CN110407854A

CN110407854A - New tetracyclic compound

Info

Publication number: CN110407854A
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: Beijing Jia Ke Si New Drug Research And Development Co Ltd; Beijing Jiakesitu New Drug R & D Co Ltd
Current assignee: Jacobio Pharmaceuticals Co Ltd
Priority date: 2018-08-17
Filing date: 2019-08-19
Publication date: 2019-11-05
Anticipated expiration: 2039-08-19
Also published as: CN110407854B

Abstract

The present invention relates to new tetracyclic compounds, and wherein the tetracyclic compound has the structure as shown in formula (III), can be used as bromine domain and additional terminals (BET) inhibitor, and the invention further relates to their synthesis and the applications for the treatment of disease.More particularly it relates to be used as the condensed Hete rocyclic derivatives of BET inhibitor, prepare the method for these compounds and inhibit the method for the treatment disease and illness of one or more BET bromines domain offer benefit.

Description

New tetracyclic compound

Technical field

The present invention relates to some new tetracyclic compounds shown in Formulas I as bromine domain and additional terminals (BET) inhibitor (Formulas I), their synthesis and the application for treating disease.More particularly it relates to be used as the condensed heterocycle of BET inhibitor Derivative prepares the method for these compounds and the treatment disease and illness for inhibiting one or more BET bromines domain offer benefit Method.

Background technique

Several physiology courses potentially contribute to epigenetic regulation, including DNA methylation, the bracket that non-coding RNA mediates (scaff alcohol ding) and compound is formed and histone modification.Histone modification is covalent modification after the translation with histone Relevant process, histone significantly affect the ability that related DNA is transcribed.Relying amino acid acetylation is a kind of posttranslational modification, with Cell signal transduction and disease biological have extensive correlation.It adjusts and the enzyme of amino acid acetylation is relied referred to as " to write in histone Writer " or histone acetyltransferase (HATs), and adjust the deacetylated enzyme of the bad amino acid in histone and be referred to as " rubber Wipe " or histone deacetylase (HDAC).Bromine structural domain (bromine domains, BRDs), " reader " of epigenetic label, especially Ground identifies that the ε-N- acetyl group on histone tail relies amino acid (Kac) residue.

The 110 conservative Amino acid structural domains that BRD is made of four alpha-helixes (α Z, α A, α B and α C), it includes left hands Beam (bundle) (S.Mujtaba, L.Zeng, MMZhou, Oncogene, 2007 (26), 5521-5527).Alpha-helix passes through two A ring region (ZA and BC) links together and forms the surface for relying amino acid interaction with the acetylation in nucleosome histone (C.Dhalluin,J.E.Carlson,L.Zengetal,Nature,1999(399),491-496).Based on structure/sequence phase Like property, there is the protein of brominated structural domain known to 46 kinds from people, crosses over 8 families.Wherein, bromine structural domain and volume Acetylation in outer terminal domains (BET) identification histone H 3 and H4 relies amino acid residue.BET family, comprising BRD2, BRD3, Tetra- members of BRD4 and BRDT share two end N- bromine structural domains and additional C- terminal domains (ET), show height Sequence conservation.It has been reported that BRD2 and BRD3 may participate in promoting in conjunction with histone along the gene of active transcription Extend (Leroyetal., M alcohol .Cell, 200830 (1), 51-60) into transcription.BRD4 seems to take part in positive transcriptional elongation factor The recruitment of compound (pTEF-I3) is adjusted in transcription and increase transcription output in RNA polymerase and is played an important role (Hargreavesetal.,Cell,2009138(1):1294145).It is different from other three kinds of BET albumen of common manifestation, BRDT performance is usually (M.H.J ketone setal, Genomics, 1997 (45), the 529-534) of testes specificity, and BRDT is for essence Son is necessary (E.Shangetal, Development, 2007 (134), 3507-3515).BET albumen and acetylation group The combination of albumen leads to raise in BET albumen enhancer and promoter region to gene to carry out active transcription.As a result, they Activation factor, inhibiting factor, transcription factor and transcription mechanism interaction are together to form protein complex and influence target base Because of transcription (A.Deyetal, Proc.Natl.Acad.Sci, U.S.A., 2003 (100), 8758-8763).Although BET albumen has There are similar structure and usually enhancing transcription, but adjust different processes based on their binding partner, this is usually group Knit specificity.

It is thought that BET albumen is generally mainly the super enhancer (SEs) by being positioned at pathology related gene and drives Their performance is moved to mediate their effect (M.A.Daws ketone tal, Nature, 2011 in disease incidence mechanism and progress (478),529-533；B.Chapuyetal,CancerCell,2013(24),777-790).In cancer, SEs is enriched in cancer Gene such as MYC, RUNX1, FOSL2, CCND1, MCL1 and BCL2L1 (B.Chapuyetal., CancerCell, 2013 (24), 777-790；J.Loven,Cell,2013(153),320-334；W.A.Whyteetal.,Cell,2013(153),307-319； D.Hniszetal.,Cell,2013(155),934-947).BET albumen is inhibited to have become being hopeful for treatment human diseases Target, these diseases include virology, heart failure, inflammation, central nervous system (CNS) disease and kinds cancer (J.M.Sahnietal., Pharmac alcohol .Res., 2017,1-21；P.An and etal., Cell, 2013 (154), 569-582； C.-Y.Wangetal.,TrendsBiochem.Sci,2015(40),468-479；A.Stathisetal., CancerDiscovery,2017,8(1),1-13).Small molecule BET inhibitor reported in clinical development include 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 Inhibitor.Need to generate other BET inhibitor that there is improved property than existing BET inhibitor, for example, improving activity, peace Quan Xing, pharmacokinetics and/or pharmacokinetics.

Summary of the invention

On the one hand, the compound, its pharmaceutically acceptable salt or its stereoisomer of Formulas I are provided:

X is selected from NR₅, O or S；

Ring A is the heteroatomic 5 yuan of miscellaneous aromatic rings or 5 yuan of amide rings that N, O or S are selected from containing 1,2 or 3；

It is attached to same atoms or not homoatomic each R₁、R₂And R₃At each occurrence independently selected from being not present； Hydrogen；Deuterium；Halogen；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_2-6Alkenyl；-C_2-6Alkynyl；-C_1-6Alkoxy；- NH₂；-NH(C_1-6Alkyl)；-N(C_1-6Alkyl)₂；-SC_1-6Alkyl；-SOC_1-6Alkyl；-SO₂C_1-6Alkyl；-SO₂NH₂；- SO₂NHC_1-6Alkyl；-SO₂N(C_1-6Alkyl)₂；-COC_1-6Alkyl；-CONH₂；-CONHC_1-6Alkyl；-CON(C_1-6Alkyl)₂；-P (O)H₂；-P(O)HC_1-6Alkyl；-P(O)(C_1-6Alkyl)₂；3-8 member carbocyclic ring；The heteroatomic 3- of N, O or S are selected from containing 1,2 or 3 8 circle heterocyclic rings；6-10 member aryl；Or the heteroatomic 5-10 unit's heteroaryl of N, O or S are selected from containing 1,2 or 3；And each R₁、R₂With R₃Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group exists Independently selected from deuterium, halogen ,-OH ,-CN ,-NH when occurring every time₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, it is formed together 3-8 member carbocyclic ring with the atom that they individually or collectively connect, or contain 1,2 or 3 heteroatomic 3-8 circle heterocyclic rings selected from N, O or S；And each ring system at each occurrence optionally by 1,2, 3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen Element ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、- C_1-6Alkyl or-C_1-6Alkoxy；Each R_aAnd R_bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or It is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

M is selected from 0,1,2,3,4,5 or 6；

R₄It is selected from

Each R_4aAnd R_4bAt each occurrence independently selected from hydrogen；Deuterium；Halogen；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkane Base；-C_2-6Alkenyl；-C_2-6Alkynyl；-C_1-6Alkoxy；-NH₂；-NH(C_1-6Alkyl)；-N(C_1-6Alkyl)₂；-SC_1-6Alkyl；- SOC_1-6Alkyl；-SO₂C_1-6Alkyl；-SO₂NH₂；-SO₂NHC_1-6Alkyl；-SO₂N(C_1-6Alkyl)₂；-COC_1-6Alkyl；-CONH₂；- CONHC_1-6Alkyl；-CON(C_1-6Alkyl)₂；-P(O)H₂；-P(O)HC_1-6Alkyl；-P(O)(C_1-6Alkyl)₂；3-8 member carbocyclic ring；Contain 1,2 or 3 heteroatomic 3-8 circle heterocyclic rings selected from N, O or S；6-10 member aryl；Or the miscellaneous original of N, O or S are selected from containing 1,2 or 3 The 5-10 unit's heteroaryl of son；And each R_4aAnd R_4bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or It is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-NH₂,-CN, carboxyl ,- NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

R₅At each occurrence independently selected from hydrogen；Deuterium；Halogen；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_2-6Alkene Base；-C_2-6Alkynyl；-C_1-6Alkoxy；-NH₂；-NH(C_1-6Alkyl)；-N(C_1-6Alkyl)₂；-SC_1-6Alkyl；- SOC_1-6Alkyl；-SO₂C_1-6Alkyl；-SO₂NH₂；-SO₂NHC_1-6Alkyl；-SO₂N(C_1-6Alkyl)₂；-COC_1-6Alkyl；-CONH₂；- CONHC_1-6Alkyl；-CON(C_1-6Alkyl)₂；-P(O)H₂；-P(O)HC_1-6Alkyl；-P(O)(C_1-6Alkyl)₂；3-8 member carbocyclic ring；Contain 1,2 or 3 heteroatomic 3-8 circle heterocyclic rings selected from N, O or S；6-10 member aryl；Or the miscellaneous original of N, O or S are selected from containing 1,2 or 3 The 5-10 unit's heteroaryl of son；Each R₅Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or is not taken Generation, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6 Alkyl or-C_1-6Alkoxy；

Each R_5aAnd R_5bAt each occurrence independently selected from hydrogen, deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、- C_1-6Alkyl or-C_1-6Alkoxy；Each R_5aAnd R_5bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or It is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

N is selected from 0,1,2,3,4,5 or 6；

W₁Selected from hydrogen；Deuterium；Halogen；-NH₂；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_1-6Alkoxy；-C_1-6Alkylene Base-C_1-6Alkoxy；6-10 member aryl；N, O, S, SO or SO are selected from containing 1,2,3 or 4₂Heteroatomic 5-10 unit's heteroaryl； N, O, S, SO or SO are selected from containing 1,2,3 or 4₂Heteroatomic 3-8 circle heterocyclic ring；Or 3-8 member carbocyclic ring；And each W₁Going out every time Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted now, and each substituent group is at each occurrence Independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

W₂Selected from hydrogen；Deuterium；Halogen；-NH₂；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_1-6Alkoxy；6-10 member virtue Base；N, O, S, SO or SO are selected from containing 1,2,3 or 4₂Heteroatomic 5-10 unit's heteroaryl；Containing 1,2,3 or 4 selected from N, O, S, SO or SO₂Heteroatomic 3-8 circle heterocyclic ring；Or 3-8 member carbocyclic ring, and each W₂At each occurrence optionally by 1,2,3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,- CN、-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Z is selected from hydrogen, deuterium, halogen ,-NH₂,-CN ,-OH, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy.

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

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

In some embodiments of Formulas I, Formula II or formula III, wherein being attached to same atoms or not homoatomic every A R₁、R₂And R₃At each occurrence independently selected from be not present, hydrogen, deuterium, halogen ,-CN ,-OH ,-C_1-6Alkyl ,-C_1-6Alcoxyl Base,-NH₂、-NH(C_1-6Alkyl) ,-N (C_1-6Alkyl)₂、-SO₂C_1-6Alkyl ,-SO₂NH₂、-SO₂NHC_1-6Alkyl ,- SO₂N(C_1-6Alkyl)₂、-COC_1-6Alkyl ,-CONH₂、-CONHC_1-6Alkyl ,-CON (C_1-6Alkyl)₂、-P(O)H₂、-P(O)HC_1-6 Alkyl or-P (O) (C_1-6Alkyl)₂；And each R₁、R₂And R₃At each occurrence optionally by 1,2,3,4,5 or 6 substituent group Replace or be not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、 Carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, it is formed together 3-6 member carbocyclic ring with the atom that they individually or collectively connect, or contain 1,2 or 3 heteroatomic 3-6 circle heterocyclic rings selected from N, O or S；And each ring system at each occurrence optionally by 1,2, 3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen Element ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；Each R_aAnd R_bAt each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium ,-F ,-Cl ,-Br or-C_1-6Alkyl；

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

In some embodiments of Formulas I, Formula II or formula III, wherein being attached to same atoms or not homoatomic every A R₁、R₂And R₃At each occurrence independently selected from be not present, hydrogen, deuterium ,-F ,-Cl ,-Br ,-CN ,-OH ,-C_1-3Alkyl ,-C_1-3 Alkoxy,-NH₂、-NH(C_1-3Alkyl) ,-N (C_1-3Alkyl)₂、-SO₂C_1-3Alkyl ,-SO₂NH₂、-SO₂NHC_1-3Alkane Base ,-SO₂N(C_1-3Alkyl)₂、-COC_1-3Alkyl ,-CONH₂、-CONHC_1-3Alkyl ,-CON (C_1-3Alkyl)₂、-P(O)H₂、-P(O) HC_1-3Alkyl or-P (O) (C_1-3Alkyl)₂；And each R₁、R₂And R₃It is optionally taken at each occurrence by 1,2,3,4,5 or 6 For base replace or be not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,- NH₂、-C_1-3Alkyl or-C_1-3Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbon are formed together with the atom that they individually or collectively connect Ring, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle is occurring every time Shi Hanyou 1 or 2 are heteroatomic selected from N's or O；Each ring system is at each occurrence optionally by 1,2,3,4,5 or 6 Substituent group replace or be not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,- CN、-NH₂、-C_1-3Alkyl or-C_1-3Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-3Alkyl；Each R_aAnd R_bAt each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium or-F；

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

In some embodiments of Formulas I, Formula II or formula III, wherein being attached to same atoms or not homoatomic every A R₁、R₂And R₃At each occurrence independently selected from be not present, hydrogen, deuterium ,-F ,-Cl ,-Br ,-CN ,-OH, methyl, ethyl, propyl, Isopropyl, methoxyl group, ethyoxyl, propoxyl group, 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) (CH₃)(CH₂CH₃)；Each R₁、R₂And R₃At each occurrence optionally by 1,2, 3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium ,- F、-Cl、-Br、-OH、-CN、-NH₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy； Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbon are formed together with the atom that they individually or collectively connect Ring, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle is occurring every time When include 1 be selected from N or O hetero atom；Each ring system is optionally replaced by 1,2,3,4,5 or 6 at each occurrence Base replace or be not substituted, and each substituent group at each occurrence independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,- CN、-NH₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.

In some embodiments of Formulas I, Formula II or formula III, wherein each R₁、R₂And R₃It can connect at each occurrence In same atoms or it is not homoatomic independently selected from be not present, 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)₂, methoxyl group, ethyoxyl, propoxyl group, 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)；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbon are formed together with the atom that they individually or collectively connect Ring, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle is occurring every time When include 1 be selected from N or O hetero atom.

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

In some embodiments of Formulas I, Formula II, formula III or IV, wherein each R₁、R₂And R₃It is independent at each occurrence Ground is selected from hydrogen, deuterium ,-C_1-6Alkyl orAnd each R₁、R₂And R₃At each occurrence optionally by 1,2,3,4,5 or 6 A substituent group replaces or is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-C_1-6Alkane Base or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；Each R_aAnd R_bAt each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium, halogen or-C_1-6Alkyl；

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

In some embodiments of Formulas I, Formula II, formula III or IV, wherein R₁At each occurrence independently selected from-C_1-6 The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each of described takes Dai Ji is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

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

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；And each R_aAnd R_bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium, halogen or-C_1-6Alkyl；

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or IV, wherein R₁At each occurrence independently selected from-C_1-6 The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each of described takes Dai Ji is at each occurrence independently selected from deuterium or-F；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；And each R_aAnd R_bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F；

M is selected from 0 or 1；

R₃Selected from hydrogen, deuterium or-C_1-6Alkyl.

