CN110407854B

CN110407854B - Novel tetracyclic compounds

Info

Publication number: CN110407854B
Application number: CN201910766381.7A
Authority: CN
Inventors: 方海权; 李海军; 杨贵群; 王燕萍; 吴领军; 李庆龙; 杜曰雷; 张蕾; 胡邵京
Original assignee: Jacobio Pharmaceuticals Co Ltd
Current assignee: Jacobio Pharmaceuticals Co Ltd
Priority date: 2018-08-17
Filing date: 2019-08-19
Publication date: 2020-09-15
Anticipated expiration: 2039-08-19
Also published as: CN110407854A

Abstract

The present invention relates to novel tetracyclic compounds, wherein the tetracyclic compounds have the structure shown in formula (III), which are useful as bromodomain and extra-terminal (BET) inhibitors, their synthesis and their use in the treatment of diseases. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of preparing these compounds, and methods of treating diseases and conditions where inhibition of one or more BET bromodomains provides a benefit.

Description

Novel tetracyclic compounds

Technical Field

The present invention relates to certain novel tetracyclic compounds of formula (I) as bromodomain and extra-terminal (BET) inhibitors, their synthesis and their use in the treatment of disease. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of preparing these compounds, and methods of treating diseases and conditions where inhibition of one or more BET bromodomains provides a benefit.

Background

Several physiological processes may contribute to epigenetic regulation, including DNA methylation, non-coding RNA-mediated scaffold (scaffold alcohol ding) and complex formation, and histone modification. Histone modification is a process associated with post-translational covalent modification of histones, which significantly affects the ability of the associated DNA to be transcribed. Lysine acetylation is a post-translational modification that has a wide correlation with cellular signaling and disease biology. Enzymes that modulate the acetylation of lysine in histones are referred to as "writers" or Histone Acetyltransferases (HATs), and enzymes that modulate the deacetylation of lysine in histones are referred to as "erasers" or Histone Deacetylases (HDACs). The bromodomains (bromodomains, BRDs), the "reader" of epigenetic marks, specifically recognize the-N-acetyllysine (Kac) residue on the tail of histone proteins.

BRD is a conserved 110 amino acid domain consisting of four alpha-helices (α Z, α a, α B and α C) that contains the left-hand tract (bundlet) (s.mujtaba, l.zeng, MMZhou, Oncogene,2007(26), 5521-. The alpha-helices are joined together by two loop regions (ZA and BC) and form a surface that interacts with acetylated lysine in nucleosome histones (c.dhalluin, j.e.carlson, l.zengel, Nature,1999(399), 496). Based on structure/sequence similarity, there are 46 known bromodomain-containing proteins from humans, which span 8 families. Among them, the bromodomain and extra terminal domain (BET) recognize acetylated lysine residues in histones H3 and H4. The BET family, comprising four members of BRD2, BRD3, BRD4, and BRDT, share two N-terminal bromodomains and an additional C-terminal domain (ET), exhibits a high degree of sequence conservation. It has been reported that BRD2 and BRD3 bind to histones along with actively transcribed genes and may be involved in promoting transcriptional elongation (leroyetil, M alcohol. Cell,200830(1), 51-60). BRD4 appears to be involved in the recruitment of the positive transcriptional elongation factor complex (pTEF-I3), which plays an important role in RNA polymerase regulation of transcription and increased transcriptional export (Hargreavetotal, Cell,2009138(1): 1294145). Unlike the other three BET proteins that are ubiquitously expressed, BRDT expression is usually testis-specific (m.h. j ketone total, Genomics,1997(45), 529-. Binding of BET proteins to acetylated histones results in recruitment of BET proteins to enhancer and promoter regions of the gene for active transcription. Thus, they interact with coactivators, repressors, transcription factors and transcription mechanisms to form protein complexes and affect target gene transcription (a. deuctal, proc.natl.acad.sci, u.s.a.,2003(100), 8758-. BET proteins, while having a similar structure and generally enhancing transcription, regulate different processes based on their binding partners, which are often tissue-specific.

BET proteins are thought to mediate their role in disease pathogenesis and progression primarily through Super Enhancers (SEs) that localize to and drive their expression in pathologically-associated genes (m.a. daws ketotal, Nature,2011(478), 529-. In cancer, SEs are enriched in oncogenes such as MYC, RUNX1, FOSL2, CCND1, MCL1 and BCL2L1 (B.Chapuyeet al., cancer Cell,2013(24), 777-. Inhibition of BET proteins has become a promising target for the treatment of human diseases including virology, heart failure, inflammation, Central Nervous System (CNS) diseases and a variety of cancers (j.m. sahnietal, Pharmac alcohol res.,2017, 1-21; p.an and et., Cell,2013(154), 569-582; c.y.wangtal, trends biochem. sci,2015(40), 468-479; a.stathiset al, cancer recovery, 2017,8(1), 1-13). Small molecule BET inhibitors reported in clinical development include inhibitors of RVX-208, GSK-525762A, GSK2820151, OTX-015, CPI-0610, TEN-010/RO6870810, ABBV-075/ABBV-744, BI894999, BMS-986158, INCB054329/INCB057643, ZEN-3694, GS-5829, AZD5153, and Celgene. There is a need to produce other BET inhibitors with improved properties over existing BET inhibitors, e.g., improved activity, safety, pharmacokinetics, and/or pharmacokinetics.

Disclosure of Invention

In one aspect, there is provided a compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

x is selected from NR₅O or S;

ring a is a 5-membered heteroaromatic ring or a 5-membered amide ring containing 1,2 or 3 heteroatoms selected from N, O or S;

each R which may be attached to the same atom or different atoms₁、R₂And R₃Independently at each occurrence is selected from absent; hydrogen; deuterium; halogen; -CN; -OH; a carboxyl group; -NO₂；-C_1-6An alkyl group; -C_2-6An alkenyl group; -C_2-6An alkynyl group; -C_1-6An alkoxy group;

-NH₂；-NH(C_1-6alkyl groups); -N (C)_1-6Alkyl radical)₂；-SC_1-6An alkyl group; -SOC_1-6An alkyl group; -SO₂C_1-6An alkyl group; -SO₂NH₂；-SO₂NHC_1-6An alkyl group; -SO₂N(C_1-6Alkyl radical)₂；-COC_1-6An alkyl group; -CONH₂；-CONHC_1-6An alkyl group; -CON (C)_1-6Alkyl radical)₂；-P(O)H₂；-P(O)HC_1-6An alkyl group; -P (O) (C)_1-6Alkyl radical)₂(ii) a A 3-8 membered carbocyclic ring; a 3-8 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; 6-10 membered aryl; or 5-10 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O or S; and each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group; or

R₁And R₂、R₁And R₃Or R₂And R₃Together with the atoms to which they are attached individually or together form a 3-8 membered carbocyclic ring, or a 3-8 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

each R_aAnd R_bIndependently at each occurrence, is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group; each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0, 1,2,3, 4,5 or 6;

R₄is selected from

Each R_4aAnd R_4bIndependently at each occurrence is selected from hydrogen; deuterium; halogen; -CN; -OH; a carboxyl group; -NO₂；-C_1-6An alkyl group; -C_2-6An alkenyl group; -C_2-6An alkynyl group; -C_1-6An alkoxy group; -NH₂；-NH(C_1-6Alkyl groups); -N (C)_1-6Alkyl radical)₂；-SC_1-6An alkyl group; -SOC_1-6An alkyl group; -SO₂C_1-6An alkyl group; -SO₂NH₂；-SO₂NHC_1-6An alkyl group; -SO₂N(C_1-6Alkyl radical)₂；-COC_1-6An alkyl group; -CONH₂；-CONHC_1-6An alkyl group; -CON (C)_1-6Alkyl radical)₂；-P(O)H₂；-P(O)HC_1-6An alkyl group; -P (O)(C_1-6Alkyl radical)₂(ii) a A 3-8 membered carbocyclic ring; a 3-8 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; 6-10 membered aryl; or 5-10 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O or S; and each R_4aAnd R_4bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -NH₂-CN, carboxyl, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

R₅independently at each occurrence is selected from hydrogen; deuterium; halogen; -CN; -OH; a carboxyl group; -NO₂；-C_1-6An alkyl group; -C_2-6An alkenyl group; -C_2-6An alkynyl group; -C_1-6An alkoxy group;

-NH₂；-NH(C_1-6alkyl groups); -N (C)_1-6Alkyl radical)₂；-SC_1-6An alkyl group; -SOC_1-6An alkyl group; -SO₂C_1-6An alkyl group; -SO₂NH₂；-SO₂NHC_1-6An alkyl group; -SO₂N(C_1-6Alkyl radical)₂；-COC_1-6An alkyl group; -CONH₂；-CONHC_1-6An alkyl group; -CON (C)_1-6Alkyl radical)₂；-P(O)H₂；-P(O)HC_1-6An alkyl group; -P (O) (C)_1-6Alkyl radical)₂(ii) a A 3-8 membered carbocyclic ring; a 3-8 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; 6-10 membered aryl; or 5-10 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O or S; each R₅Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

each R_5aAnd R_5bIndependently at each occurrence, is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group; each R_5aAnd R_5bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

n is selected from 0, 1,2,3, 4,5 or 6;

W₁selected from hydrogen; deuterium; halogen; -NH₂(ii) a -CN; -OH; a carboxyl group; -NO₂；-C_1-6An alkyl group; -C_1-6An alkoxy group; -C_1-6alkylene-C_1-6An alkoxy group; 6-10 membered aryl; containing 1,2,3 or 4 substituents selected from N, O, S, SO or SO₂5-10 membered heteroaryl of the heteroatom of (a); containing 1,2,3 or 4 substituents selected from N, O, S, SO or SO₂3-8 membered heterocyclic ring of the heteroatom(s); or a 3-8 membered carbocyclic ring; and each W₁Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

W₂selected from hydrogen; deuterium; halogen; -NH₂(ii) a -CN; -OH; a carboxyl group; -NO₂；-C_1-6An alkyl group; -C_1-6An alkoxy group; 6-10 membered aryl; containing 1,2,3 or 4 substituents selected from N, O, S, SO or SO₂5-10 membered heteroaryl of the heteroatom of (a); containing 1,2,3 or 4 substituents selected from N, O, S, SO or SO₂3-8 membered heterocyclic ring of the heteroatom(s); or a 3-8 membered carbocyclic ring, and each W₂Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

z is selected from hydrogen, deuterium, halogen, -NH₂-CN, -OH, carboxyl, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group.

In some embodiments of formula I, wherein the compound is formula II:

in some embodiments of formula I, wherein the compound is formula III:

in some embodiments of formula I, formula II, or formula III, each R, wherein each R may be attached to the same atom or to different atoms₁、R₂And R₃Independently at each occurrence is selected from the group consisting of absent, hydrogen, deuterium, halogen, -CN, -OH, -C_1-6Alkyl, -C_1-6Alkoxy radical,

-NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-SO₂C_1-6Alkyl, -SO₂NH₂、-SO₂NHC_1-6Alkyl, -SO₂N(C_1-6Alkyl radical)₂、-COC_1-6Alkyl, -CONH₂、-CONHC_1-6Alkyl, -CON (C)_1-6Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C)_1-6Alkyl radical)₂(ii) a And each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group; or

R₁And R₂、R₁And R₃Or R₂And R₃Together with the atoms to which they are attached individually or together form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituentsAnd each substituent is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Carboxy, -NO₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br or-C_1-6An alkyl group;

m is selected from 0, 1,2,3, 4,5 or 6.

