,28.94,22.81,22.46；C₂₁H₂₀N₃O₂S[M+H]⁺HRMS (ESI) m/z calculated 378.1276, found 378.1279.

7- (1H-pyrrolo [2,3-b ] pyridin-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

100.67,29.73,29.23,22.62；C₂₁H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 340.1562, found 340.1565.

7- (1-methyl-1H-indazol-5-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

9-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

C₁₈H₁₈N₅[M+H]⁺HRMS (ESI) m/z calculated 304.1562, found 304.1565.

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3,8,9, 10-tetrahydrocyclopenta [ c ] pyrazolo [4,3-f ] quinoline

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3,8,9,10,11, 12-hexahydrocyclohepta [ c ] pyrazolo [4,3-f ] quinoline

372.1436, found 372.1438.

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8, 9-dihydro-3H-cyclobut [ c ] pyrazolo [4,3-f ] quinoline

HRMS (ESI) m/z calculated 330.0967, found 330.0970.

9-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3H-pyrazolo [4,3-f ] quinoline

7- (1H-1,2, 3-triazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

3- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -1H-pyrrole-2-carboxylic acid methyl ester

347.1508, found 347.1513.

2- (4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -1H-pyrazol-1-yl) ethan-1-ol

60.48,54.17,29.73,28.38,22.12,22.03；C₁₉H₂₀N₅O[M+H]⁺HRMS (ESI) m/z calculated 334.1668, found 334.1675.

7- (1, 3-dimethyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Value 318.1719, found 318.1725.

7- (1H-imidazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

290.1406, found 290.1415.

1-iodo-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

484.0246, found 484.0252.

7- (3-phenyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-amine

373.1393。

3-methyl-3- (4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -1H-pyrazol-1-yl) tetrahydrothiophene 1, 1-dioxide

3H)；¹³C NMR(126MHz,DMSO)δ149.12,143.66,142.26,140.19,138.52,136.20,129.53,129.02,128.80,123.04,121.18,116.52,114.29,65.32,61.46,51.53,35.09,29.87,28.53,27.91,22.63,22.50。

7- (3- (pyridin-3-yl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

119.13,116.29,115.55,29.57,28.27,22.59,22.35；C₂₂H₁₉N₆[M+H]⁺HRMS (ESI) m/z calculated 367.1671, found 367.1675.

7- (1-phenyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

28.10,22.55,22.32；C₂₃H₂₀N₅[M+H]⁺HRMS (ESI) m/z calculated 366.1719, found 366.1720.

7- (3- (thien-3-yl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Measured value 372.1286.

7- (3- (tert-butyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) -1H-pyrazole-3-carboxylic acid

7- (1- (2-chloroethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

2, 3-dimethyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3,6,8,9,10, 11-hexahydro-2H-pyrazolo [3,4-a ] phenanthridine

5-fluoro-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-5-ol

5-bromo-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

5-chloro-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H- [1,2,3] triazolo [4,5-a ] phenanthridine

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydroisooxazolo [4,5-a ] phenanthridine

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydroisothiazolo [4,5-a ] phenanthridine

m/z calculated 375.0891, found 375.0899.

3-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

(ESI) m/z calculated 372.1436, found 372.1438.

6- (5-fluoro-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

6- (8,9,10, 11-tetrahydro-3H- [1,2,3] triazolo [4,5-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

7- (3-isopropyl-1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

4- (7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) morpholine

6- (3-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-amine

7- (2-aminobenzo [ d ] thiazol-6-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-1-carboxylic acid methyl ester

N- (6- (8,9,10, 11-T-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ d ] thiazol-2-yl) acetamide

Compound HSD992(93mg, 0.25mmol) was dissolved in a mixture of DMF (2mL) and triethylamine (2 equiv.) and acetyl chloride (30mg, 1.5mmol) was added. After that, the reaction was continued at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (2X 20mL) and washed with brine solution and purified by flash column chromatography with dichloromethane: the crude product was purified with methanol (90:10) to give the desired product as a yellow solid (73mg, 70%).

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-imidazo [4,5-a ] phenanthridine

Measured value 358.1286.

2- (trifluoromethyl) -7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-imidazo [4,5-a ] phenanthridine

H]⁺HRMS (ESI) m/z calculated 426.1153, found 426.1155.

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-1-carboxylic acid methyl ester

+H]⁺HRMS (ESI) m/z calculated 416.1334, found 416.1343.