In some embodiments of Formulas I, Formula II, formula III or IV, wherein R₁Selected from-C_1-3The alkyl ,-C_1-3Alkane Base is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F；

R₂For

Each R_aAnd R_bAt each occurrence independently selected from-C_1-3Alkyl；And each R_aAnd R_bAt each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium or-F；

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or IV, wherein R₁Selected from methyl；Ethyl；Propyl；Isopropyl； What methyl deuterium or-F replaced；What ethyl deuterium or-F replaced；What propyl deuterium or-F replaced；Or isopropyl deuterium or-F replace；

R₂is

Each R_aAnd R_bAt each occurrence independently selected from methyl；Ethyl；Propyl；Isopropyl；The first that deuterium or-F replace Base；The ethyl that deuterium or-F replace；The propyl that deuterium or-F replace；Or the isopropyl that deuterium or-F replace；

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or formula IV, wherein R₁Selected from-CH₃、-CD₃、-CH₂F、- CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、- CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

R₂For

Each R_aAnd R_bAt each occurrence independently selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、- CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH (CF₃)₂Or-CH (CD₃)₂；

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or IV, wherein R₁For-CH₃；

R₂For

R₃For hydrogen.

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

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein each R₁、R₂And R₃At each occurrence solely On the spot it is selected from hydrogen, deuterium ,-C_1-6Alkyl orAnd each R₁、R₂And R₃At each occurrence optionally by 1,2,3,4,5 Or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,- C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium ,-C_1-6Alkyl；Each R_aAnd R_bAt each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium, halogen or-C_1-6Alkyl；

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

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein R₁At each occurrence independently selected from- C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each of described Substituent group is at each occurrence independently selected 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 Formulas I, Formula II, formula III or Formula V, wherein R₁At each occurrence independently selected from- C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each of described Substituent group is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium ,-C_1-6Alkyl；And each R_aAnd R_bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F；

M is selected from 0 or 1；

R₃Selected from hydrogen, deuterium or-C_1-6Alkyl.

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein R₁Selected from-C_1-3The alkyl ,-C_1-3Alkane Base is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F；

R₂For

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein R₁Selected from methyl；Ethyl；Propyl；Isopropyl Base；The methyl that deuterium or-F replace；The ethyl that deuterium or-F replace；The propyl that deuterium or-F replace；Or the isopropyl that deuterium or-F replace；

R₂For

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein R₁Selected from-CH₃、-CD₃、-CH₂F、-CF₂H、- CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH (CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

R₂For

R₃Selected from hydrogen or deuterium.

In some embodiments of Formulas I, Formula II, formula III or Formula V, wherein R₁For-CH₃；

R₂For

R₃For hydrogen.

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

In some embodiments of Formulas I, Formula II, formula III or Formula IV, wherein each R₁And R₂It is independent at each occurrence Ground is selected from hydrogen, deuterium ,-C_1-6Alkyl orAnd each R₁And R₂At each occurrence optionally by 1,2,3,4,5 or 6 Substituent group replaces or is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-C_1-6Alkyl Or-C_1-6Alkoxy；

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

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁At each occurrence independently selected from-C_1-6 Alkyl, the C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each substitution Base is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

R₂Selected from hydrogen, deuterium ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁At each occurrence independently selected from-C_1-6 The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each of described takes Dai Ji is at each occurrence independently selected from deuterium or-F；

R₂It is selected from

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁Selected from-C_1-3The alkyl ,-C_1-3Alkane Base is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F；

R₂It is selected from

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁Selected from methyl；Ethyl；Propyl；Isopropyl； The methyl that deuterium or-F replace；The ethyl that deuterium or-F replace；The propyl that deuterium or-F replace；Or the isopropyl that deuterium or-F replace；

R₂It is selected from

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁Selected from-CH₃、-CD₃、-CH₂F、-CF₂H、- CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH (CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、- CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH (CF₃)₂Or-CH (CD₃)₂。

In some embodiments of Formulas I, Formula II, formula III or VI, wherein R₁Selected from methyl；

R₂It is selected from

In some embodiments of Formulas I, Formula II or formula III, wherein the compound is Formula VII:

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁、R₂And R₃At each occurrence Independently selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy orAnd each R₁、R₂And R₃At each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂3-6 member carbocyclic ring is formed together with the carbon atom that they all connect；Or the miscellaneous original of N or O is selected from containing 1 or 2 The 3-6 circle heterocyclic ring of son；And each ring system is optionally replaced by 1,2,3,4,5 or 6 substituent group or not at each occurrence It is substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alcoxyl Base；

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

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium, halogen ,-OH, or-C_1-6Alkyl；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each institute It states ring system optionally to be replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium, halogen ,-OH or-C_1-6Alkyl；

R₃Selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each institute It states ring system optionally to be replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

R₃Selected from-OH ,-C_1-6Alkyl or

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；And each R_aAnd R_bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or halogen；

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-3The alkyl ,-C_1-3Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium or-F；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each institute It states ring system optionally to be replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium or halogen；

R₃Selected from-OH ,-C_1-3Alkyl,

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-3Alkyl；And each R_aAnd R_bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium or-F.

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、- CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings, 6 circle heterocyclic rings, each heterocycle include 1 hetero atom for being selected from N or O at each occurrence；

R₃Selected from-OH,-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、- CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁And R₂Independently selected from-CH₃、- CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle include 1 miscellaneous original for being selected from N or O at each occurrence Son；

R₃Selected from-OH,-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂。

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein R₁Selected from-CH₃；R₂Selected from-CH₃；With

R₃Selected from-OH,-CH₃Or-CH₂CH₃。

In some embodiments of Formulas I, Formula II, formula III or Formula VII, wherein each R₁Selected from-CH₃；R₂Selected from-CH₃； And R₃Selected from-CH₃。

In some embodiments of Formulas I, Formula II or formula III, wherein the compound is Formula VIII:

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁、R₂And R₃At each occurrence Independently selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy orAnd each R₁、R₂And R₃At each occurrence Optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is independent at each occurrence Ground is selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alkoxy；Or

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

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁And R₂At each occurrence solely On the spot it is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and Each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH or-C_1-6Alkyl；Or

R₃Selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁And R₂At each occurrence solely On the spot it is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and Each substituent group is at each occurrence independently selected from deuterium, halogen, or-C_1-6Alkyl；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O, and each institute It states ring system optionally to be replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

R₃Selected from-OH ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁And R₂At each occurrence solely On the spot it is selected from-C_1-3The alkyl ,-C_1-3Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and Each substituent group is at each occurrence independently selected from deuterium or-F；Or

R₃Selected from-OH ,-C_1-3Alkyl,

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁And R₂At each occurrence solely On the spot it is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、- CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；Or

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁And R₂Independently selected from- CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂；Or

R₃Selected from-OH,-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂。

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein R₁Selected from-CH₃；R₂Selected from-CH₃；And R₃ Selected from-OH,-CH₃Or-CH₂CH₃。

In some embodiments of Formulas I, Formula II, formula III or Formula VIII, wherein each R₁Selected from-CH₃；R₂Selected from- CH₃；And R₃Selected from-CH₃.

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

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁、R₂And R₃At each occurrence solely On the spot it is selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy orAnd each R₁、R₂And R₃Appoint at each occurrence Selection of land is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group is at each occurrence independently Selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂3-6 member carbocyclic ring is formed together with the carbon atom that they all connect；Or the miscellaneous original of N or O is selected from containing 1 or 2 The 3-6 circle heterocyclic ring of son, and each ring system is optionally replaced by 1,2,3,4,5 or 6 substituent group or not at each occurrence It is substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alcoxyl Base；

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

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium, halogen ,-OH or-C_1-6Alkyl；Or

R₃Selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；Or

R₃Selected from-OH ,-C_1-6Alkyl or

M is selected from 0 or 1.

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-C_1-3The alkyl ,-C_1-3Alkyl is optionally replaced by 1,2,3,4,5 or 6 substituent group or is not substituted, and institute The each substituent group stated is at each occurrence independently selected from deuterium or-F；Or

R₁And R₂3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 yuan are formed together with the carbon atom that they all connect Heterocycle, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O, and each institute It states ring system optionally to be replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium or halogen；

R₃Selected from-OH ,-C_1-3Alkyl,

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁And R₂It is independent at each occurrence Ground is selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、- CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；Or

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁And R₂Independently selected from-CH₃、- CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂；Or

R₃Selected from-OH,-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂。

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein R₁Selected from-CH₃；R₂Selected from-CH₃；And R₃Choosing From-OH,-CH₃Or-CH₂CH₃。

In some embodiments of Formulas I, Formula II, formula III or Formula IX, wherein each R₁Selected from-CH₃；R₂Selected from-CH₃； And R₃Selected from-CH₃。

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from hydrogen, deuterium ,-CN ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy ,-NH₂、-NH (C_1-6Alkyl) ,-N (C_1-6Alkyl)₂、-SO₂C_1-6Alkyl ,-SO₂NH₂、-SO₂NHC_1-6Alkyl ,-SO₂N(C_1-6Alkyl)₂、-COC_1-6 Alkyl ,-CONH₂、-CONHC_1-6Alkyl ,-CON (C_1-6Alkyl)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C_1-6Alkyl)₂；And Each R_4aAnd R_4bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and is described every A substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、-C_1-6Alkyl or-C_1-6Alkoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from hydrogen, deuterium, halogen ,-CN ,-OH ,-C_1-3Alkyl ,-C_1-3Alkoxy ,-NH₂、- NH(C_1-3Alkyl) ,-N (C_1-3Alkyl)₂、-SO₂C_1-3Alkyl ,-SO₂NH₂、-SO₂NHC_1-3Alkyl ,-SO₂N(C_1-3Alkyl)₂、- COC_1-3Alkyl ,-CONH₂、-CONHC_1-3Alkyl ,-CON (C_1-3Alkyl)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C_1-3 Alkyl)₂；And each R_4aAnd R_4bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or is not substituted, and Each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、-C_1-3Alkyl or-C_1-3Alcoxyl Base

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from hydrogen, deuterium ,-F ,-Cl ,-Br ,-CN ,-OH, methyl, ethyl, propyl, different Propyl, methoxyl group, ethyoxyl, propoxyl group, 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) (CH₃)(CH₂CH₃)；Each R_4aWith R_4bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group exists Independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,-CN ,-NH when occurring every time₂, methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group or isopropoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently 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)₂, methoxyl group, ethyoxyl, propoxyl group, 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) (CH₃) (CH₂CH₃)。

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from-C_1-6Alkyl；Or-the C that deuterium or-F replace_1-6Alkyl.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from-C_1-3Alkyl；Or-the C that deuterium or-F replace_1-3Alkyl.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bAt each occurrence independently selected from methyl；Ethyl；Propyl；Isopropyl；The methyl that deuterium or-F replace；Deuterium Or the ethyl that-F replaces；The propyl that deuterium or-F replace；Or the isopropyl that deuterium or-F replace.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, In each R_4aAnd R_4bThe methyl replaced at each occurrence independently selected from methyl or deuterium.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle R₄It is selected from:

In some embodiments of Formulas I, wherein R₅At each occurrence independently selected from hydrogen, deuterium ,-CN ,-OH ,-C_1-6 Alkyl ,-C_1-6Alkoxy,-SO₂C_1-6Alkyl ,-SO₂NH₂、-SO₂NHC_1-6Alkyl ,-SO₂N(C_1-6Alkyl)₂、- COC_1-6Alkyl ,-CONH₂、-CONHC_1-6Alkyl ,-CON (C_1-6Alkyl)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C_1-6 Alkyl)₂；Each R₅Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and is described every A substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_5aAnd R_5bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；Each R_5aAnd R_5bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium, halogen or-C_1-6Alkyl；

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

In some embodiments of Formulas I, wherein R₅At each occurrence independently selected from hydrogen, deuterium ,-CN ,-OH ,-C_1-3 Alkyl ,-C_1-3Alkoxy,-SO₂C_1-3Alkyl ,-SO₂NH₂、-SO₂NHC_1-3Alkyl ,-SO₂N(C_1-3Alkyl)₂、- COC_1-3Alkyl ,-CONH₂、-CONHC_1-3Alkyl ,-CON (C_1-3Alkyl)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C_1-3 Alkyl)₂；Each R₅Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and is described every A substituent group is at each occurrence independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,-CN ,-NH₂、-C_1-3Alkyl or-C_1-3Alcoxyl Base；

Each R_5aAnd R_5bAt each occurrence independently selected from hydrogen, deuterium or-C_1-3Alkyl；Each R_5aAnd R_5bOccurring every time When optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group is only at each occurrence On the spot it is selected from deuterium, halogen or-C_1-3Alkyl；

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

In some embodiments of Formulas I, wherein R₅At each occurrence independently selected from hydrogen, deuterium ,-CN ,-OH, methyl, Ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, -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) (CH₃)(CH₂CH₃)；Each R₅Every It is secondary optionally to be replaced by 1,2,3,4,5 or 6 substituent group or be not substituted when occurring, and each substituent group is going out every time Now independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,-CN ,-NH₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, Propoxyl group or isopropoxy.

In some embodiments of Formulas I, wherein R₅At each occurrence independently 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)₂, methoxyl group, ethyoxyl, propoxyl group, 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) (CH₃)(CH₂CH₃)。

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Carboxyl；-C_1-6Alkyl；-C_1-6Alkoxy；-C_1-3Alkylidene-C_1-3Alcoxyl Base；Phenyl；Heteroatomic 5 unit's heteroaryl of N or O is selected from containing 1,2 or 3；Heteroatomic 6 yuan of N or O are selected from containing 1,2 or 3 Heteroaryl；Heteroatomic 3 circle heterocyclic ring of N or O is selected from containing 1,2 or 3；It is miscellaneous containing 1,2 or 3 heteroatomic 4 yuan selected from N or O Ring；Heteroatomic 5 circle heterocyclic ring of N or O is selected from containing 1,2 or 3；Heteroatomic 6 circle heterocyclic ring of N or O is selected from containing 1,2 or 3；3 First carbocyclic ring；4 yuan of carbocyclic rings；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₁It is optionally taken at each occurrence by 1,2,3,4,5 or 6 Replace for base or be not substituted, and each substituent group is selected from deuterium, halogen-OH ,-CN ,-NH at each occurrence₂、-C_1-3 Alkyl or-C_1-3Alkoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Methyl；Ethyl；Propyl；Isopropyl； Methoxyl group；Ethyoxyl；Propoxyl group； Isopropoxy； -CH₂OCH₃；-CH₂CH₂OCH₃；-CH₂CH₂OCH₂CH₃；Phenyl；5 unit's heteroaryls contain 1 or 2 Selected from the heteroatomic of N or O；6 unit's heteroaryls contain 1 or 2 and are selected from the heteroatomic of N or O；5 circle heterocyclic rings contain 1 or 2 choosing From the heteroatomic of N or O；6 circle heterocyclic rings contain 1 or 2 and are selected from the heteroatomic of N or O；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And it is each W₁Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group exists Selected from deuterium ,-F ,-Cl ,-OH ,-CN ,-NH when occurring every time₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, the third oxygen Base or isopropoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁Selected from hydrogen；Deuterium；-F；Methyl；Ethyl；Propyl；Isopropyl； Methoxyl group；-CH₂OCH₃；-CH₂CH₂OCH₃；6 unit's heteroaryls contain 1 or 2 Selected from the heteroatomic of N or O；5 circle heterocyclic rings contain 1 or 2 and are selected from the heteroatomic of N or O；6 circle heterocyclic rings contain 1 or 2 selected from N Or O's is heteroatomic；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₁Deuterium is optionally substituted or is not substituted at each occurrence Or-F.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁Selected 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、 Methoxyl group ,-CH₂OCH₃、-CH₂CH₂OCH₃、

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁- the C replaced selected from-F_1-6Alkyl or heteroatomic 6 circle heterocyclic ring that O is selected from containing 1.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁- the C replaced selected from-F_1-6Alkyl,

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₁Selected from-CH₂CH₂CF₃Or

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₂Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Carboxyl；-C_1-3Alkyl；-C_1-3Alkoxy；Phenyl；Naphthalene；Containing 1,2 or 3 A heteroatomic 5 unit's heteroaryl selected from N, O or S；Heteroatomic 6 unit's heteroaryl of N, O or S are selected from containing 1,2 or 3；Containing 1,2 Or 37 unit's heteroaryls of hetero atom selected from N, O or S；Heteroatomic 8 unit's heteroaryl of N, O or S are selected from containing 1,2 or 3；Containing 1, 2 or 3 are selected from heteroatomic 9 unit's heteroaryl of N, O or S；Containing 1,2 or 3 selected from N or O heteroatomic 10 unit's heteroaryl or S；Heteroatomic 3 circle heterocyclic ring of N, O or S are selected from containing 1,2 or 3；It is miscellaneous containing 1,2 or 3 heteroatomic 4 yuan selected from N, O or S Ring；Heteroatomic 5 circle heterocyclic ring of N, O or S are selected from containing 1,2 or 3；It is miscellaneous containing 1,2 or 3 heteroatomic 6 yuan selected from N, O or S Ring；3 yuan of carbocyclic rings；4 yuan of carbocyclic rings；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₂It is optionally substituted or is not taken at each occurrence 1,2,3,4 or 5 substituent groups of generation, and each substituent group is selected from deuterium, halogen ,-OH ,-CN ,-NH at each occurrence₂, first Base, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₂Selected from hydrogen；Deuterium；Phenyl；Heteroatomic 5 unit's heteroaryl of N, O or S are selected from containing 1 or 2；Or containing 1 or 2 selected from N, Heteroatomic 6 unit's heteroaryl of O or S；And each W₂It is optionally substituted at each occurrence or not substituted 11,2,3,4 or 5 Substituent group, and each substituent group is selected from deuterium ,-F ,-Cl ,-Br ,-NH at each occurrence₂,-CN ,-OH, methyl, second Base, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₂Selected from phenyl；Heteroatomic 5 unit's heteroaryl of N, O or S are selected from containing 1 or 2；Or N, O or S are selected from containing 1 or 2 Heteroatomic 6 unit's heteroaryl；And each W₂It is optionally substituted at each occurrence or the not substituent group of substituted 11,2 or 3, and institute The each substituent group stated be selected from each occurrence-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, Propoxyl group or isopropoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₂It is selected from And each W₂It is optionally substituted at each occurrence Or the not substituent group of substituted 11,2 or 3, and each substituent group is selected from-F ,-Cl, methyl or methoxy at each occurrence.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle W₂Independently selected from:

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle Z is selected from hydrogen, deuterium ,-F ,-Cl ,-OH ,-C_1-3Alkyl or-C_1-3Alkoxy.