In some embodiments of formula I, formula II, or formula III, each R, wherein each R may be attached to the same atom or to different atoms₁、R₂And R₃Independently at each occurrence is selected from the group consisting of absent, hydrogen, deuterium, -F, -Cl, -Br, -CN, -OH, -C_1-3Alkyl, -C_1-3Alkoxy radical,

-NH₂、-NH(C_1-3Alkyl), -N (C)_1-3Alkyl radical)₂、-SO₂C_1-3Alkyl, -SO₂NH₂、-SO₂NHC_1-3Alkyl, -SO₂N(C_1-3Alkyl radical)₂、-COC_1-3Alkyl, -CONH₂、-CONHC_1-3Alkyl, -CON (C)_1-3Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C)_1-3Alkyl radical)₂(ii) a And each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂、-C_1-3Alkyl or-C_1-3An alkoxy group; or

R₁And R₂、R₁And R₃Or R₂And R₃Together with the atoms to which they are attached, individually or together, form a 3-membered carbocyclic ringA 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and each of said heterocyclic rings contains 1 or 2 heteroatoms selected from N or O at each occurrence; each said ring system being optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent being independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂、-C_1-3Alkyl or-C_1-3An alkoxy group;

each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-3An alkyl group; each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or-F;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, or formula III, each R, wherein each R may be attached to the same atom or to different atoms₁、R₂And R₃Independently at each occurrence is selected from the group consisting of absent, hydrogen, deuterium, -F, -Cl, -Br, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl, isopropyl,

-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂or-P (O) (CH)₃)(CH₂CH₃) (ii) a Each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; or

R₁And R₂、R₁And R₃Or R₂And R₃Together with the atoms to which they are attached individually or together form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and each of said heterocyclic rings, at each occurrence, comprises 1 heteroatom selected from N or O; each said ring system being optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent being independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, formula II, or formula III, wherein each R is₁、R₂And R₃Each occurrence of which may be attached to the same atom or to different atomsIndependently selected from the group consisting of absent, hydrogen, deuterium, -F, -Cl, -Br, -CN, -OH, -CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂Methoxy, ethoxy, propoxy, isopropoxy,

-NH₂、-NHCH₃、-NHCD₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CD₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂、-P(O)(CH₃)(CH₂CH₃) (ii) a Or

R₁And R₂、R₁And R₃Or R₂And R₃Together with the atoms to which they are attached individually or together form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and each of said heterocyclic rings contains at each occurrence 1 heteroatom selected from N or O.

In some embodiments of formula I, formula II, or formula III, wherein the compound is formula IV:

in some embodiments of formula I, formula II, formula III, or IV, wherein each R is₁、R₂And R₃Independently at each occurrence, selected from hydrogen, deuterium, -C_1-6Alkyl or

And each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -C_1-6Alkyl or-C_1-6An alkoxy group;

each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or IV, wherein R is₁Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

each R₂And R₃Selected from hydrogen, deuterium, -C_1-6Alkyl or

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; and each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or IV, wherein R is₁Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F;

R₂is selected from

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; and each R_aAnd R_bOptionally at each occurrence by 1,2.3, 4,5 or 6 substituents are optionally substituted, and each of said substituents is independently selected for each occurrence from deuterium or-F;

m is selected from 0 or 1;

R₃selected from hydrogen, deuterium or-C_1-6An alkyl group.

In some embodiments of formula I, formula II, formula III, or IV, wherein R is₁Is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F;

R₂is composed of

Each R_aAnd R_bIndependently at each occurrence is selected from-C_1-3An alkyl group; and each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or-F;

m is selected from 0 or 1;

R₃selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or IV, wherein R is₁Is selected from methyl; an ethyl group; propyl; isopropyl group; methyl deuterium or-F substituted; ethyl deuterium or-F substituted; deuterium propyl or-F substituted; or isopropyldeuterium or-F substituted;

R₂is

each R_aAnd R_bIndependently at each occurrence is selected from methyl; an ethyl group; propyl; isopropyl group; deuterium or-F substituted methyl; deuterium or-F substituted ethyl; deuterium or-F substituted propyl; or deuterium or-F substituted isopropyl;

m is selected from 0 or 1;

R₃selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or formula IV, wherein R is₁Is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂；

R₂Is composed of

Each R_aAnd R_bIndependently at each occurrence is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂；

R₃Selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or IV, wherein R is₁is-CH₃；

R₂Is composed of

R₃Is hydrogen.

In some embodiments of formula I, formula II, or formula III, wherein the compound is formula V:

in some embodiments of formula I, formula II, formula III, or formula V, wherein each R is R₁、R₂And R₃Independently at each occurrence, selected from hydrogen, deuterium, -C_1-6Alkyl or

each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium, -C_1-6An alkyl group; each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F;

each R₂And R₃Selected from hydrogen, deuterium, -C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

R₂is selected from

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium, -C_1-6An alkyl group; and each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or-F;

m is selected from 0 or 1;

R₃selected from hydrogen, deuterium or-C_1-6An alkyl group.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁Is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F;

R₂is composed of

m is selected from 0 or 1;

R₃selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁Is selected from methyl; an ethyl group; propyl; isopropyl group; deuterium or-F substituted methyl; deuterium or-F substituted ethyl; deuterium or-F substituted propyl; or deuterium or-F substituted isopropyl;

R₂is composed of

m is selected from 0 or 1;

R₃selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁Is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂；

R₂Is composed of

R₃Selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, or formula V, wherein R is₁is-CH₃；

R₂Is composed of

R₃Is hydrogen.

In some embodiments of formula I, formula II, or III, wherein the compound is formula VI:

in some embodiments of formula I, formula II, formula III, or formula VI, wherein each R is independently selected from the group consisting of₁And R₂Independently at each occurrence, selected from hydrogen, deuterium, -C_1-6Alkyl or

And each R₁And R₂Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -C_1-6Alkyl or-C_1-6An alkoxy group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Independently at each occurrenceIs selected from-C_1-6Alkyl radical, said C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

R₂selected from hydrogen, deuterium, -C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F;

R₂is selected from

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents each of which is as defined aboveThe substituents at each occurrence are independently selected from deuterium or-F;

R₂is selected from

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Is selected from methyl; an ethyl group; propyl; isopropyl group; deuterium or-F substituted methyl; deuterium or-F substituted ethyl; deuterium or-F substituted propyl; or deuterium or-F substituted isopropyl;

R₂is selected from

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂；

R₂Is selected from

Each R_aAnd R_bIndependently at each occurrence is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂。

In some embodiments of formula I, formula II, formula III, or VI, wherein R is₁Is selected from methyl;

R₂is selected from

In some embodiments of formula I, formula II, or formula III, wherein said compound is formula VII:

in some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁、R₂And R₃Independently at each occurrence, is selected from hydrogen, deuterium, -OH, -C_1-6Alkyl, -C_1-6Alkoxy or

And each R₁、R₂And R₃Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -C_1-6Alkyl or-C_1-6An alkoxy group; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -C_1-6Alkyl or-C_1-6An alkoxy group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen, -OH, or-C_1-6An alkyl group; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each of said heterocyclic rings containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH or-C_1-6An alkyl group;

R₃selected from hydrogen, deuterium, -OH, -C_1-6Alkyl or

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6Alkyl radical(ii) a And each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each of said heterocyclic rings containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

R₃is selected from-OH and-C_1-6Alkyl or

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; and each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or halogen;

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁And R₂Independently at each occurrence is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted by 1,2,3, 4,5 or 6 substituents or notSubstituted, and each of said substituents is independently selected for each occurrence from deuterium or-F; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each of said heterocyclic rings containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium or halogen;

R₃is selected from-OH and-C_1-3Alkyl, aryl, heteroaryl, and heteroaryl,

Each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-3An alkyl group; and each R_aAnd R_bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or-F.

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁And R₂Independently at each occurrence is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂(ii) a Or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, each of said heterocyclic rings at each occurrence comprises 1 heteroatom selected from N or O;

R₃selected from-OH,

-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂；

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁And R₂Is independently selected from-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂(ii) a Or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each of which heterocycles in each occurrence comprises 1 heteroatom selected from N or O;

R₃selected from-OH,

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂。

In some embodiments of formula I, formula II, formula III, or formula VII, wherein R is₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And

R₃selected from-OH,

-CH₃or-CH₂CH₃。

In some embodiments of formula I, formula II, formula III, or formula VII, wherein each R is R₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Is selected from-CH₃。

In some embodiments of formula I, formula II, or formula III, wherein said compound is formula VIII:

in some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁、R₂And R₃Independently at each occurrence, is selected from hydrogen, deuterium, -OH, -C_1-6Alkyl, -C_1-6Alkoxy or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted in each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is substituted on each occurrenceIndependently at occurrence, selected from deuterium, halogen, -OH, -C_1-6Alkyl or-C_1-6An alkoxy group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen, -OH or-C_1-6An alkyl group; or

R₃selected from hydrogen, deuterium, -OH, -C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium, halogen, or-C_1-6An alkyl group; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each of said heterocyclic rings containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems being optionally substituted or unsubstituted in each occurrence with 1,2,3, 4,5, or 6 substituents, and each of said substituents being independently selected from deuterium, halogen, or-C in each occurrence_1-6An alkyl group;

R₃is selected from-OH and-C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring5-or 6-membered heterocycles, each heterocycle containing 1 or 2 heteroatoms selected from N or O; and each said ring system is optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium or halogen;

R₃is selected from-OH and-C_1-3Alkyl, aryl, heteroaryl, and heteroaryl,

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁And R₂Independently at each occurrence is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂(ii) a Or

R₃selected from-OH,

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁And R₂Is independently selected from-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂(ii) a Or

R₃selected from-OH,

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂。

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein R is₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Selected from-OH,

-CH₃or-CH₂CH₃。

In some embodiments of formula I, formula II, formula III, or formula VIII, wherein each R is₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Is selected from-CH₃.

In some embodiments of formula I, formula II, or formula III, wherein the compound is formula IX:

in some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁、R₂And R₃Independently at each occurrence, is selected from hydrogen, deuterium, -OH, -C_1-6Alkyl, -C_1-6Alkoxy or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each said ring system is optionally substituted or unsubstituted in each occurrence with 1,2,3, 4,5 or 6 substituents, and each said substituent is independently selected in each occurrence from deuterium, halogen, -OH, -C_1-6Alkyl or-C_1-6An alkoxy group;

each R_aAnd R_bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; each R_aAnd R_bIs optionally at each occurrence1.2, 3, 4,5 or 6 substituents are optionally substituted and each substituent is independently selected for each occurrence from deuterium, halogen or-C_1-6An alkyl group;

m is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, and each substituent is independently selected at each occurrence from deuterium, halogen, -OH or-C_1-6An alkyl group; or

R₃selected from hydrogen, deuterium, -OH, -C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-6Alkyl of said-C_1-6Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5 or 6 substituents, andeach substituent is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group; or

R₃is selected from-OH and-C_1-6Alkyl or

m is selected from 0 or 1.