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-9-carbonitrile

1-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-9-carbonitrile

30.56,29.87,24.22,23.60,23.54,17.53。

8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-7-carboxylic acid (HSD1251)

Off-white solid (40%).¹H NMR(500MHz,DMSO-d₆)δ8.60(s,1H),7.90(d,J＝9.0Hz,1H),7.83(d,J＝9.5Hz,1H),3.32-3.26(m,11H),3.06-2.96(m,2H),2.03-1.92(m,2H),1.87-1.75(m,2H)。

N-cyclopropyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-7-carboxylic acid amine

0.54(m,2H)；¹³C NMR(126MHz,DMSO)δ169.02,150.75,143.04,142.46,138.96,136.49,129.42,129.13,123.13,116.31,114.78,29.62,26.70,23.08,22.44,22.07,6.21.C₁₈H₁₉N₄O[M+H]⁺HRMS (ESI) m/z calculated 307.1559, found 307.1565.

9-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-indazolo [5,4-c ] [2,7] naphthyridine

6- (9-methyl-8, 9,10, 11-tetrahydro-3H-indazolo [5,4-c ] [2,7] naphthyridin-7-yl) benzo [ d ] thiazol-2-amine

46.15。

N- (7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-yl) acetamide

7- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) -5-fluoro-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Method A off-white solid (37mg, 10%).¹H NMR(500MHz,DMSO-d₆)δ8.50(s,1H),

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-indazolo [5,4-c ] [2,7] naphthyridine

In this example, using method A, tert-butyl 4-oxapiperidine-1-carboxylate was used as the cyclic ketone, the Boc-group could be deprotected in situ due to the presence of HCl in the reaction, and the desired compound was precipitated from it by filtration and washing of the reaction mixture with ethanol.

Method A off-white solid (100mg, 28%).¹H NMR(500MHz,DMSO-d₆)δ9.70(s,

5-fluoro-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-indazolo [5,4-c ] [2,7] naphthyridine

N- (4- ((4-methylpiperazin-l-yl) methyl) -3- (trifluoromethyl) phenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-7-carboxylic acid amine

MHz,DMSO-d₆)δ10.93(s,1H),8.63(s,1H),8.29(d,J＝2.2Hz,1H),8.05(dd,J＝8.5,2.3Hz,1H),7.98-7.89(m,2H),7.71(d,J＝8.5Hz,1H),3.56(s,2H),3.34-3.30(m,2H),3.13(t,J＝6.2Hz,2H),2.37(s,8H),2.14(s,3H),1.99(ddt,J＝8.9,6.3,2.9Hz,2H),1.87-1.79(m,2H)；¹³C NMR(126MHz,DMSO)δ166.54,149.19,143.71,142.60,138.52,132.53,131.81,129.74,129.42,128.11(q,J＝28.9Hz),125.91(q,J＝274.6Hz),123.78,123.53,117.19,117.14,116.03,57.94,55.22,53.19,46.22,29.73,26.89,22.37,22.07；C₂₈H₃₀F₃N₆O[M+H]⁺HRMS (ESI) m/z calculated 523.2433, practiceMeasured value 523.2433.

7- (2-aminobenzo [ d ] thiazol-6-yl) -3H-pyrazolo [4,3-f ] quinoline-9-carboxylic acid

7- (isoquinolin-6-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

22.40。

7- (isoquinolin-8-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (isoquinolin-7-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

7- (quinolin-2-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

22.43；C₂₃H₁₉N₄[M+H]⁺HRMS (ESI) m/z calculated 351.1610, found 351.1608.

7- (isoquinolin-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

HRMS (ESI) m/z calculated 351.1610, found 351.1611.

9- (pyridin-2-yl) -7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3H-pyrazolo [4,3-f ] quinoline

7- (quinolin-6-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

122.43,121.73,116.49,114.82,29.57,27.63,22.47,22.06C₂₃H₁₉N₄[M+H]⁺HRMS (ESI) m/z calculated 351.1610, found 351.1611.

7- (quinolin-3-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Found 351.1613.

3-chloro-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

m/z calculated 350.1060, found 350.1063.

3-fluoro-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

7- (isoquinolin-1-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

351.1610, found 351.1606.

1-methoxy-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

1-methyl-7- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-9-carbonitrile

7- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

372.1444。

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3,8,10, 11-tetrahydropyrazolo [4,3-f ] mercaptopyrano [3,4-c ] quinolone

Method A Gray solid (124mg, 33%).¹H NMR(500MHz,DMSO-d₆)δ8.78(s,1H),

1- (7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3,8,10, 11-tetrahydro-9H-indazolo [5,4-c ] [2,7] naphthyridin-9-yl) ethan-1-one

9-cyclopropyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3H-pyrazolo [4,3-f ] quinolone

4- (3,8,9,10,11, 12-hexahydrocyclohepta [ c ] pyrazolo [4,3-f ] quinolin-7-yl) -2, 6-diiodophenol

7- (4-hydroxy-3, 5-diiodophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-ol

Measured value 583.9336.