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Middle Z is selected from hydrogen, deuterium ,-F ,-Cl ,-OH, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.

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

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

In some embodiments of Formulas I, Formula II, formula III, formula IV, Formula V, Formula IV, Formula VII, Formula VIII or Formula IX, Described inIt is selected from:

And it is eachIt is optionally substituted at each occurrence or substituted 11,2 or 3 does not replace Base, and each substituent group be selected from each occurrence-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group or isopropoxy.

And it is eachIt is optionally substituted at each occurrence or the not substituent group of substituted 11,2 or 3, and described Each substituent group is selected from-F ,-Cl, methyl or methoxy at each occurrence.

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

On the other hand, a kind of pharmaceutical composition is provided, it includes the compound of at least one formula I, its pharmaceutically Acceptable salt or its stereoisomer, and at least one pharmaceutically acceptable excipient.

In the embodiment of some described pharmaceutical compositions, wherein the weight ratio of the compound and the excipient Range is about 0.0001 to about 10.

On the other hand, the present invention provides compound, its pharmaceutically acceptable salt or its alloisomerism of the Formulas I Body；The pharmaceutical composition, the application in the drug that disease relevant to bromine domain protein or illness are treated in preparation.

In preferable embodiment, the disease relevant to bromine domain protein or illness are selected from solid tumor (solid tumor) and/or blood tumor (blood tumor).

In preferable embodiment, the solid tumor is selected from lung cancer (lung cancer), tumor in digestive tract (gastrointestinal cancer), colon cancer (colon cancer), the carcinoma of the rectum (rectal cancer), colorectal cancer (colorectal cancer) and/or oophoroma (ovarian cancer)；The blood tumor (blood tumor) is selected from bone Myeloma (myeloma) and/or leukaemia (leukemia).

In preferable embodiment, the lung cancer includes non-small cell lung cancer (non-small cell lung ) and/or Small Cell Lung Cancer (small cell lung cancer) cancer；The tumor in digestive tract (gastrointestinal cancer) includes the cancer of the esophagus (esophageal cancer)；Leukaemia (leukemia) packet Include acute myeloid leukaemia (acute myeloid leukemia (AML)) and/or acute lymphoblastic leukemia (acute lymphocytic leukemia(ALL))；The myeloma (myeloma) includes Huppert's disease (multiple myeloma)。

Definition

Unless otherwise indicated, the term as used herein " halogen " refers to fluorine, chlorine, bromine or iodine.Preferably halogen group includes F, Cl and Br.

Unless otherwise indicated, the term as used herein " alkyl " includes the saturation univalent alkyl with linear chain or branched chain.Example Such as, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclobutyl, just Amyl, 3- (2- methyl) butyl, 2- amyl, 2- methyl butyl, neopentyl, cyclopenta, n-hexyl, 2- hexyl, 2- methyl amyl And cyclohexyl.Similarly, C_1-6C in alkyl_1-6Being defined as the group in linear chain or branched chain arrangement has 1,2,3,4,5 or 6 A carbon atom.

Term " alkylidene " refers to the difunctional obtained and removing hydrogen atom from alkyl as defined above.For example, Methylene (i.e.-CH₂), ethylidene (i.e.-CH₂-CH₂Or-CH (CH₃) -) and propylidene (i.e.-CH₂-CH₂-CH₂-、-CH(-CH₂- CH₃))-or-CH₂-CH(CH₃)-)。

Term " alkenyl " refers to containing one or more double bonds and normal length is the linear chain or branched chain of 2 to 20 carbon atoms Alkyl.For example, " C_2-6Alkenyl " contains 2 to 6 carbon atoms.Alkenyl includes but is not limited to such as vinyl, acrylic, butylene Base, 2- methyl-2-butene -1- base, heptenyl, octenyl etc..

Term " alkynyl " contains one or more three keys and normal length is the linear chain or branched chain hydrocarbon of 2 to 20 carbon atoms Base.For example, " C_2-6Alkynyl " contains 2 to 6 carbon atoms.Representative alkynyl includes but is not limited to, for example, acetenyl, 1- propine Base, 1- butynyl, heptynyl, octynyl etc..

Term " alkoxy " group is the oxygen ether formed by aforesaid alkyl.

Unless otherwise indicated, the term as used herein " aryl " refers to the unsubstituted or substituted monocycle containing carboatomic ring atom Or polycyclic aromatic ring system.Preferred aryl is monocycle or bicyclic 6-10 member aromatic ring system.Phenyl and naphthalene are preferred aryl.It is optimal The aryl of choosing is phenyl.

Unless otherwise indicated, the term as used herein " heterocycle " refers to heteroatomic unsubstituted containing one or more and takes The monocycle in generation or polycyclic non-aromatic ring system.Preferred hetero atom includes N, O and S, including N- oxide, oxysulfide and titanium dioxide Object.Preferably, which is three to eight yuan and is fully saturated or has one or more degrees of unsaturation.This definition includes more A degree of substitution, preferably one, two or three degree of substitution.The example of this heterocycle include but is not limited to azetidinyl, Pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, oxo-piperidine base, oxo aza ring heptyl, azacycloheptyl, tetrahydro furan It mutters base, dioxolanyl, imidazolidine base, tetrahydro-thienyl, tetrahydro oxazolyl, THP trtrahydropyranyl, morpholinyl, thiomorpholine Base, thiomorpholino sulfoxide, thio-morpholinyl sulfone and oxadiazoles.

Unless otherwise indicated, the term as used herein " heteroaryl " is indicated containing carbon and at least one heteroatomic aromatic ring system System.Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.Bicyclic heteroaryl can have in ring 1 to 4 it is miscellaneous Atom, and polyheteroaromatic may include 1 to 10 hetero atom.Polyheteroaromatic ring can be combined containing condensed, loop coil or bridged ring, example Such as, bicyclic heteroaryl is polyheteroaromatic.Bicyclic heteroaryl ring can contain 8 to 12 member atoms.Bicyclic heteroaryl ring can contain There is 5 to 8 member atoms (carbon atom and hetero atom).The example of heteroaryl includes, but are not limited to thienyl, furyl, imidazoles Base, isoxazolyl, oxazolyl, pyrazolyl, pyrrole radicals, thienyl, thiadiazolyl group, triazolyl, pyridyl group, pyridazinyl, indyl, Azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzo isoxazolyl, benzoxazolyl, benzene And pyrazolyl, benzothienyl, diazosulfide base, benzotriazole base adenyl, quinolyl or isoquinolyl.

Term " carbocyclic ring " refers to substituted or unsubstituted monocycle, bicyclic or polycyclic non-aromatic saturated rings, optionally includes Alkylidene linker, naphthenic base can be connected by the alkylidene linker.Illustratively " naphthenic base " group includes but is not limited to Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..

Term " oxo " refers to that oxygen is formed together with the carbon atom being connectGroup.

Term " carboxyl " refers to group C (O) OH.

Term " P (O) " refers to group P=O.

Term " substitution " refers to that at least one hydrogen atom is substituted by non-hydrogen group, as long as keeping normal chemical bond and replacing The stable compound in result position.

As used herein, term " composition " be intended to cover comprising specific quantity special component product, and directly or Any product generated indirectly by the combination of the special component of specific quantity.Therefore, contain the compounds of this invention as active constituent Pharmaceutical composition and the method for preparing the compounds of this invention be also a part of the invention.In addition, some knots of compound Crystalline form can be used as polymorphic presence, and therefore these are intended to include in the present invention.In addition, some compounds can be with water It forms solvate (i.e. hydrate) or common organic solvent, these solvates is intended to be included within the scope of the present invention.

The compounds of this invention can also exist as a pharmaceutically acceptable salt form.For being used in medicine, the present invention The salt of compound refers to nontoxic " pharmaceutically acceptable salt ".Pharmaceutically acceptable salt form includes pharmaceutically acceptable Acidity/anion or basic/cationic salts.Pharmaceutically acceptable acidity/anion salt generallys use wherein basic nitrogen nothing Machine acid or the form of organic acid protonation.Representative organic or inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulphur Acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, Benzoic acid, mandelic acid, methanesulfonic acid, ethylenehydrinsulfonic acid, benzene sulfonic acid, oxalic acid, pamoic acid, 2- naphthalene sulfonic acids, p-methyl benzenesulfonic acid, hexamethylene Alkylamino sulfonic acid, salicylic acid, saccharin or trifluoroacetic acid.Pharmaceutically acceptable basic/cationic salts include but is not limited to aluminium, Calcium, chloroprocanine, choline, diethanol amine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc salt.

The present invention includes the prodrug of the compounds of this invention within its scope.In general, this prodrug is the functionality of compound Derivative is easy to be converted into required compound in vivo.Therefore, in treatment method of the invention, term " administration " should be wrapped Include with specifically disclosed compound, or with may not specifically disclosed compound, but be converted into spy in vivo after giving subject Determine the various illnesss of the compound treatment description of compound.Conventional method for selecting and preparing suitable prodrug derivant is retouched It is set forth in such as " prodrug design " (" Design of Prodrugs ", ed.H.Bundgaard, Elsevier, 1985.).

The definition of any substituent group of specific position or variable is intended to take independently of other positions in the molecule in molecule The definition of Dai Ji or variable.It should be appreciated that those of ordinary skill in the art can choose substituent group on the compounds of this invention and Substitute mode to provide chemically stable compound, and can pass through techniques known in the art and side set forth herein Method is easily synthesized.

The present invention include the compound can containing one or more asymmetric centers, therefore can produce enantiomter, Diastereoisomer and optical isomer.The present invention include all these possible enantiomters, diastereoisomer and its Racemic mixture, the enantiomter of their substantially pure fractionations, all possible geometric isomer and its pharmaceutically may be used The salt of receiving.

The present invention includes all stereoisomers and its pharmaceutically acceptable salt of compound.In addition, further including solid The mixture of isomers and isolated particular stereoisomer.In the process for the synthetic method for being used to prepare these compounds In, or during using racemization well known by persons skilled in the art or epimereation process, the production of these methods Object can be the mixture of stereoisomer.

The present invention is intended to include all atom isotopes present in the compounds of this invention.Isotope is with same atoms Ordinal number but the different atom of mass number.It as general example rather than limits, the isotope of hydrogen includes deuterium and tritium.The isotope of hydrogen can It is expressed as¹H (hydrogen),²H (deuterium) and³H (tritium).They are often also indicated as D (deuterium) and T (tritium).In this application, CD₃Indicate first Base, wherein all hydrogen atoms are all deuteriums.The isotope of carbon includes¹³C and¹⁴C.The compound of isotope labelling of the invention is usual Can be by routine techniques well known by persons skilled in the art or by being prepared with similar method described herein, use is appropriate The reagent of isotope labelling replaces non-marked reagent.

Unless otherwise indicated, in the presence of the tautomer of compound of formula I, the present invention includes any possible mutual variation Structure body and its pharmaceutically acceptable salt and their mixture.

In the presence of compound of formula I and its pharmaceutically acceptable salt are with solvate or polymorphic forms, packet of the present invention Include any possible solvate and polymorphic.The type for forming the solvent of solvate is not particularly limited, as long as solvent is It is pharmacologically acceptable.It is, for example, possible to use water, ethyl alcohol, propyl alcohol, acetone etc..

Term " pharmaceutically acceptable salt " refers to the salt by pharmaceutically acceptable nontoxic alkali or acid preparation.Work as the present invention When compound is acidity, corresponding salt is prepared in which can be convenient by pharmaceutically acceptable nontoxic alkali, including inorganic base and is had Machine alkali.When the compound of the present invention is alkalinity, corresponding salt is prepared in which can be convenient by pharmaceutically acceptable non-toxic acid, Including inorganic acid and organic acid.Since compound of formula I is used for medicinal usage, they are preferably provided in a substantially pure form, example If at least 60% is pure, more suitably at least 75% is pure, especially at least 98% pure (% is weight % by weight)).

Pharmaceutical composition of the invention include Formulas I represent compound (or its pharmaceutically acceptable salt) as activity at Point, pharmaceutically acceptable carrier and optional other therapeutic components or adjuvant.Although most suitable in any given situation Approach will depend on specific host, and be illness (to treat the illness and applying the active constituent) property and sternly Weight degree, but the composition includes being suitable for oral, rectum, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration Composition.Pharmaceutical composition exists in which can be convenient with unit dosage forms, and passes through any method preparation known to pharmaceutical field.

In practice, according to conventional medicine preparation technique, the compound or its prodrug or metabolin of Formulas I representative of the invention Or its pharmaceutically acceptable salt can be used as active constituent and pharmaceutical carrier is combined into immixture.Carrier can be taken more Kind form, dosage form needed for this depends on administration route, such as oral or extra-parenteral (including intravenous) administration route.Cause This, pharmaceutical composition of the invention can be used as to be existed suitable for the discrete unit of oral administration, such as each containing predetermined amount Capsule, cachet (cachets) or the tablet of active constituent.In addition, composition can in powder form, particle form, solution shape Suspension, on-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion form in formula, waterborne liquid exist.In addition to above-mentioned common dose Outside type, the compound or its pharmaceutically acceptable salt that Formulas I represents can also be administered by controlled-release device and/or delivery apparatus. The composition can be prepared by any method of pharmacy.In general, these methods include keeping active constituent and composition one or more The carrier-bound step of essential component.In general, by by active constituent and liquid-carrier or solid carrier fine crushing or both Uniformly and closely mix to prepare composition.Then can be convenient by product shaping be required pattern.

Therefore, pharmaceutical composition of the invention may include the compound or pharmaceutically of pharmaceutically acceptable carrier and Formulas I Acceptable salt.The compound of Formulas I or its pharmaceutically acceptable salt can also be with one or more other treatment active ingredients Object is included in pharmaceutical composition together.

Pharmaceutical carrier used may, for example, be solid, liquid or gas.The example of solid carrier includes lactose, gypsum Powder, sucrose, talcum powder, gelatin, agar, pectin, Arabic gum, magnesium stearate and stearic acid.The example of liquid-carrier be syrup, Peanut oil, olive oil and water.The example of gaseous carrier includes carbon dioxide and nitrogen.In preparation compositions for oral dosage form In, any convenient drug media can be used.For example, water, ethylene glycol, oil, alcohol, flavoring agent, preservative, colorant etc. can quilts It is used to form the oral liquid of such as suspension, elixir and solution；And starch, sugar, microcrystalline cellulose, diluent, granulation The carriers such as agent, lubricant, adhesive, disintegrating agent may be used to form the oral solid formulation such as powder, capsule and tablet.Due to It is easy to be administered, tablet and capsule are preferred oral dosage units, wherein using solid pharmaceutical carriers.Optionally, tablet can be with It is coated by standard aqueous or nonaqueous techniques.