In some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁And R₂Independently at each occurrence is selected from-C_1-3Alkyl of said-C_1-3Alkyl is optionally substituted or unsubstituted with 1,2,3, 4,5, or 6 substituents, and each of said substituents is independently selected for each occurrence from deuterium or-F; or

R₁And R₂Together with the carbon atom to which they are both attached form a 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems being optionally substituted or unsubstituted in each occurrence with 1,2,3, 4,5, or 6 substituents, and each of said substituents being independently selected for each occurrence from deuterium or halogen;

R₃is selected from-OH and-C_1-3Alkyl, aryl, heteroaryl, and heteroaryl,

In some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁And R₂Independently at each occurrence is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂or-CH (CD)₃)₂(ii) a Or

R₃selected from-OH,

In some embodiments of formula I, formula II, formula III, or formula IX, wherein each R is₁And R₂Is independently selected from-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂(ii) a Or

R₃selected from-OH,

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃or-CH (CH)₃)₂。

In some embodiments of formula I, formula II, formula III, or formula IX, wherein R is₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Selected from-OH,

-CH₃or-CH₂CH₃。

In the formula I, formula II, formula III or formula IXIn some embodiments, wherein each R is₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Is selected from-CH₃。

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence, is selected from hydrogen, deuterium, -CN, -OH, -C_1-6Alkyl, -C_1-6Alkoxy, -NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-SO₂C_1-6Alkyl, -SO₂NH₂、-SO₂NHC_1-6Alkyl, -SO₂N(C_1-6Alkyl radical)₂、-COC_1-6Alkyl, -CONH₂、-CONHC_1-6Alkyl, -CON (C)_1-6Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C)_1-6Alkyl radical)₂(ii) a And each R_4aAnd R_4bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂、-C_1-6Alkyl or-C_1-6An alkoxy group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence, is selected from hydrogen, deuterium, halogen, -CN, -OH, -C_1-3Alkyl, -C_1-3Alkoxy, -NH₂、-NH(C_1-3Alkyl), -N (C)_1-3Alkyl radical)₂、-SO₂C_1-3Alkyl, -SO₂NH₂、-SO₂NHC_1-3Alkyl, -SO₂N(C_1-3Alkyl radical)₂、-COC_1-3Alkyl, -CONH₂、-CONHC_1-3Alkyl, -CON (C)_1-3Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C)_1-3Alkyl radical)₂(ii) a And each R_4aAnd R_4bOptionally 1,2,3, 4,5 or 6 at each occurrenceThe substituents being substituted or unsubstituted and each of said substituents being independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂、-C_1-3Alkyl or-C_1-3An alkoxy group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence, is selected from the group consisting of hydrogen, deuterium, -F, -Cl, -Br, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂or-P (O) (CH)₃)(CH₂CH₃) (ii) a Each R_4aAnd R_4bOptionally substituted at each occurrence with 1,2,3, 4,5 or 6 substituentsSubstituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence is selected from hydrogen, deuterium, -F, -Cl, -Br, -CN, -OH, -CH₃、-CD₃、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CD₃、-CH₂CH₂CF₃、-CH(CH₃)₂、-CH(CD₃)₂、-CH(CF₃)₂Methoxy, ethoxy, propoxy, isopropoxy, -NH₂、-NHCH₃、-NHCD₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CD₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂or-P (O) (CH)₃)(CH₂CH₃)。

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence is selected from-C_1-6An alkyl group; or deuterium or-F substituted-C_1-6An alkyl group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence is selected from-C_1-3An alkyl group; or deuterium or-F substituted-C_1-3An alkyl group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence is selected from methyl; an ethyl group; propyl; isopropyl group; deuterium or-F substituted methyl; deuterium or-F substituted ethyl; deuterium or-F substituted propyl; or deuterium or-F substituted isopropyl.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein each R is independently selected from the group consisting of_4aAnd R_4bIndependently at each occurrence is selected from methyl or deuterium substituted methyl.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein R is₄Selected from:

in some embodiments of formula I, wherein R is₅Independently at each occurrence, is selected from hydrogen, deuterium, -CN, -OH, -C_1-6Alkyl, -C_1-6Alkoxy radical,

-SO₂C_1-6Alkyl, -SO₂NH₂、-SO₂NHC_1-6Alkyl, -SO₂N(C_1-6Alkyl radical)₂、-COC_1-6Alkyl, -CONH₂、-CONHC_1-6Alkyl, -CON (C)_1-6Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C)_1-6Alkyl radical)₂(ii) a Each R₅Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂、-C_1-6Alkyl or-C_1-6An alkoxy group;

each R_5aAnd R_5bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-6An alkyl group; each R_5aAnd R_5bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-6An alkyl group;

n is selected from 0, 1,2,3, 4,5 or 6.

In some embodiments of formula I, wherein R is₅Independently at each occurrence, is selected from hydrogen, deuterium, -CN, -OH, -C_1-3Alkyl, -C_1-3Alkoxy radical,

-SO₂C_1-3Alkyl, -SO₂NH₂、-SO₂NHC_1-3Alkyl, -SO₂N(C_1-3Alkyl radical)₂、-COC_1-3Alkyl, -CONH₂、-CONHC_1-3Alkyl, -CON (C)_1-3Alkyl radical)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C)_1-3Alkyl radical)₂(ii) a Each R₅Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH₂、-C_1-3Alkyl or-C_1-3An alkoxy group;

each R_5aAnd R_5bIndependently at each occurrence, selected from hydrogen, deuterium or-C_1-3An alkyl group; each R_5aAnd R_5bOptionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or-C_1-3An alkyl group;

n is selected from 0, 1,2,3 or 4.

In some embodiments of formula I, wherein R is₅Independently at each occurrence is selected from the group consisting of hydrogen, deuterium, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, o,

-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂or-P (O) (CH)₃)(CH₂CH₃) (ii) a Each R₅Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, wherein R is₅Independently at each occurrence is selected from hydrogen, deuterium, -CN, -OH, -CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂Methoxy, ethoxy, propoxy, isopropoxy,

-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂or-P (O) (CH)₃)(CH₂CH₃)。

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from hydrogen; deuterium; -F; -Cl; -NH₂(ii) a -CN; -OH; a carboxyl group; -C_1-6An alkyl group; -C_1-6An alkoxy group; -C_1-3alkylene-C_1-3An alkoxy group; a phenyl group; a 5-membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N or O; 6-membered heteroaryl containing 1,2 or 3 heteroatoms selected from N or O; a 3-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O; a 4-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O; a 5-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O; a 6 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O; a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; or a 6 membered carbocyclic ring; and each W₁Optionally substituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is selected at each occurrence from deuterium, halogen-OH, -CN, -NH₂、-C_1-3Alkyl or-C_1-3An alkoxy group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from hydrogen; deuterium; -F; -Cl; -NH₂(ii) a -CN; -OH; a methyl group; an ethyl group; propyl; isopropyl group;

a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group;

-CH₂OCH₃；-CH₂CH₂OCH₃；-CH₂CH₂OCH₂CH₃(ii) a A phenyl group; 5-membered heteroaryl contains 1 or 2 heteroatoms selected from N or O; 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N or O; 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; the 6-membered heterocycle contains 1 or 2 heteroatoms selected from N or O; a 5-membered carbocyclic ring; or a 6 membered carbocyclic ring; and each W₁Optionally substituted at each occurrence with 1,2,3, 4,5 or 6 substituents, and each of said substituents is selected at each occurrence from deuterium, -F, -Cl, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from hydrogen; deuterium; -F; a methyl group; an ethyl group; propyl; isopropyl group；

A methoxy group; -CH₂OCH₃；-CH₂CH₂OCH₃(ii) a 6-membered heteroaryl contains 1 or 2 heteroatoms selected from N or O; 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; the 6-membered heterocycle contains 1 or 2 heteroatoms selected from N or O; a 5-membered carbocyclic ring; or a 6 membered carbocyclic ring; and each W₁Optionally substituted or unsubstituted at each occurrence with deuterium or-F.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from hydrogen, deuterium, -F, -CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂、

Methoxy, -CH₂OCH₃、-CH₂CH₂OCH₃、

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from-F substituted-C_1-6Alkyl or a 6-membered heterocyclic ring containing 1 heteroatom selected from O.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Selected from-F substituted-C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₁Is selected from-CH₂CH₂CF₃Or

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₂Selected from hydrogen; deuterium; -F; -Cl; -NH₂(ii) a -CN; -OH; a carboxyl group; -C_1-3An alkyl group; -C_1-3An alkoxy group; a phenyl group; a naphthyl group; a 5 membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; a 6 membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; a 7-membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; an 8-membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; a 9-membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; 10-membered heteroaryl or S containing 1,2 or 3 heteroatoms selected from N or O; a 3-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; a 4-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; a 5-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; a 6 membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O or S; a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; or a 6 membered carbocyclic ring; and each W₂At each occurrence optionallySubstituted or unsubstituted with 1,2,3, 4 or 5 substituents, and each of said substituents is selected at each occurrence from deuterium, halogen, -OH, -CN, -NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₂Selected from hydrogen; deuterium; a phenyl group; a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S; or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and each W₂Optionally substituted or unsubstituted at each occurrence with 1,2,3, 4 or 5 substituents, and each of said substituents at each occurrence is selected from deuterium, -F, -Cl, -Br, -NH₂CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₂Is selected from phenyl; a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S; or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and each W₂Optionally substituted or unsubstituted at each occurrence with 1,2 or 3 substituents, and each said substituent at each occurrence is selected from the group consisting of-F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₂Is selected from

And each W₂Optionally substituted or unsubstituted at each occurrence with 1,2 or 3 substituents, andeach substituent at each occurrence is selected from-F, -Cl, methyl, or methoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein W is₂Independently selected from:

in some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein Z is selected from hydrogen, deuterium, -F, -Cl, -OH, -C_1-3Alkyl or-C_1-3An alkoxy group.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein Z is selected from hydrogen, deuterium, -F, -Cl, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein Z is selected from hydrogen or deuterium.

In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein Z is selected from hydrogen.

In certain embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, or formula IX, wherein said

Selected from:

and each is

Optionally substituted or unsubstituted at each occurrence with 1,2 or 3 substituents, and each said substituent at each occurrence is selected from the group consisting of-F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

Selected from:

and each is

Optionally substituted or unsubstituted at each occurrence with a 1,2 or 3 substituent, and each said substituent at each occurrence is selected from-F, -Cl, methyl or methoxy.

In some embodiments of formula I, wherein the compound is selected from:

in another aspect, there is provided a pharmaceutical composition comprising at least one compound of formula I of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

In some embodiments of the pharmaceutical composition, wherein the weight ratio of the compound to the excipient ranges from about 0.0001 to about 10.

In another aspect, the present invention provides said compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of a disease or condition associated with a bromodomain protein.

In preferred embodiments, the disease or disorder associated with bromodomain proteins is selected from a solid tumor (solid tumor) and/or a blood tumor (blood tumor).

In preferred embodiments, the solid tumor is selected from lung cancer (lung cancer), gastrointestinal cancer (gastroenterological cancer), colon cancer (colon cancer), rectal cancer (rectal cancer), colorectal cancer (colorectal cancer), and/or ovarian cancer (ovarian cancer); the hematological tumor (blood tumor) is selected from myeloma (myeloma) and/or leukemia (leukamia).

In preferred embodiments, the lung cancer comprises non-small cell lung cancer (non-small cell lung cancer) and/or small cell lung cancer (small cell lung cancer); the gastrointestinal tumor (gastroenterological cancer) comprises esophageal cancer (esophageal cancer); the leukemia (leukemia) includes Acute Myelogenous Leukemia (AML) and/or Acute Lymphocytic Leukemia (ALL); the myeloma (myeloma) includes multiple myeloma (multiplyeloma).

Definition of

The term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine. Preferred halo groups include F, Cl and Br.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent alkyl groups having a straight or branched chain. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-methylCyclopentyl and cyclohexyl. Similarly, C_1-6C in alkyl_1-6Is defined as a group having 1,2,3, 4,5 or 6 carbon atoms in a linear or branched arrangement.