2, 6-dibromo-4- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

7- (4-hydroxy-3, 5-diiodophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-1-carbonitrile

Found 590.9325.

2, 6-diiodo-4- (1-methyl-8, 9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenol

(5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) thiophen-3-yl) boronic acid

N- (2- (4-methylpiperazin-1-yl) ethyl) -7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine-1-carboxylic acid amine

Hz),121.24,119.27,111.50,110.90,55.67,52.74,49.61,42.13,36.36,30.49,26.83,21.20,20.97.C₂₆H₃₀F₃N₈O[M+H]⁺HRMS (ESI) m/z calculated 527.2495, found 527.2495.

1-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-9-amine

(2-methoxy-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenyl) boronic acid

(5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) furan-2-yl) boronic acid

5-fluoro-7- (1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

(7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-1-yl) methanol

Compound HSD1329(100mg) was dissolved in anhydrous THF and cooled under argon using dry ice acetone. After cooling, LAH (1 molar solution in THF, 1 eq) was added dropwise and stirring was continued overnight at room temperature. The reaction was quenched by slow addition of a water and THF mixture under cooling. The reaction mixture was filtered and purified by flash column chromatography.

1-methyl-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a]Phenanthridine-8, 8,9,9,10,10, -d₆

Using the same procedure A, with deuteration (D)₈) Cyclohexanone as the ketone.

5-fluoro-7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a]Phenanthridine-8, 8,9,9,10,10, -d₆

Using the same procedure A, with deuteration (D)₈) Cyclohexanone as the ketone.

7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -3H-pyrazolo [4,3-f ] quinoline-9-carboxylic acid

Pyruvate acts as a substrate for ketones.

3, 3-dimethyl-5- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ c ] [1,2] oxaborole-1 (3H) -ol

3, 3-dimethyl-6- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) benzo [ c ] [1,2] oxaborole-1 (3H) -ol

(2-methoxy-3- (8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-7-yl) phenyl) boronic acid

(7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridin-5-yl) ethane-1, 2-diamine

131.49,131.11,123.95,122.86,120.72,119.24,112.05,56.25,52.86,44.02,43.71,39.62,29.85,27.71,22.14,21.75；C₂₃H₂₄F₃N₇[M+H]⁺HRMS (ESI) m/z calculated value 458.2280,found 458.2276.

5- (piperidin-1-yl) -7- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

441.2012。

7- (4-fluoro-3-nitrophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

2-fluoro-5- (8,9,10, 11-tetrahydro-3H-naphtho [1,2-e ] indazol-7-yl) aniline

Compound HSD1404(100mg) was dissolved in 5mL THF and purged with argon for 15 minutes. After that, palladium (10% on carbon, 20 mol%) was added and hydrogenation reaction was carried out for 6 hours using a hydrogen balloon. Upon completion, the reaction mixture was filtered through a sintered funnel, concentrated and purified by flash column chromatography.

114.39,114.24,113.58,29.59,28.41,22.17,22.06.C₂₁H₁₉FN₃[M+H]⁺HRMS (ESI) m/z calculated 332.1563, found 332.1560.

7- (3-fluoro-4-nitrophenyl) -8,9,10, 11-tetrahydro-3H-pyrazolo [4,3-a ] phenanthridine

Those skilled in the art will recognize that numerous modifications may be made to the specific embodiments described above. The embodiments should not be limited to the specific limitations described. Other embodiments are also possible.

While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only certain embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.

The scope of the methods and compositions of the present invention is defined by the appended claims. However, it must be understood that this disclosure may be practiced otherwise than as specifically explained and illustrated without departing from its spirit or scope. It will be understood by those skilled in the art that various alternatives to the embodiments described herein may be employed in practicing the claims without departing from the spirit and scope as defined in the following claims.

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4)Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML.Lindblad et al.Oncogene 2016,35(39),5119-31

5)Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT,FLT3,and BCR-ABL.Mali et al.Cancer Cell 2011,20(3),357-69.

6)Jakinibs:a new class of kinase inhibitors in cancer and autoimmune disease.Kontzias et al.Curr.Opin.Pharmacol,2012,12(4),464-70.

7)Rho Kinase(ROCK)Inhibitors.James et al.J Cardiovasc Pharmacol.2007,50(1),17-24

8)An emerging treatment option for glaucoma:Rho kinase inhibitors.Wang and Chang Clin Ophthalmol.2014,8,883-90.

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