Tablet containing the present composition can optionally contain one or more auxiliary by suppressing or molding preparation Ingredient or adjuvant.Compressed tablets can by suppressed in suitable machine the activity such as powder or Particle free liquid form at Point, optionally prepared with adhesive, lubricant, inert diluent, surfactant or dispersant.Molded tablet can be with It is prepared by the mixture for the powder compounds that molding is soaked with inert liquid diluent in suitable machine.Every preferably Containing about 0.05mg to about 5g active constituent, each cachet or capsule preferably comprise from about 0.05mg to about 5g active constituent.Example Such as, about 0.5mg to the about 5g activity mixed with appropriate and the amount of convenience carrier mass is contained for the preparation of oral administration in human Agent, carrier mass can account for about the 0.05% to about 95% of total composition.Unit dosage forms usually contain about 0.01mg to about 2g activity Ingredient, usual 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

It is suitble to the pharmaceutical composition of the present invention of parenteral administration that can be prepared into the solution or outstanding of reactive compound in water Supernatant liquid.It may include suitable surfactant, such as hydroxypropyl cellulose.Dispersion can also be in glycerol, the poly- second two of liquid It is prepared in alcohol and its mixture in the oil.Furthermore, it is possible to prevent the obnoxious growth of microorganism comprising preservative.

Pharmaceutical composition of the present invention suitable for injecting purposes includes aseptic aqueous solution or dispersion liquid.In addition, composition can By be for the aseptic powdery of this sterile injectable solution of extemporaneous preparation or dispersion in the form of.In all cases, finally Injectable forms must be sterile and must be effective flowing in order to injecting.Pharmaceutical composition is being manufactured and is being stored Under the conditions of must be stable；It is therefore preferable that preservation under the pollution of the microorganism such as bacterium and fungi should be prevented.Carrier can be with It is for example containing water, ethyl alcohol, polyalcohol (such as glycerol, propylene glycol and liquid macrogol), vegetable oil and its suitable mixing The solvent or decentralized medium of object.

Pharmaceutical composition of the invention can be the form suitable for local use, for example, aerosol, emulsifiable paste, ointment, lotion, Dusting etc..In addition, composition can be the form suitable for transdermal device.Using compound of formula I of the invention or its pharmaceutically Acceptable salt, these preparations can be prepared by Conventional processing methods.For example, by by hydrophilic material and water and about The compound mixing of 0.05wt% to about 10wt% prepares emulsifiable paste or ointment to generate emulsifiable paste with required consistency or ointment.

Pharmaceutical composition of the invention can be the form suitable for rectally, and wherein carrier is solid.Preferred mixture Form unit dose suppositories.Suitable carrier includes cocoa butter and other materials commonly used in the art.Suppository can be by first Composition is mixed with the carrier of softening or fusing, then cooling in a mold and molding is to easily form.

Other than above-mentioned carrier components, said medicine preparation can uitably include one or more other carriers at Point, such as diluent, buffer, flavoring agent, adhesive, surfactant, thickener, lubricant, preservative be (including anti-oxidant Agent) etc..Furthermore, it is possible to include other adjuvants so that preparation and the blood of expected recipient are isotonic.Contain compound shown in Formulas I Or the composition of its pharmaceutically acceptable salt can also be prepared into powder or liquid concentrate form.

In general, the dosage level of about 0.001mg/kg to about 150mg/kg weight can be used for treating above-mentioned illness daily, or Person's every patient about 0.05mg to about 7g daily.For example, inflammation, cancer, psoriasis, allergy/asthma, the disease of immune system and The disease and illness of illness, central nervous system (CNS), can be by applying per kilogram of body weight about 0.001 to 50mg's daily About 0.05mg is effectively treated to about 3.5g daily for compound or every patient.

However, it should be understood that the specific dosage level of any particular patient will depend on including age, weight, general health Situation, gender, diet, administration time, administration route, excretion rate, pharmaceutical composition and receive treatment specified disease it is serious The many factors of degree.

From in written description of the invention, these and other aspects be will become obvious below.

Abbreviation

AIBN 2,2'- azodiisobutyronitrile LC-MS liquid chromatography-mass spectrography

The LDA lithium diisopropylamine of aq water

Bis- (trimethyl silyl) lithium amides of Bn benzyl LiHMDS

Boc tert-butoxy carbonyl Me methane

Boc₂O di-tert-butyl dicarbonate MeI iodomethane

CuI cuprous iodide MeCN acetonitrile

DCM methylene chloride MeOH methanol

DIAD diisopropyl azodiformate min minutes

ML milliliters of DIEA diisopropylamine

Mmol mMs of DMAP 4-dimethylaminopyridine

DMF dimethylformamide MTBE methyl tertiary butyl ether(MTBE)

DMSO dimethyl sulfoxide NaHCO₃Sodium bicarbonate

Bis- (trimethyl silyl) Sodamides of bis- (diphenylphosphino) the ethane NaHMDS of DPPE 1,2-

Dtbpy iodine (4,4- di-t-butyl -2, NBS N- bromine succinimide

2- bipyridyl) methyl palladium (II)

Equiv. equivalent n-BuLi n-BuLi

Et₃N triethylamine NH₄OAc ammonium acetate

Et₂O ether Pd (OAc) 2 palladium acetate

EtOAc ethyl acetate Pd (dppf) Cl₂[bis- (diphenylphosphinos) two of 1,1'-

Luxuriant iron] palladium chloride (II)

EtOH ethyl alcohol Prep-TLC prepares thin-layer chromatography

G grams of SEM trimethylsilyl ethoxyl methyl

H or hr hours SEM-Cl 2- (trimethyl silyl) second

Oxygroup methyl chloride

HBPin pinacol borine RT retention time

HPLC high pressure liquid chromatography r.t. room temperature

IPrOH isopropanol TEA triethylamine

KOtBu potassium tert-butoxide THF tetrahydrofuran

Preparation method

If it is known that drying method and synthetic organic chemical art as described below can be used in the technical staff of organic synthesis field Synthetic method or the variation of the above method known of field technical staff synthesize compound of the present invention well.It is excellent The method of choosing is not limited to method as described below.The document cited herein is incorporated hereby.

The synthetic method meant for illustration present invention described below, rather than limit the change claimed in its theme and these embodiments Close object range.When the initial compounds of preparation are not described, they are commercially available or can be with knownization It closes object or method described herein is similarly prepared.Substance described in document can be prepared according to disclosed synthetic method.

The compound of Formulas I can refer to the method preparation that following scheme illustrates.As shown here, target compound be have with The product of the identical structural formula of Formulas I description.It should be appreciated that any compound of formula I can suitably be replaced by selecting to have It is prepared by reagent.Those skilled in the art can be readily selected solvent, temperature, pressure and other reaction conditions.According to organic Standard method (T.W.Green and P.G.M.Wuts (1999) the Protective Groups in Organic of synthesis Synthesis, the 3rd edition, John Wiley&Sons) operation protection group.Use the obvious method of those skilled in the art These groups are removed in certain stages of compound synthesis.

Scheme 1

The general synthesis path of compound shown in the present invention is described in scheme 1, wherein the R₁、R₂、R₃、R₄、W₁ And W₂Substituent group is the functional group being described in text before or being converted into needs that base is finally replaced.L It is the leaving group such as halogen.M is suitable coupling ligand, such as boric acid, borate or tin hydrocarbon.As shown in scheme 1, described Pyridine (the such as, but not limited to, bromo- 3- nitro of 2,5- bis- that intermediate (its synthesis is illustrated in scheme 2 into scheme 5) and halogen replace Pyridine (1)) between Suzuki react can get function dough pyridine (2).In high temperature (such as, but not limited to, 150 DEG C), in phosphonate reagent (bis- (diphenylphosphino) ethane (DPPE) of such as, but not limited to, 1,2-) and solvent (such as, but not limited to, 1,2- dichloro Benzene) in the presence of, the tetracyclic compound of the formula (3) of the available function dough of the Cadogan reductive cyclization of (2).Use reagent The Mitsunobu of (3) and alkylating agent (4) of (such as, but not limited to, triphenylphosphine and diisopropyl azodiformate (DIAD)) is even Connection reaction provides (5).Using Suzuku or Stille reaction condition, (furthermore M is suitably to be coupled for the suitable coupling of (5) and (6) Ligand, such as boric acid, boron ester or stannane) compound (7) can be generated, which has identical structure shown in logical formula (I), Or the compound of final general formula formula (I) can be further converted to.If compound (7) has functional group's (such as, but not limited to, second Base ester), the compound of general formula formula (I) can be provided using reagent (such as, but not limited to, MeMgBr).If compound (7) has protection Group (such as, but not limited to, SEM) can be deprotected, and then further function dough is to provide the compound of general formula formula (I).

As shown in scheme 2, physical efficiency is acquired among a kind of general formula.

Scheme 2

In solvent (such as, but not limited to, EtOH), NaOEt, the reaction of compound (8) and 2- ethyl triazoacetate are used The compound of offer formula (9).Under raised temperature (such as at about 110 DEG C), in solvent (such as, but not limited to, dry toluene), formula (9) compound is converted into the compound of formula (10).In the presence of alkali (such as, but not limited to, NaH), (such as, but not limited to, in solvent DMF in), (10) and alkyl halide R₁- hal (such as, but not limited to, MeI) protects the N of reagent (SEM-Cl) to be alkylated offer formula (11) Compound.In raised temperature (such as 70 DEG C), in a solvent (such as, but not limited to, THF), in bis- (1,5- cyclo-octadiene) dimethoxies Two iridium of base and 4 in the presence of 4'- di-t-butyl -2,2'- bipyridyl, uses HBPin processing (11) to provide the intermediate.

Additionally, as shown in Scheme 3, physical efficiency is synthesized among a kind of general formula.

Scheme 3

In solvent (such as, but not limited to, EtOH), NaOEt, the reaction of compound (12) and 2- ethyl triazoacetate are used The compound of offer formula (13).Under raised temperature (such as at about 110 DEG C), in solvent (such as, but not limited to, dry toluene), The compound of formula (13) is converted into the compound of formula (14).It is (such as but unlimited in solvent in the presence of alkali (such as, but not limited to, NaH) In DMF) in, (14) and alkyl halide R₁- hal (such as, but not limited to, MeI) protects the N of reagent (SEM-Cl) to be alkylated offer formula (15) Compound.In raised temperature (such as 70 DEG C), in a solvent (such as, but not limited to, THF), in bis- (1,5- cyclo-octadiene) diformazans Two iridium of oxygroup and 4 in the presence of 4'- di-t-butyl -2,2'- bipyridyl, uses HBPin processing (15) to provide the intermediate.

Additionally, as shown in Scheme 4, physical efficiency is synthesized among a kind of general formula:

Scheme 4

In raised temperature (such as, but not limited to, 85 DEG C), N₂Under, in the presence of NBS and AIBN, solvent (such as, but not limited to, Acetonitrile) in, processing 3 methyl thiophene -2- carboxylate methyl ester (16) provides (17).Under raised temperature (such as, but not limited to, 80 DEG C), In alkali (such as, but not limited to, K₂CO₃) in the presence of, in solvent (such as, but not limited to, MeOH), use reagent N H₂R₃(18) it handles, (17) it is converted into the compound of formula (19).In the solvent of DMF, in the presence of alkali (such as, but not limited to, NaH) handle (19) and with Alkyl halide R is added afterwards₁- hal or R₂- hal (such as MeI) can provide the compound of formula (20).It is (such as but unlimited in solvent at -78 DEG C In THF) in, using highly basic (such as, but not limited to, LDA), the reaction of (20) and can then be provided using triisopropyl borate ester described General formula intermediate.

Additionally, as shown in scheme 5, a kind of general formula centre physical efficiency is synthesized.

Scheme 5

At -60 DEG C to room temperature, in solvent (such as, but not limited to, THF), using alkali (such as, but not limited to, t-BuONa), in 2- Coupling reaction between nitrothiophene (21) and 2- ethyl chloroacetate (22) can provide compound (23).Raised temperature (such as 110 DEG C), in dioxane and H₂In the combination solvent of O (5:1, v:v), in iron powder and FeSO₄.7H₂In the presence of O, compound (23) NO₂The also proper energy of functional group provides compound (24).At -80 DEG C between room temperature, at solvent (such as, but not limited to, THF) In, (24) and AlMe₃Reaction compound (25) can be provided.In solvent (such as, but not limited to, DMF), alkali (such as, but not limited to, NaH in the presence of), with alkyl halide R₃The N of (25) of-hal (such as, but not limited to, MeI) is alkylated, or with as protecting group (PG) The N alkylation of (25) of such as, but not limited to, SEM-Cl can provide the compound of formula (26).In 0 DEG C, solvent (such as, but not limited to, THF in), (26) is handled using highly basic (such as, but not limited to, NaH), then add alkyl halide R₁- hal or R₂- hal is (such as, but not limited to, Iodomethane and iodoethane) compound of formula (27) can be provided.At -20 DEG C between room temperature, at solvent (such as, but not limited to, DCM) In, at [Ir (COD) (OMe)]₂In the presence of dtbpy, HBPin can provide the intermediate with reacting for compound (27).

Embodiment 1

(S) -2- (7- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -9- (phenyl (tetrahydro -2H- pyrrole Mutter -4- base) methyl) -1,9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2- base) third Alkane -2- alcohol (" compound 1 ")

Step 1:(Z) -2- azido -3- (thiophene -2- base) ethyl acrylate

In N₂, 2- triazoacetic acid is added into EtOH (220mL) solution of thiophene -2-formaldehyde (29.7g, 0.16mol) Ethyl ester (40.32g, 0.31mol).At -10 DEG C to -5 DEG C, fresh NaOEt solution is added dropwise into the mixture (at 0 DEG C, by Na (8.90g, 0.39mol) and dehydrated alcohol (350mL) preparation).Obtained suspension stirs 2 hours between -5 DEG C to 0 DEG C. The reaction mixture is quenched using cold saturated ammonium chloride solution, to adjust its pH to about 8.The solid of precipitating is filtered, is used Cold water (50mL) is washed and is dried under vacuum to generate 3.56g crude product.By the silica gel chromatography crude product, with 0- The hexanes of 5%EtOAc obtain title compound (5.67g, 12% yield).

Step 2:4H- thiophene [3,2-b] pyrroles's -5- carboxylic acid, ethyl ester

(Z) -2- azido -3- (thiophene -2- base) ethyl acrylate (5.62g, 25.2mmol) is dissolved in dry toluene In (60mL).The mixture is in 110 DEG C of stirring 1h.Then, which is poured into water and EtOAc (2 ×) is used to extract. Combined extract is washed with salt water (2 ×), and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Residue passes through silica gel Chromatogram purification obtains title compound (4.34g, 22.2mmol, 88% yield) with the hexanes of 0-10%EtOAc. LC-MS[M+H]⁺=196.

Step 3:4- methyl -4H- thiophene [3,2-b] pyrroles's -5- carboxylic acid, ethyl ester

At room temperature, molten to the DMF (20mL) of 4H- thiophene [3,2-b] pyrroles -5- carboxylic acid, ethyl ester (4.24g, 21.7mmol) K is added in liquid₂CO₃Then iodomethane (2.52g, 17.8mmol) is added dropwise in (7.82g, 56.6mmol).The mixture is at room temperature Stir 2h.Make that the reaction is quenched with water and is extracted with EtOAc (3 ×).It is washed with brine the organic phase of merging, anhydrous sodium sulfate is dry It is dry, it filters and is concentrated under reduced pressure.Residue is obtained by silica gel chromatography with the hexanes of 0-10%EtOAc The title compound (3.96g, 18.9mmol, 87% yield).LC-MS[M+H]⁺=210.

Step 4:4- methyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -4H- thiophene [3,2-b] pyrrole Cough up -5- carboxylic acid, ethyl ester

In N₂Under, to the THF of 4- methyl -4H- thiophene [3,2-b] pyrroles -5- carboxylic acid, ethyl ester (720mg, 3.44mmol) Bis- two iridium (126mg, 0.19mmol) of (1,5- cyclo-octadiene) dimethoxy and 4,4'- di-t-butyl-are added in (15mL) solution 2,2'- bipyridyl (285mg, 1.06mmol).Then, HBPin (2.25g, 17.6mmol) is added between -10 DEG C to -5 DEG C. The mixture is deaerated, N is filled₂, and repeat the process 3 times.Mixture obtained is in 75 DEG C of stirring 2h.It is concentrated under reduced pressure this Reaction mixture obtains dirty oil, the not purified reaction for being directly used in next step.LC-MS[M+H]⁺=336.