The term "alkylene" refers to a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH)₂-), ethylene (i.e. -CH₂-CH₂-or-CH (CH)₃) -) and propylene (i.e., -CH₂-CH₂-CH₂-、-CH(-CH₂-CH₃) -or-CH₂-CH(CH₃)-)。

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically 2 to 20 carbon atoms in length. For example, "C_2-6Alkenyl "contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "C_2-6Alkynyl "contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-to 10-membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

The term "heterocycle" as used herein, unless otherwise specified, refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to eight membered and is fully saturated or has one or more unsaturations. The present definition includes a plurality of degrees of substitution, preferably one, two or three degrees of substitution. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothienyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazole.

The term "heteroaryl" as used herein, unless otherwise indicated, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. The polycyclic heteroaryl ring may contain a fused, spiro, or bridged ring combination, e.g., bicyclic heteroaryl is polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thienyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiophenyl, benzothiadiazolyl, benzotriazolyladenourinyl, quinolinyl, or isoquinolinyl.

The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which a cycloalkyl group may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "oxo" means that oxygen is formed together with the carbon atom to which it is attached

A group.

The term "carboxy" refers to the group C (O) OH.

The term "P (O)" refers to the group P ═ O.

The term "substituted" refers to compounds in which at least one hydrogen atom is replaced with a non-hydrogen group, so long as the normal chemical bond is maintained and the result of the substitution is site-stable.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients and processes for preparing the compounds of the invention are also part of the invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some compounds may form solvates (i.e., hydrates) with water or common organic solvents, and such solvates are also included within the scope of the present invention.

The compounds of the invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acid/anion salts generally take the form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclamic, salicylic, saccharin or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc salts.

The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs are functional derivatives of the compounds that are readily converted in vivo to the desired compounds. Thus, in the methods of treatment of the present invention, the term "administering" shall include treating the various conditions described with a specifically disclosed compound, or with a compound that may not be specifically disclosed, but which converts to the specific compound in vivo upon administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "prodrug Design" ("Design of Prodrugs", ed.h. bundgaard, Elsevier, 1985.).

The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of substituents or variables at other positions in the molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide chemically stable compounds, and can be readily synthesized by techniques known in the art and by the methods set forth herein.

The invention includes that the compounds may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers and optical isomers. The present invention includes all such possible enantiomers, diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. The products of these processes may be mixtures of stereoisomers during the course of the synthetic procedures used to prepare these compounds, or during the course of using racemization or epimerization procedures known to those skilled in the art.

The present invention is intended to include all atomic isotopes present in the compounds of the invention. Isotopes are atoms having the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as¹H (hydrogen) is selected from the group consisting of,²h (deuterium) and³h (tritium). They are also commonly denoted as D (deuterium) and T (tritium). In this application, CD₃Represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include¹³C and¹⁴C. isotopically-labelled compounds of the inventionThe compounds may generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using appropriate isotopically-labelled reagents in place of the non-labelled reagents.

When tautomers of compounds of formula I exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

When the compounds of formula I and pharmaceutically acceptable salts thereof are present in solvate or polymorphic form, the present invention includes any possible solvates and polymorphs. The type of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, or the like can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of formula I are for pharmaceutical use, they are preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% in weight by weight)).

The pharmaceutical composition of the present invention comprises a compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Although the most suitable route in any given case will depend on the particular host, and the nature and severity of the condition for which the active ingredient is being administered to treat it, the compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by formula I of the present invention or prodrugs or metabolites thereof or pharmaceutically acceptable salts thereof may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for the route of administration, e.g., oral or parenteral (including intravenous) routes of administration. Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, for example, capsules, cachets (cachets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in powder form, in particulate form, in solution form, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil emulsion. In addition to the above-described conventional dosage forms, the compound represented by formula I or a pharmaceutically acceptable salt thereof may also be administered via a controlled release device and/or a delivery device. The composition may be prepared by any pharmaceutical method. Generally, these methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more required ingredients. Generally, compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired pattern.

Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt. The compound of formula I or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition together with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units wherein solid pharmaceutical carriers are employed. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.

Tablets containing the composition of the invention may be prepared by compression or moulding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of active ingredient, and each cachet or capsule preferably contains from about 0.05mg to about 5g of active ingredient. For example, formulations for oral administration to humans may contain from about 0.5mg to about 5g of the active agent, in admixture with a suitable and convenient amount of carrier material which may comprise from about 0.05% to about 95% of the total composition. Unit dosage forms typically contain from about 0.01mg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000 mg.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the unwanted growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid to facilitate injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, it is preferable that preservation should be prevented from contamination by microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders and the like. In addition, the composition may be in a form suitable for use in a transdermal device. Using the compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, these formulations can be prepared by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.

In addition to the above-mentioned carrier ingredients, the above-mentioned pharmaceutical preparations may suitably comprise one or more additional carrier ingredients, such as diluents, buffers, flavouring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.

Typically, dosage levels of about 0.001mg/kg to about 150mg/kg body weight per day are useful for treating the above conditions, or about 0.05mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the Central Nervous System (CNS) can be effectively treated by administering about 0.001 to 50mg of the compound per kilogram of body weight per day, or about 0.05mg to about 3.5g per patient per day.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

These and other aspects will become apparent from the following written description of the invention.

Abbreviations

AIBN 2,2' -azobisisobutyronitrile LC-MS liquid chromatography-mass spectrometry

LDA lithium diisopropylamide in aq water

Bn benzyl LiHMDS lithium bis (trimethylsilyl) amide

Boc tert-butoxycarbonylMe methane

Boc₂O-Dicarbonic acid di-tert-butyl ester MeI methyl iodide

CuI cuprous iodide MeCN acetonitrile

DCM dichloromethane MeOH methanol

DIAD azodicarbonic acid diisopropyl ester min

DIEA diisopropylamine mL mL

DMAP 4-dimethylaminopyridine mmol

DMF dimethylformamide MTBE methyl tert-butyl ether

DMSO dimethyl sulfoxide NaHCO₃Sodium bicarbonate

DPPE 1, 2-bis (diphenylphosphino) ethane NaHMDS sodium bis (trimethylsilyl) amide

dtbpy iodine (4, 4-di-tert-butyl-2, 2-bipyridine) methyl palladium (II) NBS N-bromosuccinimide

equiv. n-BuLi n-butyllithium

Et₃N Triethylamine NH₄OAc ammonium acetate

Et₂O diethyl ether Pd (OAc)2 palladium acetate

EtOAc ethyl acetate Pd (dppf) Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

EtOH ethanol Prep-TLC preparative thin layer chromatography

g SEM trimethylsilyl ethoxymethyl

h or hr SEM-Cl 2- (trimethylsilyl) ethoxymethyl chloride

HBPin pinacolborane RT retention time

HPLC high pressure liquid chromatography r.t. Room temperature

iPrOH isopropanol TEA Triethylamine

KOtBu potassium tert-butoxide THF tetrahydrofuran

Preparation method

The compounds of the present invention can be synthesized by a person skilled in the art of organic synthesis using several methods as described below and synthetic methods well known in the art of organic synthetic chemistry or variations of the above methods known to a person skilled in the art. The preferred method is not limited to the method described below. The documents cited herein are incorporated by reference in their entirety.

The synthetic methods described below are intended to illustrate the invention, not to limit its subject matter and the scope of the compounds claimed in these examples. Where the starting compounds for the preparation are not described, they are commercially available or can be prepared analogously to known compounds or the methods described herein. Substances described in the literature can be prepared according to published synthetic methods.

The compounds of formula I can be prepared by reference to the methods illustrated in the following schemes. As shown herein, the target compound is a product having the same structural formula as described for formula I. It will be appreciated that any compound of formula I may be prepared by selecting reagents with appropriate substitutions. The solvent, temperature, pressure and other reaction conditions can be readily selected by those skilled in the art. The protecting Groups were manipulated according to standard methods of organic synthesis (T.W.Green and P.G.M.Wuts (1999) Protective Groups in organic Synthesis, 3 rd edition, John Wiley & Sons). These groups are removed at some stage of the compound synthesis using methods apparent to those skilled in the art.

Scheme 1

A general synthetic route to the compounds of the present invention is depicted in scheme 1, wherein R is depicted₁、R₂、R₃、R₄、W₁And W₂Substituents are described in the preceding text or are functional groups that can be converted into the desired final substituent. L is a leaving group such as halogen. M is a suitable coupling ligand, for example a boronic acid, boronic ester or stannane. As shown in scheme 1, a Suzuki reaction between the intermediate, whose synthesis is illustrated in scheme 2 to scheme 5, and a halogen substituted pyridine, such as but not limited to 2, 5-dibromo-3-nitropyridine (1), can yield functionalized pyridine (2). Reductive cyclization of (2) with Cadogan can afford functionalized tetracyclic compounds of formula (3) at elevated temperatures such as, but not limited to, 150 ℃ in the presence of a phosphine reagent such as, but not limited to, 1, 2-bis (diphenylphosphino) ethane (DPPE) and a solvent such as, but not limited to, 1, 2-dichlorobenzene. Mitsunobu coupling reaction of (3) with an alkylating agent (4) using reagents such as, but not limited to, triphenylphosphine and diisopropyl azodicarboxylate (DIAD) provides (5). Using Suzuku or Stille reaction conditions, (5) suitable coupling to (6) (in addition M is a suitable coupling ligand, such as a boronic acid, boron ester or stannane) can produceA chemical compound (7), wherein the chemical compound (7) has the same structure shown in the general formula (I) or can be further converted into a final compound shown in the general formula (I). If compound (7) has a functional group (such as, but not limited to, an ethyl ester), the use of a reagent (such as, but not limited to, MeMgBr) can provide a compound of formula (I). If compound (7) has a protecting group (such as but not limited to SEM), it can be deprotected and then further functionalized to provide a compound of general formula (I).

As shown in scheme 2, a generic intermediate can be obtained.

Scheme 2

Reaction of compound (8) and ethyl 2-azidoacetate in a solvent such as, but not limited to, EtOH using NaOEt provides a compound of formula (9). The compound of formula (9) is converted to the compound of formula (10) in a solvent such as, but not limited to, anhydrous toluene at elevated temperature (e.g., at about 110 ℃). (10) with a haloalkane R in the presence of a base such as but not limited to NaH in a solvent such as but not limited to DMF₁N-alkylation of-hal (such as but not limited to MeI) or a protecting reagent (SEM-Cl) provides the compound of formula (11). Treatment of (11) with HBPin in the presence of bis (1, 5-cyclooctadiene) dimethoxydiidium and 4,4 '-di-tert-butyl-2, 2' -bipyridine at elevated temperature (e.g., 70 ℃) in a solvent (such as, but not limited to, THF) affords the intermediate.

Alternatively, as shown in scheme 3, a generic intermediate can be synthesized.

Scheme 3

Reaction of compound (12) and ethyl 2-azidoacetate in a solvent such as, but not limited to, EtOH using NaOEt provides a compound of formula (13). The compound of formula (13) is converted to the compound of formula (14) in a solvent such as, but not limited to, anhydrous toluene at elevated temperature (e.g., at about 110 ℃). In the presence of a base (such as, but not limited to NaH), dissolvingIn an agent such as but not limited to DMF, (14) with a haloalkane R₁N-alkylation of-hal (such as but not limited to MeI) or a protecting reagent (SEM-Cl) provides the compound of formula (15). Treatment of (15) with HBPin in the presence of bis (1, 5-cyclooctadiene) dimethoxydiidium and 4,4 '-di-tert-butyl-2, 2' -bipyridine at elevated temperature (e.g., 70 ℃) in a solvent (such as, but not limited to, THF) affords the intermediate.

Alternatively, as shown in scheme 4, an intermediate of general formula can be synthesized:

scheme 4

At elevated temperatures (such as, but not limited to, 85 ℃), N₂Next, methyl 3-methylthiophene-2-carboxylate (16) is treated in a solvent such as, but not limited to, acetonitrile in the presence of NBS and AIBN to provide (17). At elevated temperature (such as but not limited to 80 ℃), in a base (such as but not limited to K)₂CO₃) Using a reagent NH in the presence of a solvent such as, but not limited to, MeOH₂R₃(18) Treatment, (17) conversion to a compound of formula (19). Treatment of (19) in DMF solvent in the presence of a base such as but not limited to NaH and subsequent addition of an alkyl halide R₁-hal or R₂Hal (e.g. MeI) provides compounds of formula (20). The reaction of (20) with a strong base (such as but not limited to LDA) followed by triisopropyl borate in a solvent (such as but not limited to THF) at-78 ℃ can provide the intermediates of the general formula.

Alternatively, as shown in scheme 5, a generic intermediate can be synthesized.

Scheme 5

Coupling reactions between 2-nitrothiophene (21) and ethyl 2-chloroacetate (22) using a base such as but not limited to t-BuONa in a solvent such as but not limited to THF at-60 ℃ to room temperature can provide compound (23). At elevated temperatures (e.g. 110 ℃ C.) in dioxane and H₂Combinations of O (5:1, v: v)In a solvent of iron powder and FeSO₄.7H₂NO of Compound (23) in the Presence of O₂The reduction of the functional group provides the compound (24). (24) and AlMe in a solvent such as but not limited to THF at between-80 deg.C and room temperature₃The reaction of (4) can provide the compound (25). With an alkyl halide R in a solvent such as but not limited to DMF in the presence of a base such as but not limited to NaH₃N-alkylation of (25) with hal (such as but not limited to MeI), or with (25) as Protecting Group (PG) such as but not limited to SEM-Cl can provide compounds of formula (26). Treatment of (26) with a strong base (such as but not limited to NaH) in a solvent (such as but not limited to THF) at 0 deg.C, followed by addition of alkyl halide R₁-hal or R₂Hal (such as but not limited to methyl iodide and ethyl iodide) can provide compounds of formula (27). Between-20 ℃ and room temperature in a solvent such as, but not limited to DCM in [ Ir (COD) water (OMe)]₂And dtbpy, the reaction of HBPin with compound (27) provides the intermediate.

Example 1

(S) -2- (7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrole [2 ", 3": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-2-yl) propan-2-ol ("Compound 1")

Step 1 (Z) -2-azido-3- (thien-2-yl) acrylic acid ethyl ester

In N₂To a solution of thiophene-2-carbaldehyde (29.7g,0.16mol) in EtOH (220mL) was added ethyl 2-azidoacetate (40.32g,0.31 mol). To this mixture was added dropwise a fresh solution of NaOEt (prepared from Na (8.90g,0.39mol) and absolute ethanol (350mL) at 0 ℃ from-10 ℃ to-5 ℃). The resulting suspension was stirred for 2 hours at a temperature between-5 ℃ and 0 ℃. The reaction mixture was quenched with cold saturated ammonium chloride solution to adjust its pH to about 8. The precipitated solid was filtered, washed with cold water (50mL) and dried under vacuum to yield 3.56g of crude product. The crude product was purified by silica gel chromatography, eluting with 0-5% EtOAc in hexane to afford the title compoundCompound (5.67g, 12% yield).

Step 2-4H-Thiophen [3,2-b ] pyrrole-5-carboxylic acid ethyl ester

Ethyl (Z) -2-azido-3- (thiophen-2-yl) acrylate (5.62g,25.2mmol) was dissolved in anhydrous toluene (60mL) the mixture was stirred at 110 ℃ for 1H then the reaction mixture was poured into water and extracted with EtOAc (2 ×). the combined extracts were washed with brine (2 ×), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexane to give the title compound (4.34g,22.2mmol, 88% yield). LC-MS [ M + H]⁺＝196。

Step 3 4-methyl-4H-thieno [3,2-b ] pyrrole-5-carboxylic acid ethyl ester

To 4H-thiophene [3,2-b ] at room temperature]To a solution of ethyl pyrrole-5-carboxylate (4.24g,21.7mmol) in DMF (20mL) was added K₂CO₃(7.82g,56.6mmol), followed by dropwise addition of methyl iodide (2.52g,17.8 mmol). the mixture was stirred at room temperature for 2H, the reaction was quenched with water and extracted with EtOAc (3 ×), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexane to give the title compound (3.96g,18.9mmol, 87% yield)]⁺＝210。

Step 4 Ethyl 4-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H-thieno [3,2-b ] pyrrole-5-carboxylate

In N₂To 4-methyl-4H-thiophene [3,2-b ]]To a solution of ethyl pyrrole-5-carboxylate (720mg,3.44mmol) in THF (15mL) were added bis (1, 5-cyclooctadiene) dimethoxydiiridium (126mg,0.19mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (285mg,1.06 mmol). Then HBPin (2.25g,17.6mmol) was added between-10 deg.C and-5 deg.C. Degassing the mixture and charging N₂And the process was repeated 3 times. The resulting mixture was stirred at 75 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give a black oil, which was used directly in the next reaction without purification. LC-MS [ M + H ]]⁺＝336。

Step 5 Ethyl 2- (5-bromo-3-nitropyridin-2-yl) -4-methyl-4H-thieno [3,2-b ] pyrrole-5-carboxylate

To the above crude compound 4-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H-thiophene [3,2-b ]]To a solution of ethyl pyrrole-5-carboxylate in water (7mL) and THF (21mL) were added 2, 5-dibromo-3-nitropyridine (1.18g,4.19mmol) and K₃PO₄(2.21g,10.41 mmol). Using N₂The mixture is degassed by flowing and then in N₂Pd (PPh) was added dropwise thereto₃)₄(410mg,0.35 mmol.) the reaction mixture was refluxed overnight, the reaction mixture was extracted with EtOAc (2 × 100mL), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexane to afford the title compound (820mg, 58% yield)]⁺＝410。

Step 6 Ethyl 7-bromo-1-methyl-1, 9-dihydropyrrolo [2 ", 3": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

In N₂Next, 2- (5-bromo-3-nitropyridin-2-yl) -4-methyl-4H-thiophene [3,2-b ] in 1, 2-dichlorobenzene (20mL)]A mixture of ethyl pyrrole-5-carboxylate (770mg,1.88mmol) and DPPE (1.89g,4.74mmol) was heated to 150 ℃ and stirred for 2 h. The reaction mixture was then cooled to room temperature. Most of the solvent was removed on a rotary evaporator. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in DCM to give the title compound (280mg, 39% yield). LC-MS [ M + H ]]⁺＝378。

Step 7 (S) -ethyl 7-bromo-1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrolo [2 ", 3": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

To 7-bromo-1-methyl-1, 9-dihydropyrrole [2 ", 3": 4',5' at room temperature ']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Ethyl pyridine-2-carboxylate (250mg,0.66mmol), (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (260mg,1.37mmol) and triphenylphosphine (526mg,2.00mmol) in dry toluene (10mL) was added dropwise diisopropyl azodicarboxylate (412mg,2.04 mmol). The resulting solution was refluxed for 2H, cooled to room temperature, the reaction was quenched with water (20mL) and extracted with EtOAc (3 × 30 mL). the combined organic phases were washed with brine, dried over anhydrous sodium sulfateThe filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in hexanes to give the title compound (110mg, 30% yield). LC-MS: [ M + H]⁺＝552。

Step 8 (S) -ethyl 7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrole [2',3': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridine-2-carboxylate

N₂To (S) -7-bromo-1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrole [2 ", 3": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]To a solution of pyridine-2-carboxylic acid ethyl ester (110mg,0.20mmol) in 1, 4-dioxane (5mL) was added 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (289mg,0.75mmol), PdCl₂(PPh₃)₂(21mg,0.030mmol) and DIEA (85mg,0.66 mmol). Using N₂The reaction mixture was degassed, sealed and stirred at 125 ℃ overnight, the reaction mixture was cooled to room temperature, poured into water (10mL) and extracted with EtOAc (3 × 15mL), the combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate, the filtrate was collected and concentrated under reduced pressure, the crude product was purified by preparative HPLC eluting with a gradient of 0% to 5% MeOH in EtOAc to afford the title compound (80mg, 70% yield)]⁺＝569。

Step 9 (S) -2- (7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrole [2 ", 3": 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2-yl) propan-2-ol

N₂Then, (S) -7- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -1-methyl-9- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 9-dihydropyrrole [2',3': 4',5' at the temperature of between-10 ℃ and-5℃ ']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Ethyl pyridine-2-carboxylate (60mg,0.10mmol) in THF (5mL) was added methylmagnesium bromide (2.5mL) dropwise, the mixture warmed to room temperature and stirred for 2h, the reaction quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3 × 30mL), the combined organic layers were washed with brine (2 ×), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressureLC purification eluting with a gradient of 0% to 5% MeOH in DCM afforded the title compound (29mg, 52% yield). LC-MS [ M + H ]]⁺＝555.¹H-NMR(400MHz,DMSO-d₆)8.34(s,1H),8.02(s,1H),7.65(d,J＝8.0Hz,2H),7.33(m,3H),6.53(s,1H),5.91(d,J＝12.0Hz,1H),4.48(s,3H),3.89(d,J＝4.0Hz,1H),3.85(s,3H),3.77(d,J＝8.0Hz,1H),3.51-3.48(m,2H),3.29-3.21(m,1H),2.18(s,3H),1.88(d,J＝12.0Hz,1H),1.65(s,6H),1.51-1.49(m,1H),1.43–1.33(m,1H),0.99(d,J＝12.0Hz,1H)。

Example 2

(S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-2-yl) propan-2-ol ("Compound 2")

Step 1 (Z) -2-azido-3- (thien-3-yl) acrylic acid ethyl ester

N₂Next, between-10 ℃ and-5 ℃, to a solution of thiophene-3-carbaldehyde (4.95g,44.14mol) and ethyl 2-azidoacetate (8.61g,66.68mol) in EtOH (50mL) was added dropwise a freshly prepared NaOEt solution (Na (2.41g,104.78mol) suspended in absolute ethanol (50mL) at 0 ℃. the resulting suspension was stirred between-5 ℃ and 0 ℃ for 2 h. the reaction mixture was quenched with cold saturated aqueous ammonium chloride solution and its pH was adjusted to about 8. the mixture was extracted with EtOAc (3 × 300 mL.) the combined organic phases were washed with brine (100mL), dried over anhydrous sodium sulfate residue, filtered and concentrated under reduced pressure.