Step 5:2- (the bromo- 3- nitropyridine -2- base of 5-) -4- methyl -4H- thiophene [3,2-b] pyrroles's -5- carboxylic acid, ethyl ester

To above-mentioned crude compound 4- methyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -4H- thiophene The bromo- 3- nitropyridine of 2,5- bis- is added in the water (7mL) and THF (21mL) solution of [3,2-b] pyrroles -5- carboxylic acid, ethyl ester (1.18g, 4.19mmol) and K₃PO₄(2.21g,10.41mmol).Use N₂The mixture is deaerated and then in N by stream₂Lower drop Add Pd (PPh₃)₄(410mg,0.35mmol).The reaction mixture is refluxed overnight.The reaction is extracted using EtOAc (2 × 100mL) Mixture.Make the organic phase for being washed with brine merging, anhydrous sodium sulfate is dried, filtered and is concentrated at reduced pressure conditions.Residue By silica gel chromatography, title compound (820mg, 58% yield) is obtained with the hexanes of 0-10%EtOAc. LC-MS[M+H]⁺=410.

The bromo- 1- methyl-1 of step 6:7-, 9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] Pyridine-2-carboxylic acids ethyl ester

In N₂Under, it will be in 2- (the bromo- 3- nitropyridine -2- base of 5-) -4- methyl -4H- thiophene in 1,2- dichloro-benzenes (20mL) The mixture of pheno [3,2-b] pyrroles -5- carboxylic acid, ethyl ester (770mg, 1.88mmol) and DPPE (1.89g, 4.74mmol) are heated to 150 DEG C and stir 2h.Then, which is cooled to room temperature.Most of solvent is removed on a rotary evaporator.It is remaining Object obtains title compound (280mg, 39% yield) by silica gel chromatography, with the DCM solution elution of 0-10%EtOAc. LC-MS[M+H]⁺=378.

Step 7:(S) the bromo- 1- methyl -9- of -7- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine-2-carboxylic acids ethyl ester

At room temperature, to the bromo- 1- methyl-1 of 7-, 9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3, 2-b] pyridine-2-carboxylic acids ethyl ester (250mg, 0.66mmol), (R)-phenyl (tetrahydro -2H- pyrans -4- base) methanol (260mg, Diisopropyl azo diformazan 1.37mmol) and in dry toluene (10mL) solution of triphenylphosphine (526mg, 2.00mmol) is added dropwise Acid esters (412mg, 2.04mmol).Acquired solution reflux 2h.After being cooled to room temperature, the reaction is quenched with water (20mL) and is used in combination EtOAc (3 × 30mL) extraction.With the organic phase that salt water washing merges, anhydrous sodium sulfate is dry, collects filtrate and is concentrated under reduced pressure. Residue obtains title compound by silica gel chromatography, using the hexanes of the 0-30%EtOAc of gradient (110mg, 30% yield).LC-MS:[M+H]⁺=552.

Step 8:(S) -7- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -9- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -1,9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2- carboxylic Acetoacetic ester

N₂Under, to the bromo- 1- methyl -9- of (S) -7- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,9- pyrrolin The 1,4- of [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles's [3,2-b] pyridine-2-carboxylic acids ethyl ester (110mg, 0.20mmol) In the solution of dioxane (5mL) add 1,4- dimethyl -5- (tributyl tin) -1H-1,2,3- triazole (289mg, 0.75mmol)、PdCl₂(PPh₃)₂(21mg, 0.030mmol) and DIEA (85mg, 0.66mmol).Use N₂Stream mixes reaction Object degassing, seals and is stirred overnight at 125 DEG C.Reaction mixture is cooled to room temperature, is poured into water (10mL) and with EtOAc (3 × 15mL) extraction.Combined organic phase is washed using salt water (20mL), anhydrous sodium sulfate is dry, collects filtrate and is concentrated under reduced pressure. Crude product obtains title compound by preparation HPLC purifying, with 0% to the 5%MeOH EtOAc solution elution of gradient (80mg, 70% yield).LC-MS[M+H]⁺=569.

Step 9:(S) -2- (7- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -9- (phenyl (tetrahydro - 2H- pyrans -4- base) methyl) -1,9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrroles's [3,2-b] pyridine -2- Base) propane -2- alcohol

N₂Under, between -10 DEG C to -5 DEG C, to (S) -7- (Isosorbide-5-Nitrae-dimethyl -1H-1,2,3- triazole -5- bases) -1- first Base -9- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,9- pyrrolin [2 ", 3 ": 4', 5'] thiophene [2', 3':4,5] pyrrole Cough up dropwise addition methyl-magnesium-bromide (2.5mL) in THF (5mL) solution of [3,2-b] pyridine-2-carboxylic acids ethyl ester (60mg, 0.10mmol). The mixture is warmed to room temperature and stirs 2h.The reaction is quenched using the aqueous ammonium chloride solution of saturation and with EtOAc (3 × 30mL) Extraction.Combined organic layer is washed using salt water (2 ×), anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Crude product passes through system Standby HPLC is purified, and obtains title compound (29mg, 52% yield) with 0% to the 5%MeOH DCM solution elution of gradient.LC- MS[M+H]⁺=555.¹H-NMR(400MHz,DMSO-d₆) δ 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).

Embodiment 2

(S) -2- (6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -4- (phenyl (tetrahydro -2H- pyrrole Mutter -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2- base) third Alkane -2- alcohol (" compound 2 ")

Step 1:(Z) -2- azido -3- (thiene-3-yl) ethyl acrylate

N₂Under, between -10 DEG C to -5 DEG C, to thiophene -3- formaldehyde (4.95g, 44.14mol) and 2- triazoacetic acid second Be added dropwise in EtOH (50mL) solution of ester (8.61g, 66.68mol) freshly prepared NaOEt solution (at 0 DEG C, by Na (2.41g, 104.78mol) it is suspended in dehydrated alcohol (in 50mL).Gained suspension stirs 2h between -5 DEG C to 0 DEG C.Use cold saturation The reaction mixture is quenched in aqueous ammonium chloride solution, and its pH is adjusted to about 8.It is mixed that this is extracted using EtOAc (3 × 300mL) Close object.Combined organic phase is washed using salt water (100mL), anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Residue uses Hexane obtains title compound (4.69g, 48% yield) by silica gel chromatography.

Step 2:6H- thiophene [2,3-b] pyrroles's -5- carboxylic acid, ethyl ester

(Z) -2- azido -3- (thiene-3-yl) ethyl acrylate (4.16g, 18.63mmol) is dissolved in anhydrous to two In toluene (10mL).By the mixture in 145 DEG C of stirring 3h.Residue uses the 0-10% of gradient by silica gel chromatography The hexanes of EtOAc obtain title compound (1.77g, 48% yield).LC-MS[M+H]⁺=196.¹H-NMR (400MHz,DMSO-d₆) δ 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- thiophene [2,3-b] pyrroles's -5- carboxylic acid, ethyl ester

At room temperature, to the molten of the DMF (15mL) of 6H- thiophene [2,3-b] pyrroles -5- carboxylic acid, ethyl ester (1.77g, 9.06mmol) K is added in liquid₂CO₃Then iodomethane (1.65g, 11.6mmol) is added dropwise in (3.81g, 27.6mmol).By the mixture in room temperature Lower stirring 3h.The reaction is quenched with water (30ml) and is extracted with EtOAc (3 × 50mL).Merging is washed with salt water (4 × 50ml) Organic phase, anhydrous sodium sulfate are dried, filtered and are concentrated under reduced pressure.Residue uses the 0-5% of gradient by silica gel chromatography The hexane solution of EtOAc obtains title compound (1.83g, 96% yield).LC-MS[M+H]⁺=210.

Step 4:6- methyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -6H- thiophene [2,3-b] pyrrole Cough up -5- carboxylic acid, ethyl ester

According to step similar described in 1 step 4 of embodiment, by 6- methyl -6H- thiophene [2,3-b] pyrroles's -5- carboxylic acid Ethyl ester (1.42g, 6.78mmol) is converted into title crude compound, is directly used in next step.LC-MS[M+H]⁺=336.

Step 5:2- (the bromo- 3- nitropyridine -2- base of 5-) -6- methyl -6H- thiophene [2,3-b] pyrroles's -5- carboxylic acid, ethyl ester

To the bromo- 3- nitropyridine (2.31g, 8.19mmol) of 2,5- bis- water (10mL) and THF (50mL) solution in plus Enter 6- methyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -6H- thiophene [2,3-b] pyrroles's -5- carboxylic acid, ethyl ester (4.61g, 6.78mmol) and K₃PO₄(4.38g,20.64mmol).Use N₂Gained mixture is deaerated and, then, in N₂Under add Add Pd (dppf) Cl₂(568mg,0.70mmol).The reaction mixture is stirred overnight at 50 DEG C.With EtOAc (3 × 150mL) Extract the reaction mixture.The organic phase merged is washed with salt water (200mL), anhydrous sodium sulfate is dry, collects filtrate and depressurizes Concentration.Residue obtains title compound by silica gel chromatography, using the hexanes of the 0-10%EtOAc of gradient (1.18g, 42% yield).LC-MS[M+H]⁺=410.

The bromo- 1- methyl-1 of step 6:6-, 4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] Pyridine-2-carboxylic acids ethyl ester

According to similar step described in 1 step 6 of embodiment, by 2- (the bromo- 3- nitropyridine -2- base of 5-) -6- methyl - 6H- thiophene [2,3-b] pyrroles -5- carboxylic acid, ethyl ester (1.18g, 2.88mmol) is converted into title compound, and (320mg, 29% produces Rate).LC-MS[M+H]⁺=378.

Step 7:(S) the bromo- 1- methyl -4- of -6- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine-2-carboxylic acids ethyl ester

According to similar step described in 1 step 7 of embodiment, by the bromo- 1- methyl-1 of 6-, 4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles's [3,2-b] pyridine-2-carboxylic acids ethyl ester (300mg, 0.79mmol) and (R)-phenyl (four Hydrogen -2H- pyrans -4- base) methanol (320mg, 1.68mmol) is converted into title compound (810mg crude product).Use the 0% of gradient Methanol in ethyl acetate to 2% obtains product (160mg, 37% yield) to the purifying products by preparing HPLC.LC-MS [M+H]⁺=552.

Step 8:(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -4- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2- carboxylic Acetoacetic ester

According to step similar in 1 step 8 of embodiment, by the bromo- 1- methyl -4- of (S) -6- (phenyl (tetrahydro -2H- pyrans - 4- yl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine-2-carboxylic acids ethyl ester The conversion of (160mg, 0.29mmol) and 1,4- dimethyl -5- (tributyl tin) -1H-1,2,3- triazole (466mg, 1.21mmol) For thick title compound, by preparation HPLC purifying, the EtOAc solution elution of use 0% to 2%MeOH obtains compound (79mg, 48% yield).LC-MS[M+H]⁺=569.

Step 9:(S) -2- (6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1- methyl -4- (phenyl (tetrahydro - 2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles's [3,2-b] pyridine -2- Base) propane -2- alcohol

Similar step in step 9 according to embodiment 1, by (S) -6- (Isosorbide-5-Nitrae-dimethyl -1H-1,2,3- triazole -5- Base) -1- methyl -4- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine-2-carboxylic acids ethyl ester (60mg, 0.10mmol) is converted into thick title compound, passes through system Standby HPLC is purified, and the DCM solution elution of use 0% to 5%MeOH obtains title compound (35mg, 63% yield).LC-MS[M +H]⁺=555.¹H-NMR(400MHz,DMSO-d₆) δ 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)。

Embodiment 3

(S) -3- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -6,6,7- trimethyl -5- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one (" compound 3 ")

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

N₂Under, NBS is added into acetonitrile (38mL) solution of 3 methyl thiophene -2- carboxylate methyl ester (2.99g, 19.2mmol) (3.98g, 22.4mmol) and AIBN (1.01g, 6.20mmol), by the mixture in 85 DEG C of stirring 15h.The reaction system is cold But it to room temperature, is concentrated under reduced pressure.Residue adds water (50mL) and is extracted with EtOAc (100mL).It is washed with brine organic phase, nothing Aqueous sodium persulfate, which is dried, filtered and is concentrated under reduced pressure, obtains thick 3- (bromomethyl) thiophene-2-carboxylic acid methyl esters (5.57g), without pure Change is directly used in next step.LC-MS[M+H]⁺=236.

Step 2:3- (aminomethyl) thiophene-2-carboxylic acid methyl esters

NH is added into methanol (30mL) solution of 3- (bromomethyl) thiophene-2-carboxylic acid methyl esters (5.57g, crude product)₃First Alcoholic solution (7N, 40mL).Gained mixture is in 25 DEG C of stirring 3h.Reaction system is concentrated under reduced pressure and is added into residue EtOAc(25mL).The mixture is stirred into 30min, obtained solid is collected by filtration and washs described with EtOAc (2mL) Title compound (66% yield of 2.17g, 12.6mmol, two step).LC-MS[M+H]⁺=172.

Step 3:4,5- dihydro -6H- thiophene [2,3-c] pyrroles's -6- ketone

K is added into methanol (20mL) solution of 3- (aminomethyl) thiophene-2-carboxylic acid methyl esters (2.27g, 14.5mmol)₂CO₃ (5.27g,38.1mmol).By gained mixture in 80 DEG C of stirring 10h.Reaction system is cooled to room temperature, is concentrated under reduced pressure.To this Water (100mL) is added in residue and is extracted with EtOAc (500mL).It is washed with brine organic phase, anhydrous sodium sulfate is dry, mistake It filters and is concentrated under reduced pressure.The residue obtains title compound by silica gel chromatograph, using the hexane solution of 25%EtOAc (0.61g, 31% yield).LC-MS:[M+H]⁺=140.¹H-NMR(400MHz,DMSO-d₆)δ8.38(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- thiophene [2,3-c] pyrroles's -6- ketone

At 0 DEG C, in 10min, to 4,5- dihydro -6H- thiophene [2,3-c] pyrroles -6- ketone (2.02g, 14.5mmol) NaH (60%, 2.98g, 72.7mmol) is added portionwise in DMF (20mL) solution, then the mixture is warmed to room temperature and is stirred 30min.Reaction system is cooled to 0 DEG C, is subsequently added into CH₃I (10.8g, 73.0mmol), is slowly increased to room temperature and in N₂Under stir Mix 1.5h.At 0 DEG C, the reaction is quenched with water (20mL) and is extracted with EtOAc (100mL).It is washed with brine the organic phase, it is anhydrous Sodium sulphate is dry, collects filtrate and is concentrated under reduced pressure.Residue uses the 5-10%EtOAc of gradient by silica gel chromatography Solution elution obtains title compound (1.75g, 70% yield).LC-MS[M+H]⁺=182.¹H-NMR(400MHz,CDCl₃)δ 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- thiophene [2,3-c] pyrroles -2- base) boric acid

At -78 DEG C, N₂Under, in 30min, to 4,4,5- trimethyl -4,5- dihydro -6H- thiophene [2,3-c] pyrroles's -6- ketone LDA (2N, 14mL, 28.5mmol) is added dropwise in THF (60mL) solution of (2.72g, 15.0mmol) and by gained mixture -78 DEG C stirring 1h.Then, in 30min, in -78 DEG C of dropwise addition triisopropyl borate esters.Gained reaction mixture stirs other 1h, and It is quenched between 0 DEG C to 10 DEG C by 2N HCl (25mL), reaches pH5-6.Salt water 50mL is added into the mixture, and so It is extracted afterwards with EtOAc (150mL).It is washed with brine organic phase, anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Gained is remaining Object is stirred with EtOAc (20mL).Be collected by filtration the solid and in air it is dry obtain title compound (2.18g, 70% Yield).LC-MS[M+H]⁺=226.