Step 2 6H-Thiophen [2,3-b ] pyrrole-5-carboxylic acid ethyl ester

Ethyl (Z) -2-azido-3- (thien-3-yl) acrylate (4.16g,18.63mmol) was dissolved in anhydrous p-xylene (10 mL). The mixture was stirred at 145 ℃ for 3 h. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexanes to give the title compound (1.77g, 48% yield). LC-MS [ M + H ]]⁺＝196。¹H-NMR(400MHz,DMSO-d₆)12.2(s,1H),7.11(d,J＝8.0Hz,1H),7.01(d,J＝4.0Hz,1H),6.99(d,J＝2.0Hz,1H),4.28-4.24(m,2H),1.30(t,J＝7.1Hz,3H)。

Step 3 6-methyl-6H-thieno [2,3-b ] pyrrole-5-carboxylic acid ethyl ester

To 6H-thiophene [2,3-b ] at room temperature]To a solution of ethyl pyrrole-5-carboxylate (1.77g,9.06mmol) in DMF (15mL) was added K₂CO₃(3.81g,27.6mmol), followed by dropwise addition of methyl iodide (1.65g,11.6 mmol). the mixture was stirred at room temperature for 3H, the reaction was quenched with water (30mL) and extracted with EtOAc (3 × 50mL), the combined organic phases were washed with brine (4 × 50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure]⁺＝210。

Step 4 Ethyl 6-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6H-thieno [2,3-b ] pyrrole-5-carboxylate

Following a similar procedure as described in example 1, step 4, 6-methyl-6H-thiophene [2,3-b ]]Ethyl pyrrole-5-carboxylate (1.42g,6.78mmol) was converted to the title crude compound which was used directly in the next step. LC-MS [ M + H ]]⁺＝336。

Step 5 Ethyl 2- (5-bromo-3-nitropyridin-2-yl) -6-methyl-6H-thieno [2,3-b ] pyrrole-5-carboxylate

To a solution of 2, 5-dibromo-3-nitropyridine (2.31g,8.19mmol) in water (10mL) and THF (50mL) was added 6-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6H-thiophene [2,3-b]Pyrrole-5-carboxylic acid ethyl ester (4.61g,6.78mmol) and K₃PO₄(4.38g,20.64 mmol). With N₂Degassing the resulting mixture and, subsequently, reacting it with N₂Pd (dppf) Cl was added₂(568mg,0.70 mmol.) the reaction mixture was stirred at 50 ℃ overnight, the reaction mixture was extracted with EtOAc (3 × 150mL), the combined organic phases were washed with brine (200mL), dried over anhydrous sodium sulfate, the filtrate was collected and concentrated under reduced pressure, the residue was purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexane to afford the title compound (1.18g, 42% yield)]⁺＝410。

Step 6 Ethyl 6-bromo-1-methyl-1, 4-dihydropyrrolo [3 ", 2": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

Following a similar procedure to that described in example 1, step 6, 2- (5-bromo-3-nitropyridin-2-yl) -6-methyl-6H-thiophene [2,3-b ]]Ethyl pyrrole-5-carboxylate (1.18g,2.88mmol) was converted to the title compound (320mg, 29% yield). LC-MS [ M + H ]]⁺＝378。

Step 7 (S) -6-bromo-1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridine-2-carboxylic acid ethyl ester

Following a similar procedure to that described in example 1, step 7, 6-bromo-1-methyl-1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridine-2-carboxylic acid ethyl ester (300mg,0.79mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) -methanol (320mg,1.68mmol) were converted to the title compound (810mg crude). The product was purified by preparative HPLC using a gradient of 0% to 2% methanolic ethyl acetate solution to give the product (160mg, 37% yield). LC-MS [ M + H ]]⁺＝552。

Step 8 (S) -ethyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [ 3', 2': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridine-2-carboxylate

Following a procedure analogous to that in step 8 of example 1, (S) -6-bromo-1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Ethyl pyridine-2-carboxylate (160mg,0.29mmol) and 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (466mg,1.21mmol) were converted to the crude title compound, which was purified by preparative HPLC eluting with 0% to 2% MeOH in EtOAc to give the compound (79mg, 48% yield). LC-MS [ M + H ]]⁺＝569。

Step 9 (S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [ 3', 2': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2-yl) propan-2-ol

Pressing to realSimilar to the procedure in step 9 of example 1, (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridine-2-carboxylic acid ethyl ester (60mg,0.10mmol) was converted to the crude title compound, which was purified by preparative HPLC eluting with 0% to 5% MeOH in DCM to give the title compound (35mg, 63% yield). LC-MS [ M + H ]]⁺＝555。¹H-NMR(400MHz,DMSO-d₆)8.32(s,1H),8.28(s,1H),7.62(d,J＝8.0Hz,2H),7.28(m,3H),6.79(s,1H),5.65(d,J＝12.0Hz,1H),5.31(s,1H),3.95(s,3H),3.94(s,3H),3.89(d,J＝8.0Hz,1H),3.77(d,J＝12.0Hz,1H),3.50-3.37(m,1H),3.30-3.16(m,2H),2.25(s,3H),1.65(s,3H),1.64(s,3H),1.55(s,2H),1.39-1.19(m,2H)。

Example 3

(S) -3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6,6, 7-trimethyl-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyrrole [3 ", 4": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-8 (5H) -one ("Compound 3")

Step 1 3- (bromomethyl) thiophene-2-carboxylic acid methyl ester

N₂Next, NBS (3.98g,22.4mmol) and AIBN (1.01g,6.20mmol) were added to a solution of methyl 3-methylthiophene-2-carboxylate (2.99g, 19.2mmol) in acetonitrile (38mL), and the mixture was stirred at 85 ℃ for 15 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was added water (50mL) and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude methyl 3- (bromomethyl) thiophene-2-carboxylate (5.57g), which was used in the next step without purification. LC-MS [ M + H ]]⁺＝236。

Step 2 3- (aminomethyl) thiophene-2-carboxylic acid methyl ester

To a solution of methyl 3- (bromomethyl) thiophene-2-carboxylate (5.57g, crude) in methanol (30mL) was added NH₃Methanol solution (7N,40 mL). The resulting mixture was stirred at 25 ℃ for 3 h. Concentrating the reaction system under reduced pressureAnd EtOAc (25mL) was added to the residue. The mixture was stirred for 30min, the resulting solid was collected by filtration and washed with EtOAc (2mL) to give the title compound (2.17g, 12.6mmol, 66% yield over two steps). LC-MS [ M + H ]]⁺＝172。

Step 34, 5-dihydro-6H-thieno [2,3-c ] pyrrol-6-one

To a solution of methyl 3- (aminomethyl) thiophene-2-carboxylate (2.27g,14.5mmol) in methanol (20mL) was added K₂CO₃(5.27g,38.1 mmol). The resulting mixture was stirred at 80 ℃ for 10 h. The reaction was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (100mL) and extracted with EtOAc (500 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 25% EtOAc in hexanes to give the title compound (0.61g, 31% yield). LC-MS: [ M + H]⁺＝140。¹H-NMR(400MHz,DMSO-d₆)8.38(s,1H),7.94(d,J＝4.0Hz,1H),7.19(d,J＝4.0Hz,1H),4.29(s,2H)。

Step 4:4,4, 5-trimethyl-4, 5-dihydro-6H-thieno [2,3-c ] pyrrol-6-one

4, 5-dihydro-6H-thiophene [2,3-c ] at 0 ℃ within 10min]To a solution of pyrrol-6-one (2.02g,14.5mmol) in DMF (20mL) was added NaH (60%, 2.98g,72.7mmol) portionwise, and the mixture was warmed to room temperature and stirred for 30 min. The reaction was cooled to 0 ℃ followed by the addition of CH₃I (10.8g,73.0mmol), slowly warmed to room temperature and at N₂Stirring for 1.5 h. The reaction was quenched with water (20mL) at 0 ℃ and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-10% EtOAc to afford the title compound (1.75g, 70% yield). LC-MS [ M + H ]]⁺＝182。¹H-NMR(400MHz,CDCl₃)7.59(d,J＝4.0Hz,1H),7.00(d,J＝4.0Hz,1H),2.98(s,3H),1.44(s,6H)。

Step 5(4, 4, 5-trimethyl-6-oxo-5, 6-dihydro-4H-thieno [2,3-c ] pyrrol-2-yl) boronic acid

At-78 ℃ N₂Then, within 30min, 4, 5-trimethyl-4, 5-dihydro-6H-thiophene [2,3-c ] is added]Pyrrol-6-ones(2.72g,15.0mmol) in THF (60mL) was added LDA (2N,14mL,28.5mmol) dropwise and the resulting mixture was stirred at-78 deg.C for 1 h. Triisopropyl borate was then added dropwise at-78 ℃ over 30 min. The resulting reaction mixture was stirred for an additional 1h and quenched by 2N HCl (25mL) between 0 ℃ and 10 ℃ to reach pH 5-6. To the mixture was added 50mL of brine, and then extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was stirred with EtOAc (20 mL). The solid was collected by filtration and dried in air to give the title compound (2.18g, 70% yield). LC-MS [ M + H ]]⁺＝226。

Step 6 2- (5-bromo-3-nitropyridin-2-yl) -4,4, 5-trimethyl-4, 5-dihydro-6H-thieno [2,3-c ] pyrrol-6-one

To (4,4, 5-trimethyl-6-oxo-5, 6-dihydro-4H-thiophene [2, 3-c)]To a solution of pyrrol-2-yl) boronic acid (2.16g,9.62mmol) in THF (100mL) and water (25mL) was added 2, 5-dibromo-3-nitropyridine (2.98g,10.6mmol), Pd (dppf) Cl₂(0.69g,0.67mmol) and K₃PO₄(6.02g,28.4mmol), charging the mixture with N₂And 2 min. The resulting mixture was stirred at 35 ℃ for 2.5h, then water (50mL) was added and extracted with EtOAc (100 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, and the filtrate was collected by filtration. The solvent was removed on a rotary evaporator and the resulting residue was purified by silica gel chromatography eluting with a gradient of 10-20% EtOAc in hexanes to give the title compound (2.32g, 65% yield). LC-MS [ M + H ]]⁺＝382。

Step 7 3-bromo-6, 6, 7-trimethyl-6, 7-dihydropyrrolo [3 ", 4": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-8 (5H) -one

To 2- (5-bromo-3-nitropyridin-2-yl) -4,4, 5-trimethyl-4, 5-dihydro-6H-thiophene [2,3-c ]]To a solution of pyrrol-6-one (1.61g,4.21mmol) in dimethylbenzene was added triethyl phosphate (4.55g,27.4mmol) and N-charged₂For 1 min. The resulting mixture was stirred at 130o C for 3 h. The reaction mixture was cooled to room temperature. The solid came out of the solvent and was collected by filtration and washed with hexane to give the title compound (0.67g, 43% yield). LC-MS [ M + H ]]⁺＝350。

Step 8 (S) -3-bromo-6, 6, 7-trimethyl-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyrrolo [ 3', 4': 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-8 (5H) -one

Following a similar procedure to that described in step 7 of example 2, 3-bromo-6, 6, 7-trimethyl-6, 7-dihydropyrrole [3 ", 4": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-8 (5H) -one (1.05g,3mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) -methanol (0.98g,5.16mmol) were converted to the title compound (0.45g, 30% yield) and purified by chromatography on silica gel using a gradient of 0-20% EtOAc in hexane. LC-MS [ M + H ]]⁺＝524。

Step 9 (S) -3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6,6, 7-trimethyl-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyrrole [ 3', 4': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-8 (5H) -one

Following a procedure analogous to that in step 8 of example 2, (S) -3-bromo-6, 6, 7-trimethyl-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyrrolo [3 ", 4": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-8 (5H) -one (0.45g,0.85mmol) and 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (0.59g,1.50mmol) were converted to the title compound (170mg, 53% yield) and purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM. LC-MS [ M + H ]]⁺＝541。¹H-NMR(400MHz,DMSO-d₆)8.59(s,1H),8.07(s,1H),7.71(d,J＝8.0Hz,2H),7.49-7.40(m,3H),5.53(d,J＝8.0Hz,1H),3.99(m,1H),3.90(s,3H),3.63-3.57(m,3H),3.33(m,1H),3.11(s,3H),2.21(s,3H),2.11-2.07(m,1H),1.89(s,3H),1.84(s,3H),1.68-1.64(m,1H),1.23-1.41(m,2H)。

Example 4

3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -6,6, 7-trimethyl-6, 7-dihydropyrrole [3 ", 4": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-8 (5H) -one ("Compound 4")

Step 1 (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol

In N₂Next, three iodine crystals were added to a suspension of magnesium (24.3g,1.00mol) in THF (500mL), followed by dropwise addition of pure 4-bromotetrahydro-2H-pyran (100g,607mmoL) while controlling the internal temperature below 45 ℃ during the dropwise addition. The reaction mixture was stirred for a further 2h at ambient temperature. The reaction mixture was cooled to-30 ℃ and then a solution of 3-fluoropyridine carboxaldehyde (50.3g,402mmoL) in THF (300mL) was added dropwise with the internal temperature maintained at-20 ℃ to-30 ℃ during the addition. After 1h, the reaction mixture was filtered through a thin pad of celite. Adding saturated NH to the filtrate₄Aqueous Cl (100mL) separated into two layers. Anhydrous Na₂SO₄The organic phase was dried and the filtrate was collected. The filtrate was concentrated on a rotary evaporator. The crude compound was purified using reverse phase chromatography with 40-50% MeCN in H₂Elution with O solution gave the racemic compound (52g, 61% yield) which was separated by chiral prep SFC to give enantiomer a (25.1g, 29.6% yield) and enantiomer B (25.3g, 29.7% yield).

Enantiomer A LC-MS [ M + H ]]⁺Chiral chromatography reports RT 12.25min (column: ChiralpakAY-H (ADH0CE-VC 0010.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0mL/min).¹HNMR(400MHz,DMSO-d₆)8.42(dd,J＝3.20,1.32Hz,1H),7.66(ddd,J＝9.8,8.36,1.12Hz,1H),7.42-7.35(m,1H),5.23(d,J＝6.52Hz,1H),4.52(dd,J＝7.32,7.28Hz,1H),3.88(dd,J＝11.4,2.92Hz,1H),3.75(dd,J＝11.2,3.02Hz,1H),3.26(dt,J＝12.0,2.04Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.12-2.01(m,1H),1.82(dd,J＝13.3,1.52Hz,1H),1.38-1.24(m,1H),1.24-1.12(m,1H),1.00(dd,J＝12.9,1.34,1H)。

Enantiomer B LC-MS [ M + H ]]⁺Chiral chromatography reports RT 13.57min (column: ChiralpakAY-H (ADH0CE-VC 0010.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0mL/min).¹HNMR(400MHz,DMSO-d₆)8.42(dd,J＝3.2,1.35Hz,1H),7.66(ddd,J＝1.12,8.4,9.8Hz,1H),7.42-7.35(m,1H),5.23(d,J＝6.48Hz,1H),4.52(dd,J＝7.32,7.24Hz,1H),3.88(dd,J＝11.3,2.96,1H),3.75(dd,J＝2.96,11.2Hz,1H),3.26(dt,J＝12.0,2.0Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.01-2.12(m,1H),1.82(dd,J＝13.3,1.52Hz,1H),1.24-1.38(m,1H),1.24–1.12(m,1H),1.00(dd,J＝12.9,1.34,1H)。

Step 2 3-bromo-5- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -6,6, 7-trimethyl-6, 7-dihydropyrrolo [3 ", 4": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-8 (5H) -one

Following a similar procedure as in example 2 step 7, 3-bromo-6, 6, 7-trimethyl-6, 7-dihydropyrrole [3 ", 4": 4',5' in dry toluene (15mL) ']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-8 (5H) -one (200mg,0.57mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (enantiomer A from step 1, 150mg,0.69mmol), triphenylphosphine (387mg,1.47mmol) were converted to the title compound (73mg, 25% yield) which was purified by silica gel chromatography using a gradient of 10-20% EtOAc in hexane. LC-MS [ M + H ]]⁺＝543。

Step 3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -6,6, 7-trimethyl-6, 7-dihydropyrrole [3 ", 4": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-8 (5H) -one

Following a synthetic procedure analogous to that in step 8 of example 2, 3-bromo-5- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -6,6, 7-trimethyl-6, 7-dihydropyrrole [3 ", 4": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-8 (5H) -one (73mg,0.13mmol) and 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (91mg,0.24mmol) were converted to the title compound (42mg, 56% yield) which was purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM. LC-MS [ M + H ]]⁺＝560。¹H NMR(400MHz,DMSO-d₆)8.59(d,J＝4.52Hz,1H),8.56(d,J＝1.76Hz,1H),8.26(d,J＝1.80Hz,1H),7.85-7.79(m,1H),7.59-7.55(m,1H),5.80(d,J＝10.48Hz,1H),3.95(s,3H),3.86(d,J＝8.0Hz,1H),3.66(d,J＝12.0Hz,1H),3.43-3.34(m,2H),3.15-3.12(m,1H),3.02(s,3H),2.21(s,3H),1.85(s,3H),1.72-1.69(m,1H),1.66(s,3H),1.57-1.47(m,1H),1.26-1.21(m,1H),0.51(m,1H)。

Example 5

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1,3, 3-trimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one ("Compound 5")

Step 1 Ethyl 2- (2-nitrothiophen-3-yl) acetate

To a solution of 2-nitrothiophene (24.9g,0.19mol) in THF (800mL) at-60 deg.C was added t-BuONa (54.33g,0.57mol) in THF (100mL) dropwise. The mixture was stirred at-60 ℃ for 1 h. Ethyl 2-chloroacetate (23.7g,0.19mol) was added at-60 ℃ and stirred at-60 ℃ for 1 h. The mixture was warmed to room temperature and stirred at room temperature for 1 h. To this mixture was added saturated NH₄Aqueous Cl (15mL) and stirred at room temperature for 10 min. Adding Na into the mixture₂SO₄(30g) The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-50% EtOAc in hexanes to give the title compound. (19.6g, 48% yield). LC-MS [ M + H ]]⁺＝216；¹H NMR(400MHz,DMSO-d₆)7.97(d,J＝5.2Hz,1H),7.22(d,J＝5.2Hz,1H),4.13-4.07(m,4H),1.18(t,J＝7.2Hz,3H)。

Step 2 Ethyl 2- (2-aminothiophen-3-yl) acetate

N₂Next, to a solution of ethyl 2- (2-nitrothiophen-3-yl) acetate (19.6g,91.0mmol) in dioxane (400mL) and H₂Iron powder (18.3g,328mmol) and FeSO were added to a solution of O (80mL)₄.7H₂O (5.26g,18.9 mmol). The mixture is vacuumized and backfilled with N₂And the process was repeated three times and stirred at 110 ℃ for 16 h. The reaction mixture was cooled to room temperature, and Na was added to the mixture₂SO₄(120g) And the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude ethyl 2- (2-aminothiophen-3-yl) acetate (19.5 g). LC-MS [ M + H ]]⁺＝186。

Step 34, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

In N₂Next, AlMe was added dropwise to a solution of crude ethyl 2- (2-aminothiophen-3-yl) acetate (19.5g,91.0mmol) in THF (400mL) at-80 deg.C₃Hexane solution (2M,50 mL). The mixture was stirred at-80 ℃ for 1h, warmed to room temperature and stirred for a further 16 h. 4M aqueous HCl (80mL) was added dropwise and stirred at room temperature for 20 min. To the mixture was added Na₂SO₄(140g) And the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-30% EtOAc in hexanes to give the title compound (6.96g, two steps 41% yield). LC-MS [ M + H ]]⁺＝140；¹H NMR(400MHz,DMSO-d₆)10.47(br s,1H),6.91(d,J＝5.2Hz,1H),6.83(d,J＝5.2Hz,1H),3.39(s,2H)。

Step 4:4,4, 6-trimethyl-4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

At 0 deg.C, to 4, 6-dihydro-5H-thiophene [2,3-b ]]Pyrrole-5-one (3.93g,28.2mmol) in THF (80mL) was added NaH (60% in mineral oil, 4.54g,113.50mmol) slowly after addition, the mixture was stirred at 0 ℃ for 30min and then iodomethane (16.2g,114mmol) was added dropwise, the mixture was warmed to room temperature and stirred for 3H, the mixture was poured into water (100mL), extracted with EtOAc (3 × 100mL), washed with hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure, the residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexane to afford the title compound (2.71g, 53% yield), LC-MS [ M + H ] M]⁺＝182。¹H NMR(400MHz,DMSO-d₆)7.01(d,J＝4.8Hz,1H),6.98(d,J＝5.2Hz,1H),3.14(s,3H),1.24(s,6H)。

Step 5, 4, 6-trimethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

At-20 ℃ N₂In the following direction [ Ir (COD) access (OMe)]₂(0.97g,0.29mmol), 4, 6-trimethyl-4, 6-dihydro-5H-thiophene [2,3-b ]]A solution of pyrrol-5-one (1.02g,5.63mmol) and dtbpy (459mg,1.71mmol) in DCM (20mL) was added to a solution of HBPin (3.61g,28.21mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 h. Removing most of the solvent under reduced pressureTo obtain the title compound (2.62 g). LC-MS [ M + H ]]⁺＝308。

Step 6 2- (5-bromo-3-nitropyridin-2-yl) -4,4, 6-trimethyl-4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

N₂To 4,4, 6-trimethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4, 6-dihydro-5H-thiophene [2,3-b ]]To a solution of the crude pyrrol-5-one (2.62g,5.63mmol) in dioxane (50mL) and water (10mL) were added 2, 5-dibromo-3-nitropyridine (1.57g,5.57mmol), Pd (PPh)₃)₄(654mg,0.57mmol) and Na₂CO₃(1.83g,17.27 mmol). The mixture is vacuumized and backfilled with N₂And the process was repeated 3 times and stirred at 75 ℃ for 16H the reaction mixture was cooled to room temperature, poured into water (50mL) and extracted with EtOAc (3 × 50mL the combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure the residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the title compound (424mg, two steps 20% yield)]⁺＝383。¹H NMR(400MHz,DMSO-d₆)8.83(d,J＝2.4Hz,1H),8.64(d,J＝2.0Hz,1H),7.26(s,1H),3.21(s,3H),1.27(s,6H)。

Step 7 6-bromo-1, 3, 3-trimethyl-1, 4-dihydropyrrolo [3 ", 2": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2 (3H) -one

To 2- (5-bromo-3-nitropyridin-2-yl) -4,4, 6-trimethyl-4, 6-dihydro-5H-thiophene [2,3-b ]]To a solution of pyrrol-5-one (292mg,0.76mmol) in 1, 2-dichlorobenzene (6mL) was added DPPE (397mg,1.00 mmol). The mixture is vacuumized and backfilled with N₂And the process is repeated 3 times and at N₂Stirring was carried out at 160 ℃ for 5 h. The reaction was cooled to room temperature and purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexanes to give the title compound (86mg, 33% yield). LC-MS [ M + H ]]⁺＝350。

Step 8 (S) -6-bromo-1, 3, 3-trimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [ 3', 2': 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2 (3H) -one

To 6-bromo-1, 3, 3-trimethyl-1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Azole compounds[3,2-b]To a solution of pyridin-2 (3H) -one (86mg,0.25mmol) in toluene (2mL) were added triphenylphosphine (135mg,0.51mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (61mg,0.32 mmol). The mixture is vacuumized and backfilled with N₂And the process backfilled 3 times. In N₂DIAD (107mg,0.53mmol) was added at room temperature, the mixture was stirred at 110 ℃ for 16H, the reaction mixture was cooled to room temperature, poured into water (10mL) and extracted with EtOAc (3 × 10mL), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was chromatographed on silica gel using a gradient of 0-50% EtOAc in hexane to give the title compound (86mg, 64% yield) [ M + H ] LC-MS]⁺＝524。

Step 9 (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1,3, 3-trimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [ 3', 2': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one