Step 6:2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4,5- trimethyl -4,5- dihydro -6H- thiophene [2,3-c] pyrrole Cough up -6- ketone

To (4,4,5- trimethyl -6- oxo -5,6- dihydro -4H- thiophene [2,3-c] pyrroles -2- base) boric acid (2.16g, In the solution of THF (100mL) and water (25mL) 9.62mmol) be added the bromo- 3- nitropyridine of 2,5- bis- (2.98g, 10.6mmol)、Pd(dppf)Cl₂(0.69g, 0.67mmol) and K₃PO₄(6.02g, 28.4mmol), the mixture fill N₂ 2min.Gained mixture is subsequently added into water (50mL) in 35 DEG C of stirring 2.5h, and is extracted with EtOAc (100mL).It is washed with salt Gained organic phase is washed, anhydrous sodium sulfate is dry, and filtrate is collected by filtration.Solvent, gained are removed on a rotary evaporator Residue obtains title compound by silica gel chromatography, using the hexanes of the 10-20%EtOAc of gradient (2.32g, 65% yield).LC-MS[M+H]⁺=382.

Bromo- 6,6,7- trimethyl -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', the 3':4,5] pyrroles of step 7:3- [3,2-b] pyridine -8 (5H) -one

To 2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4,5- trimethyl -4,5- dihydro -6H- thiophene [2,3-c] pyrroles - Triethyl phosphate (4.55g, 27.4mmol) is added in the dimethyl benzene solution of 6- ketone (1.61g, 4.21mmol) and fills N₂ 1min.Gained mixture stirs 3h in 130o C.The reaction mixture is cooled to room temperature.Solid comes out and is led to from the solvent It is collected by filtration, hexane washs to obtain title compound (0.67g, 43% yield).LC-MS[M+H]⁺=350.

Step 8:(S) the bromo- 6,6,7- trimethyl -5- of -3- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -6,7- dihydro Pyrroles [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one

Similar step described in step 7 according to embodiment 2, by bromo- 6,6,7- trimethyl -6,7- pyrrolin of 3- [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one (1.05g, 3mmol) and (R)-phenyl (tetrahydro -2H- pyrans -4- base) methanol (0.98g, 5.16mmol) is converted into title compound (0.45g, 30% yield), and leads to Cross the silica gel chromatography of the 0-20%EtOAc hexane solution using gradient.LC-MS[M+H]⁺=524.

Step 9:(S) -3- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -6,6,7- trimethyl -5- (phenyl (four Hydrogen -2H- pyrans -4- base) methyl) -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyrrole Pyridine -8 (5H) -one

According to step similar in 2 step 8 of embodiment, by (S) -3- bromo- 6,6,7- trimethyl -5- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one (0.45g, 0.85mmol) and 1,4- dimethyl -5- (tributyl tin) -1H-1,2,3- triazole (0.59g, It 1.50mmol) is converted into title compound (170mg, 53% yield), and molten by using the DCM of the 0-50%EtOAc of gradient The silica gel chromatography of liquid.LC-MS[M+H]⁺=541.¹H-NMR(400MHz,DMSO-d₆)δ8.59(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)。

Embodiment 4

3- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -5- ((3- fluorine pyridine -2- base) (tetrahydro -2H- pyrans - 4- yl) methyl) -6,6,7- trimethyl -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyrrole Pyridine -8 (5H) -one (" compound 4 ")

Step 1:(3- fluorine pyridine -2- base) (tetrahydro -2H- pyrans -4- base) methanol

In N₂Under, three iodine crystal are added into THF (500mL) suspension of magnesium (24.3g, 1.00mol), are then added dropwise Pure 4- bromine tetrahydro -2H- pyrans (100g, 607mmoL), during dropwise addition, control internal temperature is lower than 45 DEG C.In environment temperature Under degree, which is continued to stir 2h.The reaction mixture is cooled to -30 DEG C, 3- fluorine pyridine carboxaldehyde is then added dropwise THF (300mL) solution of (50.3g, 402mmoL), internal temperature is maintained at -20 DEG C to -30 DEG C during dropwise addition.After 1h, Reaction mixture is filtered by very thin Celite pad.The NH of saturation is added into filtrate₄Cl (100mL) aqueous solution, separation At two layers.Anhydrous Na₂SO₄Dry organic phase simultaneously collects filtrate.Filtrate is concentrated on a rotary evaporator.Crude compound uses reverse phase Chromatogram purification, with the H of 40-50%MeCN₂The elution of O solution, obtains racemic compound (52g, 61% yield), passes through chirality It prepares SFC separation and obtains enantiomter A (25.1g, 29.6% yield) and enantiomter B (25.3g, 29.7% yield).

Enantiomter A:LC-MS [M+H]⁺=212.Chiral chromatogram report: RT=12.25min (column: ChiralpakAY-H(ADH0CE-VC001 0.46×25cm；Mobile phase: 90/10/0.1 hexane/EtOH/DEA；Flow velocity: 1.0mL/min).¹HNMR(400MHz,DMSO-d₆) δ 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).

Enantiomter B:LC-MS [M+H]⁺=212.Chiral chromatogram report: RT=13.57min (column: ChiralpakAY-H(ADH0CE-VC001 0.46×25cm；Mobile phase: 90/10/0.1 hexane/EtOH/DEA；Flow velocity: 1.0mL/min)。¹HNMR(400MHz,DMSO-d₆) δ 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).

The bromo- 5- of step 2:3- ((3- fluorine pyridine-2- base) (tetrahydro-2H- pyrans-4- base) methyl) trimethyl-6-6,6,7-, 7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one

According to step similar in 2 step 7 of embodiment, in dry toluene (15mL), by 3- bromo- 6,6,7- front threes Base -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -8 (5H) -one (200mg, 0.57mmol) and (3- fluorine pyridine -2- base) (tetrahydro -2H- pyrans -4- base) methanol (from the enantiomter A of step 1, 150mg, 0.69mmol), triphenylphosphine (387mg, 1.47mmol) be converted into title compound (73mg, 25% yield), pass through Silica gel chromatograph is purified using the hexane solution of the 10-20%EtOAc of gradient.LC-MS[M+H]⁺=543.

Step 3:3- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -5- ((3- fluorine pyridine -2- base) (tetrahydro -2H- Pyrans -4- base) methyl) -6,6,7- trimethyl -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3, 2-b] pyridine -8 (5H) -one

According to synthesis step similar in 2 step 8 of embodiment, by the bromo- 5- of 3- ((3- fluorine pyridine -2- base) (tetrahydro -2H- pyrrole Mutter -4- base) methyl) -6,6,7- trimethyl -6,7- pyrrolin [3 ", 4 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2- B] pyridine -8 (5H) -one (73mg, 0.13mmol) and 1,4- dimethyl -5- (tributyl tin) -1H-1,2,3- triazole (91mg, It 0.24mmol) is converted into title compound (42mg, 56% yield), the 0-50%EtOAc of gradient is used by silica gel chromatograph DCM solution purification.LC-MS[M+H]⁺=560.¹H NMR(400MHz,DMSO-d₆) δ 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)。

Embodiment 5

(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1,3,3- trimethyl -4- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one (" compound 5 ")

Step 1:2- (2- nitrothiophene -3- base) ethyl acetate

At -60 DEG C, t-BuONa is added dropwise into THF (800mL) solution of 2- nitrothiophene (24.9g, 0.19mol) THF (100mL) solution of (54.33g, 0.57mol).By the mixture in -60 DEG C of stirring 1h.At -60 DEG C, 2- monoxone is added Ethyl ester (23.7g, 0.19mol) and in -60 DEG C of stirring 1h.The mixture is warmed to room temperature and 1h is stirred at room temperature.It is mixed to this Close the NH that saturation is added in object₄Cl (15mL) aqueous solution and 10min is stirred at room temperature.Na is added in the mixture₂SO₄ (30g) and by the mixture filter and filtrate decompression be concentrated.Residue is molten using the hexane of 0-50%EtOAc by silica gel chromatograph Liquid purifying obtains title compound.(19.6g, 48% yield).LC-MS[M+H]⁺=216；¹H NMR(400MHz,DMSO-d₆)δ 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 2:2- (2- aminothiophene -3- base) ethyl acetate

N₂Under, to 2- (2- nitrothiophene -3- base) ethyl acetate (19.6g, 91.0mmol) dioxane (400mL) and H₂Iron powder (18.3g, 328mmol), FeSO are added in the solution of O (80mL)₄.7H₂O(5.26g,18.9mmol).By the mixture It vacuumizes, backfills N₂, and the process is in triplicate, and in 110 DEG C of stirring 16h.The reaction mixture is cooled to room temperature, at this Na is added in mixture₂SO₄(120g), and the mixture is filtered, filtrate decompression is concentrated and obtains 2- (2- aminothiophene -3- Base) ethyl acetate crude product (19.5g).LC-MS[M+H]⁺=186.

Step 3:4,6- dihydro -5H- thiophene [2,3-b] pyrroles's -5- ketone

In N₂Under, in -80 DEG C, to the THF of 2- (2- aminothiophene -3- base) ethyl acetate (19.5g, 91.0mmol) crude product AlMe is added dropwise in (400mL) solution₃Hexane solution (2M, 50mL).By the mixture in -80 DEG C of stirring 1h, it is warmed to room temperature simultaneously Continue to stir 16h.4M HCL aqueous solution (80mL) is added dropwise and 20min is stirred at room temperature.Na is added into the mixture₂SO₄ (140g) and the mixture is filtered.Filtrate decompression concentration and residue use the 0-30% of gradient by silica gel chromatograph The hexane solution purifying of EtOAc obtains title compound (6.96g, two steps, 41% yield).LC-MS[M+H]⁺=140；¹H NMR (400MHz,DMSO-d₆) δ 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- thiophene [2,3-b] pyrroles's -5- ketone

At 0 DEG C, the THF (80mL) to 4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- ketone (3.93g, 28.2mmol) is molten NaH is slowly added in liquid (60% in mineral oil, 4.54g, 113.50mmol).After addition, which is stirred at 0 DEG C 30min and then dropwise addition iodomethane (16.2g, 114mmol).The mixture is warmed to room temperature and stirs 3h.By the mixture It is poured into water (100mL), is extracted with EtOAc (3 × 100mL), salt acid elution, anhydrous sodium sulfate dries, filters and filtrate decompression Concentration.Residue obtains title compound using the hexane solution purifying of the 0-50%EtOAc of gradient by silica gel chromatograph (2.71g, 53% yield).LC-MS[M+H]⁺=182.¹H NMR(400MHz,DMSO-d₆) δ 7.01 (d, J=4.8Hz, 1H), 6.98 (d, J=5.2Hz, 1H), 3.14 (s, 3H), 1.24 (s, 6H).

Step 5:4,4,6- trimethyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -4,6- dihydro - 5H- thiophene [2,3-b] pyrroles's -5- ketone

At -20 DEG C, N₂Under, to [Ir (COD) (OMe)]₂(0.97g, 0.29mmol), 4,4,6- trimethyl -4,6- dihydro - DCM (20mL) solution of 5H- thiophene [2,3-b] pyrroles -5- ketone (1.02g, 5.63mmol) and dtbpy (459mg, 1.71mmol) DCM (5mL) solution of middle addition HBPin (3.61g, 28.21mmol).4h is stirred at room temperature in the reaction mixture.Decompression Most of solvent is removed to obtain title compound (2.62g).LC-MS[M+H]⁺=308.

Step 6:2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4,6- trimethyl -4,6- dihydro -5H- thiophene [2,3-b] pyrrole Cough up -5- ketone

N₂Under, to 4,4,6- trimethyl -2- (4,4,5,5- tetramethyls -1,3,2- bis- dislike borine -2- base) -4,6- dihydro - In the dioxane (50mL) of 5H- thiophene [2,3-b] pyrroles's -5- ketone crude product (2.62g, 5.63mmol) and the solution of water (10mL) The bromo- 3- nitropyridine (1.57g, 5.57mmol) of 2,5- bis-, Pd (PPh is added₃)₄(654mg, 0.57mmol) and Na₂CO₃ (1.83g,17.27mmol).The mixture is vacuumized, N is backfilled₂, and the process is repeated 3 times and in 75 DEG C of stirring 16h.It will The reaction mixture is cooled to room temperature, and is poured into water (50mL), and is extracted with EtOAc (3 × 50mL).It is washed with brine merging Organic phase, anhydrous sodium sulfate is dry, and is concentrated under reduced pressure.Residue is molten using the hexane of 0-10%EtOAc by silica gel chromatograph Liquid purifying obtains title compound (424mg, two steps, 20% yield).LC-MS:[M+H]⁺=383.¹H NMR(400MHz,DMSO- d₆) δ 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).

Bromo- 1,3,3- trimethyl -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', the 3':4,5] pyrroles of step 7:6- [3,2-b] pyridine -2 (3H) -one

To 2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4,6- trimethyl -4,6- dihydro -5H- thiophene [2,3-b] pyrroles - DPPE (397mg, 1.00mmol) is added in the solution of the 1,2- dichloro-benzenes (6mL) of 5- ketone (292mg, 0.76mmol).This is mixed It closes object to vacuumize, backfills N₂, and the process is repeated 3 times and in N₂Under in 160 DEG C of stirring 5h.The reaction is cooled to room temperature, and Title compound (86mg, 33% yield) is obtained using the hexane solution purifying of the 0-20%EtOAc of gradient by silica gel chromatograph. LC-MS[M+H]⁺=350.

Step 8:(S) the bromo- 1,3,3- trimethyl -4- of -6- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1,4- dihydro Pyrroles [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one

To bromo- 1,3,3- trimethyl -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', the 3':4,5] pyrroles [3,2- of 6- B] pyridine -2 (3H) -one (86mg, 0.25mmol) toluene (2mL) solution in be added triphenylphosphine (135mg, 0.51mmol) and (R)-phenyl (tetrahydro -2H- pyrans -4- base) methanol (61mg, 0.32mmol).The mixture is vacuumized, N is backfilled₂, and the mistake Journey backfills 3 times.In N₂, DIAD (107mg, 0.53mmol) is added at room temperature.By the mixture in 110 DEG C of stirring 16h.This is anti- It answers mixture to be cooled to room temperature, pour into water (10mL) and is extracted with EtOAc (3 × 10mL).It is washed with brine the organic of merging Phase, anhydrous sodium sulfate dry, filter and filtrate are concentrated under reduced pressure.Residue uses the 0-50%EtOAc of gradient by silica gel chromatograph Hexanes obtain title compound (86mg, 64% yield).LC-MS:[M+H]⁺=524.

Step 9:(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -1,3,3- trimethyl -4- (phenyl (four Hydrogen -2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyrrole Pyridine -2 (3H) -one

According to similar step described in 1 step 8 of embodiment, by (S) -6- bromo- 1,3,3- trimethyl -4- (phenyl (four Hydrogen -2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyrrole Pyridine -2 (3H) -one (46mg, 0.088mmol) and 1,4- dimethyl -5- (tributyl tin) -1H-1,2,3- triazole (112mg, 0.29mmol) it is converted into the DCM of title compound (14mg, 30%yield) and the 1-10%MeOH by silica gel chromatograph gradient Solution purification.LC-MS:[M+H]⁺=541；¹H NMR(400MHz,DMSO-d₆)δ8.31(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)。

Embodiment 6

(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -3,3- dimethyl -4- (phenyl (tetrahydro -2H- pyrrole Mutter -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) - Ketone (" compound 6 ")

Step 1:6- ((2- (trimethylsilyl) ethyoxyl) methyl) -4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- Ketone

In -10 DEG C, 10min, to 4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- ketone (3.51g, 25.25mmol) NaH (60% in mineral oil, 1.12g, 28.0mmol) is added in THF (50mL) solution, and in -10 DEG C of stirring 30min. At -10 DEG C, it is added dropwise SEMCl (5.19g, 31.1mmol), and 2h is stirred at room temperature.The mixture is poured into water (50mL) simultaneously It is extracted with EtOAc (3 × 100mL).It is washed with brine the organic layer of merging, anhydrous sodium sulfate is dry, and is concentrated under reduced pressure.Residue Title compound (4.17g, 61% production are obtained using the hexanes of the 0-10%EtOAc of gradient by silica gel chromatograph Rate).LC-MS[M+H]⁺=270；¹HNMR(400MHz,DMSO-d₆) δ 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- (trimethyl silicon substrate) ethyoxyl) methyl) -4,6- dihydro -5H- thiophene [2,3- B] pyrroles's -5- ketone

According to step similar described in 5 step 4 of embodiment, by 6- ((2- (trimethyl silicon substrate) ethyoxyl) methyl)- 4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- ketone (4.14g, 15.37mmol) be converted into title compound (2.20g, 48% Yield), and be purified by flash by silica gel chromatograph using the hexane solvent of the 0-10%EtOAc of gradient.LC-MS[M+H]⁺=298.¹H NMR(400MHz,DMSO-d₆) δ 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 3:4,4- dimethyl -2- (4,4,5,5- tetramethyl -1,3,2- two dislikes borine -2- base) -6- ((2- (trimethyl Silicon substrate) ethyoxyl) methyl) -4,6- dihydro -5H- thiophene [2,3-b] pyrroles's -5- ketone

According to similar step described in 5 step 5 of embodiment, by 4,4- dimethyl -6- ((2- (trimethyl silicon substrate) ethoxy Base) methyl) -4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- ketone (1.05g, 3.53mmol) is converted into thick title compound (1.36g), it is not purified to be directly used in next step LC-MS [M+H]⁺=424.