Following a similar procedure to that described in example 1, step 8, (S) -6-bromo-1, 3, 3-trimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-2 (3H) -one (46mg,0.088mmol) and 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (112mg,0.29mmol) were converted to the title compound (14mg, 30% yield) and purified by silica gel chromatography gradient of 1-10% MeOH in DCM. LC-MS: [ M + H]⁺＝541；¹H NMR(400MHz,DMSO-d₆)8.31(s,1H),7.85(s,1H),7.68-7.57(m,2H),7.44-7.25(m,3H),5.26(d,J＝10.4Hz,1H),3.95-3.82(m,1H),3.81(s,3H),3.80-3.70(m,1H),3.56-3.41(m,2H),3.28(s,3H),2.14(s,3H),2.01-1.91(m,1H),1.64(s,3H),1.62(s,3H),1.53-1.43(m,1H),1.39-1.26(m,2H),0.92-0.75(m,1H)。

Example 6

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiopheno [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one ("Compound 6")

Step 1:6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

4, 6-dihydro-5H-thiophene [2,3-b ] at-10 ℃ within 10min]Pyrrole-5-one (3.51g,25.25mmol) in THF (50mL) added NaH (60% in mineral oil, 1.12g,28.0mmol) and stirred at-10 ℃ for 30min, SEMCl (5.19g,31.1mmol) was added dropwise at-10 ℃ and stirred at room temperature for 2H, the mixture was poured into water (50mL) and extracted with EtOAc (3 × 100mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was chromatographed on silica gel using a gradient of 0-10% EtOAc in hexane to give the title compound (4.17g, 61% yield), LC-MS [ M + H ] M]⁺＝270；¹HNMR(400MHz,DMSO-d₆)7.05(d,J＝5.2Hz,1H),6.92(s,d,J＝5.2Hz,1H),4.98(s,2H),3.58(s,2H),3.53-3.49(m,2H),0.89-0.81(m,2H),-0.04(s,9H)。

Step 2:4, 4-dimethyl-6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

Following a similar procedure as described in example 5, step 4,6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thiophene [2, 3-b)]Pyrrol-5-one (4.14g,15.37mmol) was converted to the title compound (2.20g, 48% yield) and purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexane solvent. LC-MS [ M + H ]]⁺＝298。¹H NMR(400MHz,DMSO-d₆)7.04(d,J＝4.8Hz,1H),6.97(d,J＝5.2Hz,1H),5.00(s,2H),3.50-3.47(m,2H),1.27(s,6H),0.86-0.82(m,2H),-0.07(s,9H)。

Step 3, 4-dimethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

Following a similar procedure to that described in example 5, step 5, 4-dimethyl-6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thiophene [2,3-b ]]Pyrrol-5-one (1.05g,3.53mmol) was converted to the crude title compound (1.36g) which was used in the next step LC-MS [ M + H ] without purification]⁺＝424。

Step 4 2- (5-bromo-3-nitropyridin-2-yl) -4, 4-dimethyl-6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thieno [2,3-b ] pyrrol-5-one

Following a similar procedure as described in example 5, step 6, crude 4, 4-dimethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thiophene [2,3-b]Pyrrol-5-one (1.36g,3.53mmol) and 2, 5-dibromo-3-nitropyridine (1.05g,3.58mmol) were converted to the title compound (0.61g, two steps 35% yield) and purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexane. LC-MS [ M + H ]]⁺＝498。¹H NMR(400MHz,DMSO-d₆)8.84(d,J＝2.0Hz,1H),8.66(d,J＝2.0Hz,1H),7.28(s,1H),5.07(s,2H),3.51(t,J＝8.0Hz,2H),1.30(s,6H),0.86(t,J＝8.0Hz,2H),-0.06(s,9H)。

Step 5 6-bromo-3, 3-dimethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrolo [3 ", 2": 4',5' ] thiopheno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2 (3H) -one

Following a similar procedure to that described in example 5, step 7, 2- (5-bromo-3-nitropyridin-2-yl) -4, 4-dimethyl-6- ((2- (trimethylsilyl) ethoxy) methyl) -4, 6-dihydro-5H-thiophene [2,3-b]Pyrrol-5-one (593mg,1.19mmol) was converted to the title compound (236mg, 43% yield) and purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in hexane. LC-MS [ M + H ]]⁺＝466。¹H NMR(400MHz,DMSO-d₆)8.38(d,J＝1.6Hz,1H),8.11(d,J＝1.6Hz,1H),5.08(s,2H),3.54(t,J＝8.0Hz,2H),1.46(s,6H),0.87(t,J＝8.0Hz,2H),-0.06(s,9H)。

Step 6 (S) -6-bromo-3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one

Following a similar procedure as described in example 5, step 8, 6-bromo-3, 3-dimethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-2 (3H) -one (236mg,0.51mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) -methanol (121mg,0.63mmol) were converted to the title compoundMaterial (323mg) and purified by silica gel chromatography eluting with a gradient of 0-15% EtOAc in hexanes. LC-MS [ M + H ]]⁺＝640。

Step 7 (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one

Following a similar procedure as described in example 5, step 9, crude (S) -6-bromo-3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-2 (3H) -one (323mg,0.51mmol) and 1, 4-dimethyl-5- (tributyltin) -1H-1,2, 3-triazole (589mg,1.51mmol) were converted to the title compound (63mg, two steps 20% yield) and purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc in hexane. LC-MS [ M + H ]]⁺＝657。

Step 8 (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrole [ 3', 2': 4',5' ] thiophene [2',3':4,5] pyrrole [3,2-b ] pyridin-2 (3H) -one

To (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 3-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyrrole [3 ", 2": 4',5']Thiophene [2',3':4,5]]Pyrrole [3,2-b ]]Pyridin-2 (3H) -one (51mg,0.078mmol) in EtOH (4mL) was added 6N aqueous HCl (4 mL). The mixture was stirred at 75 ℃ for 48 h. The reaction mixture was cooled to room temperature and saturated NaHCO was poured in₃(10mL) in aqueous and extracted with EtOAc (3 × 50mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated the residue was purified by chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM, followed by preparative HPLC to afford the title compound (5mg, 12% yield) LC-MS [ M + H ] M]⁺＝527；¹H NMR(400MHz,DMSO-d₆)8.28(s,1H),7.82(s,1H),7.64-7.59(m,2H),7.42-7.33(m,2H),7.31-7.25(m,1H),5.24(d,J＝10.8Hz,1H),3.98-3.80(m,1H),3.80(s,3H),3.80-3.74(m,1H),3.49-3.24(m,2H),2.12(s,3H),1.99-1.91(m,1H),1.61(s,3H),1.59(s,3H),1.51-1.38(m,1H),1.33-1.16(m,2H),0.91-0.74(m,1H)。

Referring to the similar procedure of example 1 to example 6, the following compounds were synthesized:

pharmacological testing

BRD4(BD1) affinity test

Biochemical binding assays for BRD4(BD1) were performed in 384-well whiteboards (OptiPlate-384, PerkinElmer) using HTRF technology.

By passing

550 liquid handler (Labcyte, USA) 20nL of compound was transferred to 384 well plates, then 5 uL of BRD4(BD1) (reaction biology company, RD-11-157) solution or Assay buffer was added to each well after 15 minutes of incubation at room temperature, 5 uL of biotinylated H4-derived acetylated peptide (synthesized by GL Biochem (Shanghai) Ltd) and 10 uL of detection solution (Cisbio Assay) were added to each well after 1 hour of incubation at room temperature, HTRF signals were measured at 615nm and 665nm using EnVision Multilabel plate reader (PerkinElmer, USA). Strength (665 nm)/Strength (615nm) were analyzed with a two-wavelength Signal ratio analysis, the inhibition of the compound was calculated according to the following formula: Max (Max-Signal)/(Min) × 100%. the inhibition rate of the compound was fitted to the GrphadPasm software (5.0, Saneg IC data in Sanbo CA) using Grphabet software (5.0)₅₀Value, nonlinear regression analysis using equation, Y ═ bottom + (top-bottom)/(1 +10^ ((LogIC) } ^ using₅₀-X) × slope), wherein Y represents inhibition and X represents compound concentration IC of compound 3 to BRD4(BD1) was determined₅₀It was 0.28 nM.

2. Cell proliferation assay

MTS assay protocol:

the effect of the compounds on the proliferation of MV-4-11 cells was examined by the MTS (3- (4, 5-dimethylthiophen-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole, inner salt) method. Briefly, 5% CO at 37 deg.C₂And MV-4-11 cells were cultured in 10% (v/v) FBS (fetal bovine serum) IMDM (Iscove's modified Dubecco's Medium) at 95% humidity, the cells were collected at the logarithmic growth phase and counted with a cell counter (hemocytometer), the cell viability was determined by trypan blue staining (trypan blue exclusion), the cell viability exceeded 90%, MV-4-11 cell concentration was adjusted to 1.2 × 10 with the use of the whole Medium⁵Add 100. mu.L of cell suspension (three duplicate wells per concentration) to a 96-well plate at a final cell density of 1.2 × 10⁴Individual cells/well. The next day, test compounds were dissolved in DMSO as stock solutions. mu.L of the stock solution was added to 1mL of medium and 25. mu.L of drug medium was added to the 96-well plate. The final concentration of the compound after serial dilution with medium was 0, 0.03, 0.1, 0.3, 1,3, 10, 30, 100 nM. The drug was incubated for 3 days and then detected by the MTS method. The PMS (phenazinium methosulfate) solution was added to the MTS solution (1: 20). Then, 20. mu.L of the MTS/PMS mixed solution was added to each well of the 96-well plate. The 96-well plates were incubated in an incubator for 1-4 hours. Using a microplate spectrophotometer (Envision)^RPeikinElmer) at 490 nm. Fitting data and obtaining IC Using GraphPad5.0₅₀The value is obtained.

As a result:

the results of the cell proliferation activity assay are shown in table 1 below:

TABLE 1 results of cell proliferation Activity assay

It can be seen from Table 1 that the compounds of the present invention have excellent inhibitory effects on leukemia cells MV-4-11.

Claims

1. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

wherein:

ring A is selected from a 5-membered heteroaromatic ring containing 1 heteroatom selected from N or a 5-membered amide ring;

each R which may be attached to the same atom or different atoms₁、R₂And R₃Independently at each occurrence, selected from hydrogen, deuterium, -CH₃、-CD₃Ethyl, propyl, isopropyl,

R₄Selected from:

W₁is selected from

W₂Selected from:

2. the compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is of formula IV or V:

wherein:

R₁is selected from-CH₃；

R₂Is selected from

R₃Selected from hydrogen.

3. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is of formula VII, VIII or IX:

wherein:

each R₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Is selected from-CH₃。

4. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is selected from:

5. a pharmaceutical composition comprising at least one compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as claimed in any one of claims 1-4, and at least one pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5, wherein the weight ratio of the compound to the excipient ranges from 0.0001 to 10.

7. Use of a compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as claimed in any one of claims 1 to 4, or a pharmaceutical composition as claimed in claim 5, in the manufacture of a medicament for the treatment of solid and/or hematological tumours associated with bromodomain proteins.

8. Use according to claim 7, wherein the solid tumor is selected from lung cancer, tumors of the digestive tract, colon cancer, rectal cancer, colorectal cancer and/or ovarian cancer; the hematological neoplasm is selected from myeloma and/or leukemia.

9. The use of claim 8, wherein the lung cancer is non-small cell lung cancer and/or small cell lung cancer; the tumor of the digestive tract is esophageal cancer; the leukemia is acute myelogenous leukemia and/or acute lymphocytic leukemia; the myeloma is multiple myeloma.