Step 4:2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4- dimethyl -6- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -4,6- dihydro -5H- thiophene [2,3-b] pyrroles's -5- ketone

According to step similar described in 5 step 6 of embodiment, by thick 4,4- dimethyl -2- (4,4,5,5- tetramethyls Base -1,3,2- two dislikes borine -2- base) -6- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -4,6- dihydro -5H- thiophene [2,3- B] pyrroles -5- ketone (1.36g, 3.53mmol) and the bromo- 3- nitropyridine (1.05g, 3.58mmol) of 2,5- bis- be converted into it is titled It closes object (0.61g, two steps, 35% yield), and pure using the hexanes of the 0-10%EtOAc of gradient by silica gel chromatograph Change.LC-MS[M+H]⁺=498.¹H NMR(400MHz,DMSO-d₆) δ 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)。

The bromo- 3,3- dimethyl -1- of step 5:6- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one

According to similar step described in 5 step 7 of embodiment, by 2- (the bromo- 3- nitropyridine -2- base of 5-) -4,4- diformazan Base -6- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -4,6- dihydro -5H- thiophene [2,3-b] pyrroles -5- ketone (593mg, It 1.19mmol) is converted into title compound (236mg, 43%yield), and uses the 0-20% of gradient by silica gel chromatograph The hexanes of EtOAc purify.LC-MS[M+H]⁺=466.¹H NMR(400MHz,DMSO-d₆) δ 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) the bromo- 3,3- dimethyl -4- of -6- (phenyl (tetrahydro -2H- pyrans -4- base) methyl) -1- ((2- (front three Base silicon substrate) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one

According to step similar described in 5 step 8 of embodiment, by bromo- 3, the 3- dimethyl -1- ((2- (trimethyl silicane of 6- Base) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one (236mg, 0.51mmol) and the conversion of (R)-phenyl (tetrahydro -2H- pyrans -4- base) methanol (121mg, 0.63mmol) For title compound (323mg), and purified by silica gel chromatograph using the hexanes of the 0-15%EtOAc of gradient.LC- MS[M+H]⁺=640.

Step 7:(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -3,3- dimethyl -4- (phenyl (four Hydrogen -2H- pyrans -4- base) methyl) -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one

According to similar step described in 5 step 9 of embodiment, by thick bromo- 3, the 3- dimethyl -4- (phenyl (four of (S) -6- Hydrogen -2H- pyrans -4- base) methyl) -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one (323mg, 0.51mmol) and 1,4- dimethyl -5- (three Butyl tin) -1H-1,2,3- triazoles (589mg, 1.51mmol) are converted into title compound (63mg, two steps, 20% yield), and It is purified by silica gel chromatograph using the hexanes of the 50-100%EtOAc of gradient.LC-MS[M+H]⁺=657.

Step 8:(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -3,3- dimethyl -4- (phenyl (four Hydrogen -2H- pyrans -4- base) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene [2', 3':4,5] pyrroles [3,2-b] pyrrole Pyridine -2 (3H) -one

To (S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- base) -3,3- dimethyl -4- (phenyl (tetrahydro -2H- Pyrans -4- base) methyl) -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1,4- pyrrolin [3 ", 2 ": 4', 5'] thiophene It is added 6N's in EtOH (4mL) solution of [2', 3':4,5] pyrroles [3,2-b] pyridine -2 (3H) -one (51mg, 0.078mmol) HCl (4mL) aqueous solution.By the mixture in 75 DEG C of stirring 48h.Reaction mixture is cooled to room temperature, saturation is poured into NaHCO₃In (10mL) aqueous solution, and extracted with EtOAc (3 × 50mL).It is washed with brine the organic layer of merging, anhydrous sodium sulfate It is dry, and concentration.Residue is purified by flash by silica gel chromatograph using the DCM solution of the 0-10%MeOH of gradient, is then used It prepares HPLC and obtains title compound (5mg, 12% yield) LC-MS [M+H]⁺=527；¹H NMR(400MHz,DMSO-d₆)δ 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 step of 1~embodiment of embodiment 6, the present invention synthesizes to obtain following compound:

Pharmacology test

The test of 1.BRD4 (BD1) affinity

It is biochemical that BRD4 (BD1) is carried out in 384 hole blanks (OptiPlate-384, PerkinElmer) using HTRF technology Binding test.

Pass through20nL compound is transferred to 384 orifice plates by 550 liquid processors (Labcyte, USA), then by 5 μ L BRD4 (BD1) (ReactionBiologyCompany, RD-11-157) solution or measurement buffer add in each hole.In After being incubated for 15 minutes at room temperature, acetylated peptide derived from the 5 biotinylated H4 of μ L is added into each hole (by GL Biochem (Shanghai) Ltd synthesize) and 10 μ L detection solution (Cisbio Assay).After being incubated at room temperature 1 hour, use EnVision Multilabel PlateReader (PerkinElmer, USA) measures HTRF signal at 615nm and 665nm. With dual wavelength signal than analysis result: intensity (665nm)/intensity (615nm).The inhibiting rate of compound: suppression is calculated according to the following formula Rate processed=(Max-Signal)/(Max-Min) × 100%.Using in GrphaPadPrismV5.0 software (San Diego, CA) Data be fitted IC₅₀Value carries out nonlinear regression analysis, the bottom Y=+(Top-Bottom)/(1+10^ using equation ((LogIC₅₀- X) × slope), wherein Y represents inhibiting rate, X representation compound concentration.Compound 3 is measured to BRD4's (BD1) IC₅₀For 0.28nM.

2. cell Proliferation is tested

MTS measures scheme:

Pass through MTS (3- (4,5- thioxene -2- base) -5- (3- carboxy-- methoxyphenyl) -2- (4- sulfo group phenyl) - 2H- tetrazolium, inner salt) influence of the method detection compound to MV-4-11 cell Proliferation.In brief, temperature be 37 DEG C, 5% CO₂Under 95% humidity, by MV-4-11 cell IMDM (the Iscove's Modified of 10% (v/v) FBS (fetal calf serum) Dubecco's Medium) culture medium culture.Cell is collected in logarithmic growth phase and with cell counter (hemocytometer) It counts.Cell viability is measured by trypan blue staining (trypanblue exclusion), cell survival rate is more than 90%.With MV-4-11 cell concentration is adjusted to 1.2 × 10 by complete medium⁵A cell/mL.It is outstanding that 100 μ L cells are added into 96 orifice plates Supernatant liquid (three multiple holes are arranged in each concentration), final cell density are 1.2 × 10⁴A cells/well.It second day, is dissolved with DMSO Compound is tested as stock solution.5 μ L stock solutions are added in 1mL culture medium, and 25 μ L pharmaceutical culture mediums are added In 96 orifice plates.After with culture medium serial dilution, the ultimate density of compound is 0,0.03,0.1,0.3,1,3,10,30, 100nM.It drug incubation 3 days, is then detected by MTS method.PMS (phenaziniummethosulfate) solution is added to In MTS solution (1:20).20 μ L MTS/PMS mixed solutions are added in each hole of 96 orifice plates again.By 96 orifice plates in incubator Middle incubation 1-4 hours.Use microplate spectrophotometer (Envision^R, PeikinElmer) measurement 490nm at absorbance. Using GraphPad5.0 fitting data and obtain IC₅₀Value.

As a result:

The result of cell-proliferation activity test is as shown in table 1 below:

The result of 1. cell-proliferation activity of table test

The compounds of this invention has excellent inhibiting effect to leukaemia cell MV-4-11 as can be seen from Table 1.

Claims

1. the compound of formula III, its pharmaceutically acceptable salt or its stereoisomer:

Ring A is selected from the heteroatomic 5 yuan of miscellaneous aromatic rings or 5 yuan of amide rings that N, O or S are selected from containing 1,2 or 3；

It is attached to same atoms or not homoatomic each R₁、R₂And R₃At each occurrence independently selected from being not present；Hydrogen； Deuterium；Halogen；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_2-6Alkenyl；-C_2-6Alkynyl；-C_1-6Alkoxy；- NH₂；-NH(C_1-6Alkyl)；-N(C_1-6Alkyl)₂；-SC_1-6Alkyl；-SOC_1-6Alkyl；-SO₂C_1-6Alkyl；-SO₂NH₂；- SO₂NHC_1-6Alkyl；-SO₂N(C_1-6Alkyl)₂；-COC_1-6Alkyl；-CONH₂；-CONHC_1-6Alkyl；-CON(C_1-6Alkyl)₂；-P (O)H₂；-P(O)HC_1-6Alkyl；-P(O)(C_1-6Alkyl)₂；3-8 member carbocyclic ring；The heteroatomic 3- of N, O or S are selected from containing 1,2 or 3 8 circle heterocyclic rings；6-10 member aryl；Or the heteroatomic 5-10 unit's heteroaryl of N, O or S are selected from containing 1,2 or 3；And each R₁、R₂With R₃Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substituent group exists Independently selected from deuterium, halogen ,-OH ,-CN ,-NH when occurring every time₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3-8 member carbocyclic ring is formed together with the atom that they individually or collectively connect or containing 1,2 or 3 A heteroatomic 3-8 circle heterocyclic ring selected from N, O or S；And each ring system at each occurrence optionally by 1,2,3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,- CN、-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl Or-C_1-6Alkoxy；Each R_aAnd R_bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, And each substituent group is at each occurrence independently selected from deuterium, halogen or-C_1-6Alkyl；

M is selected from 0,1,2,3,4,5 or 6；

R₄It is selected from

Each R_4aAnd R_4bAt each occurrence independently selected from hydrogen；Deuterium；Halogen；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；- C_2-6Alkenyl；-C_2-6Alkynyl；-C_1-6Alkoxy；-NH₂；-NH(C_1-6Alkyl)；-N(C_1-6Alkyl)₂；-SC_1-6Alkyl；-SOC_1-6Alkane Base；-SO₂C_1-6Alkyl；-SO₂NH₂；-SO₂NHC_1-6Alkyl；-SO₂N(C_1-6Alkyl)₂；-COC_1-6Alkyl；-CONH₂；-CONHC_1-6 Alkyl；-CON(C_1-6Alkyl)₂；-P(O)H₂；-P(O)HC_1-6Alkyl；-P(O)(C_1-6Alkyl)₂；3-8 member carbocyclic ring；Containing 1,2 or 3 Heteroatomic 3-8 circle heterocyclic ring selected from N, O or S；6-10 member aryl；Or the heteroatomic 5-10 of N, O or S are selected from containing 1,2 or 3 Unit's heteroaryl；And each R_4aAnd R_4bOptionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, And each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-NH₂,-CN, carboxyl ,-NO₂、-C_1-6Alkane Base or-C_1-6Alkoxy；

W₁Selected from hydrogen；Deuterium；Halogen；-NH₂；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_1-6Alkoxy；-C_1-6Alkylidene-C_1-6 Alkoxy；6-10 member aryl；N, O, S, SO or SO are selected from containing 1,2,3 or 4₂Heteroatomic 5-10 unit's heteroaryl；Containing 1,2,3 Or 4 be selected from N, O, S, SO or SO₂Heteroatomic 3-8 circle heterocyclic ring；Or 3-8 member carbocyclic ring；And each W₁At each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

W₂Selected from hydrogen；Deuterium；Halogen；-NH₂；-CN；-OH；Carboxyl；-NO₂；-C_1-6Alkyl；-C_1-6Alkoxy；6-10 member aryl；Contain 1,2,3 or 4 are selected from N, O, S, SO or SO₂Heteroatomic 5-10 unit's heteroaryl；Containing 1,2,3 or 4 selected from N, O, S, SO or SO₂Heteroatomic 3-8 circle heterocyclic ring；Or 3-8 member carbocyclic ring and each W₂At each occurrence optionally by 1,2,3,4,5 or 6 Substituent group replace or be not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,- CN、-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

2. the compound of formula III according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein It is attached to same atoms or not homoatomic each R₁、R₂And R₃At each occurrence independently selected from be not present, hydrogen, deuterium, halogen Element ,-CN ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy,-NH₂、-NH(C_1-6Alkyl) ,-N (C_1-6Alkyl)₂、- SO₂C_1-6Alkyl ,-SO₂NH₂、-SO₂NHC_1-6Alkyl ,-SO₂N(C_1-6Alkyl)₂、-COC_1-6Alkyl ,-CONH₂、-CONHC_1-6Alkane Base ,-CON (C_1-6Alkyl)₂、-P(O)H₂、-P(O)HC_1-6Alkyl or-P (O) (C_1-6Alkyl)₂；And each R₁、R₂And R₃Each Optionally replaced by 1,2,3,4,5 or 6 substituent group when appearance or be not substituted, and each substituent group is occurring every time When independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3-6 member carbocyclic ring is formed together with the atom that they individually or collectively connect or containing 1,2 or 3 A heteroatomic 3-6 circle heterocyclic ring selected from N, O or S；And each ring system at each occurrence optionally by 1,2,3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium, halogen ,-OH ,- CN、-NH₂, carboxyl ,-NO₂、-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；Each R_aAnd R_bAt each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium ,-F ,-Cl ,-Br or-C_1-6Alkyl；

M is selected from 0,1,2,3,4,5 or 6；

Preferably, same atoms or not homoatomic each R are attached to₁、R₂And R₃At each occurrence independently selected from not depositing , hydrogen, deuterium ,-F ,-Cl ,-Br ,-CN ,-OH ,-C_1-3Alkyl ,-C_1-3Alkoxy,-NH₂、-NH(C_1-3Alkyl) ,- N(C_1-3Alkyl)₂、-SO₂C_1-3Alkyl ,-SO₂NH₂、-SO₂NHC_1-3Alkyl ,-SO₂N(C_1-3Alkyl)₂、-COC_1-3Alkyl ,- CONH₂、-CONHC_1-3Alkyl ,-CON (C_1-3Alkyl)₂、-P(O)H₂、-P(O)HC_1-3Alkyl or-P (O) (C_1-3Alkyl)₂；And it is every A R₁、R₂And R₃Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and is each of described Substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、-C_1-3Alkyl or-C_1-3Alkoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan are formed together with the atom that they individually or collectively connect Carbocyclic ring, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle contains 1 at each occurrence Or 2 hetero atoms selected from N or O；Each ring system is optionally taken by 1,2,3,4,5 or 6 substituent group at each occurrence In generation, is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-CN ,-NH₂、- C_1-3Alkyl or-C_1-3Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-3Alkyl；Each R_aAnd R_bAt each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium or-F；

M is selected from 0,1,2,3 or 4；

Preferably, same atoms or not homoatomic each R are attached to₁、R₂And R₃At each occurrence independently selected from not depositing , hydrogen, deuterium ,-F ,-Cl ,-Br ,-CN ,-OH, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen Base,-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) (CH₃)(CH₂CH₃)；Each R₁、R₂And R₃At each occurrence optionally by 1,2,3,4,5 or 6 substituent group Replace or be not substituted, and each substituent group at each occurrence independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,- CN、-NH₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan are formed together with the atom that they individually or collectively connect Carbocyclic ring, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle includes 1 at each occurrence A hetero atom selected from N or O；Each ring system optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or It is not substituted, and each substituent group is at each occurrence independently selected from deuterium ,-F ,-Cl ,-Br ,-OH ,-CN ,-NH₂、 Methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.

Preferably, same atoms or not homoatomic each R are attached to₁、R₂And R₃At each occurrence independently selected from not depositing , 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)₂, methoxy Base, ethyoxyl, propoxyl group, 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)；Or

R₁And R₂、R₁And R₃Or R₂And R₃, 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan are formed together with the atom that they individually or collectively connect Carbocyclic ring, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heterocycle includes 1 at each occurrence A hetero atom selected from N or O.

3. the compound of formula III according to claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, Described in compound be formula IV or V:

Wherein each R₁、R₂And R₃At each occurrence independently selected from hydrogen, deuterium ,-C_1-6Alkyl orAnd each R₁、 R₂And R₃Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and each substitution Base is at each occurrence independently selected from deuterium, halogen ,-C_1-6Alkyl or-C_1-6Alkoxy；

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；Each R_aAnd R_bAt each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium, halogen or-C_1-6Alkyl；

M is selected from 0,1,2,3 or 4；

Preferably, R₁At each occurrence independently selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally by 1,2,3,4,5 or 6 A substituent group replaces or is not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen or-C_1-6 Alkyl；

Each R₂Or R₃Selected from hydrogen, deuterium ,-C_1-6Alkyl or

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；And each R_aAnd R_bAppoint at each occurrence Selection of land is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group is at each occurrence independently Selected from deuterium, halogen or-C_1-6Alkyl；

M is selected from 0 or 1；

Preferably, R₁At each occurrence independently selected from-C_1-6The alkyl ,-C_1-6Alkyl is optionally by 1,2,3,4,5 or 6 A substituent group replaces or is not substituted, and each substituent group is at each occurrence independently selected from deuterium or-F；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium-C_1-6Alkyl；And each R_aAnd R_bAt each occurrence optionally Ground is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group independently selects at each occurrence From deuterium or-F；

M is selected from 0 or 1；

R₃Selected from hydrogen, deuterium or-C_1-6Alkyl；

Preferably, R₁Selected from-C_1-3The alkyl ,-C_1-3Alkyl optionally replaced by 1,2,3,4,5 or 6 substituent group or not by Replace, and each substituent group is at each occurrence independently selected from deuterium or-F；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from-C_1-3Alkyl；And each R_aAnd R_bAt each occurrence optionally by 1, 2,3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group is at each occurrence independently selected from deuterium Or-F；

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium；

Preferably, R₁Ethyl that methyl, deuterium or the-F replaced selected from methyl, ethyl, propyl, isopropyl, deuterium or-F replaces, deuterium or- The isopropyl that the propyl or deuterium or-F that F replaces replace；

R₂It is selected from

Each R_aAnd R_bMethyl, the deuterium replaced at each occurrence independently selected from methyl, ethyl, propyl, isopropyl, deuterium or-F Or the isopropyl that the propyl that replaces of-the F ethyl, deuterium or the-F that replace or deuterium or-F replace；

M is selected from 0 or 1；

R₃Selected from hydrogen or deuterium；

Preferably, R₁Selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、- CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

R₂It is selected from

Each R_aAnd R_bAt each occurrence independently selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、- CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂Or-CH (CD₃)₂；

R₃Selected from hydrogen or deuterium；

Preferably, R₁Selected from-CH₃；

R₂It is selected from

R₃Selected from hydrogen.

4. the compound of Formulas I according to claim 1-3, its pharmaceutically acceptable salt or its alloisomerism Body, wherein the compound is Formula VII, VIII or IX:

Wherein each R₁、R₂And R₃At each occurrence independently selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl ,-C_1-6Alkoxy orAnd each R₁、R₂And R₃Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or is not taken Generation, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alkoxy； Or

R₁And R₂3-6 member carbocyclic ring is formed together with the carbon atom that they all connect；Or it is heteroatomic selected from N or O containing 1 or 2 3-6 circle heterocyclic ring；And each ring system is optionally replaced by 1,2,3,4,5 or 6 substituent group at each occurrence or is not taken Generation, and each substituent group is at each occurrence independently selected from deuterium, halogen ,-OH ,-C_1-6Alkyl or-C_1-6Alkoxy；

M is selected from 0,1,2,3 or 4；

Preferably, wherein each R₁And R₂At each occurrence independently selected from-C_1-6The alkyl ,-C_1-6Alkyl optionally by 1,2,3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from Deuterium, halogen ,-OH or-C_1-6Alkyl；Or

R₁And R₂With the carbon atom that they all connect be formed together 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each ring It ties up to and is optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted when occurring every time, and each substituent group exists Independently selected from deuterium, halogen ,-OH or-C when occurring every time_1-6Alkyl；

R₃Selected from hydrogen, deuterium ,-OH ,-C_1-6Alkyl or

M is selected from 0 or 1；

Preferably, each R₁And R₂At each occurrence independently selected from-C_1-6The alkyl ,-C_1-6Alkyl optionally by 1,2, 3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group is at each occurrence independently selected from deuterium, halogen Element or-C_1-6Alkyl；Or

R₁And R₂With the carbon atom that they all connect be formed together 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each ring It ties up to and is optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted when occurring every time, and each substituent group exists Independently selected from deuterium, halogen or-C when occurring every time_1-6Alkyl；

R₃Selected from-OH ,-C_1-6Alkyl or

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-6Alkyl；And each R_aAnd R_bAppoint at each occurrence Selection of land is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group is at each occurrence independently Selected from deuterium or halogen；

M is selected from 0 or 1；

Preferably, each R₁And R₂At each occurrence independently selected from-C_1-3The alkyl ,-C_1-3Alkyl optionally by 1,2, 3,4,5 or 6 substituent groups replace or are not substituted, and each substituent group at each occurrence independently selected from deuterium or- F；Or

R₁And R₂With the carbon atom that they all connect be formed together 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle contain 1 or 2 hetero atom for being selected from N or O；And each ring It ties up to and is optionally replaced by 1,2,3,4,5 or 6 substituent group or be not substituted when occurring every time, and each substituent group exists Independently selected from deuterium or halogen when occurring every time；

R₃Selected from-OH ,-C_1-3Alkyl,

Each R_aAnd R_bAt each occurrence independently selected from hydrogen, deuterium or-C_1-3Alkyl；And each R_aAnd R_bAppoint at each occurrence Selection of land is replaced or be not substituted by 1,2,3,4,5 or 6 substituent group, and each substituent group is at each occurrence independently Selected from deuterium or-F；

Preferably, each R₁And R₂At each occurrence independently selected from-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、- CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH (CF₃)₂Or-CH (CD₃)₂；Or

R₁And R₂With the carbon atom that they all connect be formed together 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings, 6 circle heterocyclic rings, each heterocycle include 1 hetero atom for being selected from N or O at each occurrence；

Preferably, each R₁And R₂Independently selected from-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂；Or

R₁And R₂With the carbon atom that they all connect be formed together 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 3 circle heterocyclic rings, 4 circle heterocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, each heterocycle include 1 hetero atom for being selected from N or O at each occurrence；

R₃Selected from-OH,-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or-CH (CH₃)₂；

Preferably, R₁Selected from-CH₃；R₂Selected from-CH₃；With

R₃Selected from-OH,-CH₃Or-CH₂CH₃；

Preferably, each R₁Selected from-CH₃；R₂Selected from-CH₃；And R₃Selected from-CH₃。

5. the compound of formula III according to claim 1-4, its pharmaceutically acceptable salt or its alloisomerism Body, wherein each R_4aAnd R_4bAt each occurrence independently selected from-C_1-6Alkyl；Or-the C that deuterium or-F replace_1-6Alkyl；

Preferably, each R_4aAnd R_4bAt each occurrence independently selected from-C_1-3Alkyl；Or-the C that deuterium or-F replace_1-3Alkyl；

Preferably, each R_4aAnd R_4bAt each occurrence independently selected from methyl；Ethyl；Propyl；Isopropyl；What deuterium or-F replaced Methyl；The ethyl that deuterium or-F replace；The propyl that deuterium or-F replace；Or the isopropyl that deuterium or-F replace；

Preferably, each R_4aAnd R_4bThe methyl replaced at each occurrence independently selected from methyl or deuterium.

6. the compound of formula III according to claim 1-5, its pharmaceutically acceptable salt or its alloisomerism Body, wherein R₄It is selected from:

7. the compound of formula III according to claim 1-6, its pharmaceutically acceptable salt or its alloisomerism Body, wherein W₁Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Carboxyl；-C_1-6Alkyl；-C_1-6Alkoxy；-C_1-3Alkylidene-C_1-3 Alkoxy；Phenyl；Heteroatomic 5 unit's heteroaryl of N or O is selected from containing 1,2 or 3；The hetero atom of N or O is selected from containing 1,2 or 3 6 unit's heteroaryls；Heteroatomic 3 circle heterocyclic ring of N or O is selected from containing 1,2 or 3；Heteroatomic the 4 of N or O is selected from containing 1,2 or 3 Circle heterocyclic ring；Heteroatomic 5 circle heterocyclic ring of N or O is selected from containing 1,2 or 3；It is miscellaneous containing 1,2 or 3 heteroatomic 6 yuan selected from N or O Ring；3 yuan of carbocyclic rings；4 yuan of carbocyclic rings；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₁At each occurrence optionally by 1,2,3,4,5 or 6 A substituent group replaces or is not substituted, and each substituent group be selected from each occurrence deuterium, halogen-OH ,-CN ,- NH₂、-C_1-3Alkyl or-C_1-3Alkoxy；

Preferably, W₁Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Methyl；Ethyl；Propyl；Isopropyl； Methoxyl group；Second Oxygroup；Propoxyl group；Isopropoxy； -CH₂OCH₃；-CH₂CH₂OCH₃；-CH₂CH₂OCH₂CH₃；Phenyl；Contain 1 or 2 A heteroatomic 5 unit's heteroaryl selected from N or O；Heteroatomic 6 unit's heteroaryl of N or O is selected from containing 1 or 2；Contain 1 or 2 A heteroatomic 5 circle heterocyclic ring selected from N or O；Heteroatomic 6 circle heterocyclic ring of N or O is selected from containing 1 or 2；5 yuan of carbocyclic rings；Or 6 yuan Carbocyclic ring；And each W₁Optionally replaced at each occurrence by 1,2,3,4,5 or 6 substituent group or be not substituted, and is described Each substituent group is selected from deuterium ,-F ,-Cl ,-OH ,-CN ,-NH at each occurrence₂, methyl, ethyl, propyl, isopropyl, methoxy Base, ethyoxyl, propoxyl group or isopropoxy；

Preferably, W₁Selected from hydrogen；Deuterium；-F；Methyl；Ethyl；Propyl；Isopropyl； Methoxyl group；-CH₂OCH₃；- CH₂CH₂OCH₃；Heteroatomic 6 unit's heteroaryl of N or O is selected from containing 1 or 2；Heteroatomic the 5 of N or O is selected from containing 1 or 2 Circle heterocyclic ring；Heteroatomic 6 circle heterocyclic ring of N or O is selected from containing 1 or 2；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₁Going out every time Deuterium or-F are optionally substituted or are not substituted now；

Preferably, W₁Selected 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、 Methoxyl group ,-CH₂OCH₃、-CH₂CH₂OCH₃、

Preferably, W₁- the C replaced selected from-F_1-6Alkyl or heteroatomic 6 circle heterocyclic ring that O is selected from containing 1；

Preferably, W₁- the C replaced selected from-F_1-6Alkyl,

Preferably, W₁Selected from-CH₂CH₂CF₃Or

8. the compound of formula III according to claim 1-7, its pharmaceutically acceptable salt or its alloisomerism Body, wherein W₂Selected from hydrogen；Deuterium；-F；-Cl；-NH₂；-CN；-OH；Carboxyl；-C_1-3Alkyl；-C_1-3Alkoxy；Phenyl；Naphthalene；Containing 1, 2 or 3 are selected from heteroatomic 5 unit's heteroaryl of N, O or S；Heteroatomic 6 unit's heteroaryl of N or O or S is selected from containing 1,2 or 3； 7 unit's heteroaryl of hetero atom of N, O or S are selected from containing 1,2 or 3；Heteroatomic 8 yuan of heteroaryls of N, O or S are selected from containing 1,2 or 3 Base；Heteroatomic 9 unit's heteroaryl of N, O or S are selected from containing 1,2 or 3；Heteroatomic 10 yuan of N, O or S are selected from containing 1,2 or 3 Heteroaryl；Heteroatomic 3 circle heterocyclic ring of N, O or S are selected from containing 1,2 or 3；Heteroatomic the 4 of N, O or S is selected from containing 1,2 or 3 Circle heterocyclic ring；Heteroatomic 5 circle heterocyclic ring of N, O or S are selected from containing 1,2 or 3；Heteroatomic the 6 of N, O or S is selected from containing 1,2 or 3 Circle heterocyclic ring；3 yuan of carbocyclic rings；4 yuan of carbocyclic rings；5 yuan of carbocyclic rings；Or 6 yuan of carbocyclic rings；And each W₂At each occurrence optionally by 1,2,3,4 Or 5 substituent groups replace or are not substituted, and each substituent group be selected from each occurrence deuterium, halogen ,-OH ,-CN ,- NH₂, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；

Preferably, W₂Selected from hydrogen；Deuterium；Phenyl；Heteroatomic 5 unit's heteroaryl of N, O or S are selected from containing 1 or 2；Or contain 1 or 2 A heteroatomic 6 unit's heteroaryl selected from N, O or S；And each W₂Optionally replaced at each occurrence by 1,2,3,4 or 5 Base replaces or is not substituted, and each substituent group is selected from deuterium ,-F ,-Cl ,-Br ,-NH at each occurrence₂、-CN、- OH, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；

Preferably, W₂Selected from phenyl；Heteroatomic 5 unit's heteroaryl of N, O or S are selected from containing 1 or 2；Or it is selected from containing 1 or 2 N, heteroatomic 6 unit's heteroaryl of O or S；And each W₂Optionally replaced at each occurrence by 1,2 or 3 substituent group or not It is substituted, and each substituent group is selected from-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl, first at each occurrence Oxygroup, ethyoxyl, propoxyl group or isopropoxy；

Preferably, W₂It is selected from And each W₂At each occurrence Optionally replaced by 1,2 or 3 substituent group or be not substituted, and each substituent group be selected from each occurrence-F ,- Cl, methyl or methoxy；

Preferably, W₂Independently selected from:

9. the compound of formula III according to claim 1-8, its pharmaceutically acceptable salt or its alloisomerism Body, wherein Z is selected from hydrogen, deuterium ,-F ,-Cl ,-OH ,-C_1-3Alkyl or-C_1-3Alkoxy；

Preferably, Z be selected from hydrogen, deuterium ,-F ,-Cl ,-OH, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or Isopropoxy；

Preferably, Z is selected from hydrogen or deuterium；

Preferably, Z is selected from hydrogen.

10. the compound of -9 described in any item formula IIIs, its pharmaceutically acceptable salt or its solid are different according to claim 1 Structure body, wherein describedIt is selected from:

And it is eachOptionally replaced at each occurrence by 1,2 or 3 substituent group or is not taken Generation, and each substituent group be selected from each occurrence-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group or isopropoxy；

Preferably, describedIt is selected from:

And it is eachOptionally replaced at each occurrence by 1,2 or 3 substituent group or be not substituted, and is described every A substituent group is selected from-F ,-Cl, methyl or methoxy at each occurrence.

11. the compound of -10 described in any item formula IIIs, its pharmaceutically acceptable salt or its solid are different according to claim 1 Structure body, wherein the compound is selected from:

12. a kind of pharmaceutical composition, it includes the compounds of formula III at least of any of claims 1-11, its medicine Acceptable salt or its stereoisomer on, and at least one pharmaceutically acceptable excipient；

Preferably, the range of the weight ratio of the compound and the excipient is about 0.0001 to about 10.

13. the compound of formula III of any of claims 1-11, its pharmaceutically acceptable salt or its alloisomerism Pharmaceutical composition described in body or claim 12 treats the drug of disease relevant to bromine domain protein or illness in preparation In application；

Preferably, the disease relevant to bromine domain protein or illness are selected from solid tumor (solid tumor) and/or blood Liquid tumor (blood tumor)；

Preferably, the solid tumor is selected from lung cancer (lung cancer), tumor in digestive tract (gastrointestinal Cancer), colon cancer (colon cancer), the carcinoma of the rectum (rectal cancer), colorectal cancer (colorectal ) and/or oophoroma (ovarian cancer) cancer；The blood tumor (blood tumor) is selected from myeloma (myeloma) And/or leukaemia (leukemia)；

Preferably, the lung cancer includes non-small cell lung cancer (non-small cell lung cancer) and/or cellule lung Cancer (small cell lung cancer)；The tumor in digestive tract (gastrointestinal cancer) includes the cancer of the esophagus (esophageal cancer)；The leukaemia (leukemia) includes acute myeloid leukaemia (acute myeloid Leukemia (AML)) and/or acute lymphoblastic leukemia (acute lymphocytic leukemia (ALL))；The bone Myeloma (myeloma) include Huppert's disease (multiple myeloma).