CN111356695A

CN111356695A - Novel tricyclic compounds

Info

Publication number: CN111356695A
Application number: CN201880069871.5A
Authority: CN
Inventors: 方海权; 周文来; 胡邵京; 陈明明; 杨贵群; 王燕萍; 杜曰雷; 李庆龙; 吴彤; 吴领军; 李海军
Original assignee: Beijing Jiakesitu New Drug R & D Co ltd; Jacobio Pharmaceuticals Co Ltd
Current assignee: Jacobio Pharmaceuticals Co Ltd
Priority date: 2017-10-27
Filing date: 2018-10-29
Publication date: 2020-06-30
Anticipated expiration: 2038-10-29
Also published as: CN111356695B; WO2019080941A1

Abstract

The present invention relates to certain novel tricyclic compounds which are bromodomain and superterminal domain (BET) inhibitors, their synthesis, and their use in treating diseases. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of making such compounds, and methods of treating diseases and conditions in which inhibition of one or more BET bromodomains provides a benefit.

Description

Novel tricyclic compounds

Technical Field

The present invention relates to certain novel tricyclic compounds (formula (1)) as bromodomain and superterminal domain (BET) inhibitors, as shown in formula (1), their synthesis and their use in the treatment of disease. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of preparing such compounds, and methods of treating diseases and conditions in which inhibition of one or more BET bromodomains provides a benefit.

Background

Epigenetics is used to describe the genetic gene regulation or transcriptional silencing of cells and even organisms across generations, mediated through dynamic and reversible changes in chromatin accessibility and post-translational modification of histone tails (PTMs). Several physiological processes may contribute to epigenetic regulation, including DNA methylation, non-coding RNA-mediated scaffold and complex formation, and histone modification. Histone modification is a process associated with post-translational covalent modification of histones that significantly affects the ability of the associated DNA to be transcribed. Lysine acetylation is a post-translational modification widely associated with cell signaling and disease biology. Enzymes that modulate the acetylation of lysine in histones are called "writers" or Histone Acetyltransferases (HATs), and enzymes that modulate the deacetylation of lysine in histones are called "erasers" or Histone Deacetylases (HDACs). Bromodomains (bromodomainssbrds) are "readers" of epigenetic marks that specifically recognize epsilon-N-acetyl lysine (Kac) residues on histone tails.

BRDs, first described in 1992, contain about 110 amino acids. Based on structural/sequence similarity, there are 46 known bromodomain-containing proteins from humans that span eight families. Among these, bromodomains and the terminal ectodomain (BET) recognize acetylated lysine residues in histones H3 and H4. The BET families of BRD2, BRD3, BRD4, and BRDT, which comprise four members, share two N-terminal bromodomains and an additional C-terminal domain (ET) that exhibit high sequence conservation. BRD2 and BRD3 are reported to be associated with histones along genes that are actively transcribed, and may be involved in promoting transcriptional elongation (Leroy et al, mol. cell 200830 (1); 51-60). BRD4 appears to be involved in the recruitment of the positive transcriptional elongation factor complex (pTEF-I3), which plays a crucial role in RNA polymerase regulation of transcription and increased transcriptional export (Hargreaves et al, Cell, 2009138 (1): 1294145). Unlike the other three ubiquitously expressed BET proteins, the expression of BRDT is generally testis-specific (MH Jones et al, Genomics, 1997(45), 529-. All BET family members have some function in controlling or performing the cell cycle and remain complexed with chromosomes during cell division, suggesting a role in maintaining epigenetic memory. Their dysfunction plays a key role in a variety of human diseases.

Disruption of protein-protein interactions between BET proteins and acetylated lysine has been a promising target for human diseases, including virology, heart failure, inflammation, Central Nervous System (CNS) diseases, and various cancers. Small molecule BET inhibitors under development include RVX-208, GSK-525762A, GSK2820151, OTX-015, CPI-0610, TEN-010, ABBV-075, ABBV-74, BI 894999, BMS-986158, INCB054329, ZEN-3694GS-5829, and Celgene inhibitor CC-90010. There is a need to generate additional BET inhibitors that have higher performance, e.g., higher efficacy, safety, tolerability, pharmacokinetics, and/or pharmacokinetics, than existing BET inhibitors.

Summary of The Invention

In one aspect, there is provided a compound of formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

a compound of formula (1) or a pharmaceutically acceptable salt or stereoisomer thereof:

one of which is

Is a single bond, and the other is

Is a double bond;

X₁is CR_1a、O、S、S(O)、S(O)₂Or NR_1b；

X₂Is CR_2aO, S or NR_2b；

Each R_1aOr R_2aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) C_1-6Alkoxy radical, C_1-6alkylene-C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aOr R_2aIndependently optionally substituted or unsubstituted;

each R_1bOr R_2bIndependently is absent, H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3alkylene-C_5-6Aryl radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1bOr R_2bIndependently optionally substituted or unsubstituted;

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)NH-C_1-6Alkyl, C (O) N (C)_1-6Alkyl radical)₂、C(O)C_1-6Alkyl, C (O) OC_1-6Alkyl, S (O) C_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-NH-C_1-6Alkyl, -C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl radical, C_2-6alkenyl-OH, C_2-6Alkynyl, -C_2-6alkenyl-OH, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) OH, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently substituted or unsubstituted;

s is 0, 1,2,3, 4 or 5;

R₄is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)NH-C_1-6Alkyl, C (O) N (C)_1-6Alkyl radical)₂、C(O)C_1-6Alkyl, S (O) C_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₄Independently substituted or unsubstituted;

W₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, -C_1-6alkylene-C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₁Independently substituted or unsubstituted;

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently substituted or unsubstituted;

z is H, or deuterium.

In another aspect, there is provided a pharmaceutical composition comprising at least one compound of formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient of the invention.

In another aspect, there is provided a combination pharmaceutical product comprising a compound of formula (1) of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more other therapeutically active agents.

In another aspect, there is provided a method of treating a patient having a disease or disorder associated with a bromodomain protein, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; the pharmaceutical composition of the present invention; or said combination product of the invention.

In another aspect, there is provided a compound of formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the pharmaceutical composition, or the combination pharmaceutical product of the invention for use in the treatment of a disease or disorder associated with bromodomain proteins.

In another aspect, there is provided a use of the compound of formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the pharmaceutical composition, or the pharmaceutical combination product of the present invention for the manufacture of a medicament for treating a disease or disorder associated with bromodomain proteins.

Detailed description of the invention

The present invention relates to tricyclic compounds useful as BET inhibitors and for treating BET-related disorders. The compound has a general structure shown in formula (1), or pharmaceutically acceptable salt or stereoisomer thereof:

one of which is

Is a single bond, and the other is

Is a double bond;

X₁is CR_1a、O、S、S(O)、S(O)₂Or NR_1b；

X₂Is CR_2aO, S or NR_2b；

s is 0, 1,2,3, 4 or 5;

z is H, or deuterium.

In some embodiments, the compounds of the invention have the general structure shown in formula I or a pharmaceutically acceptable salt thereof:

one is

Is a single bond and the other

Is a double bond;

X₁is CR_1a、O、S、S(O)、S(O)₂Or NR_1b；

X₂Is CR_2aO, S or NR_2b；

Each R_1aOr R_2aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) C_1-6Alkoxy radical, C_1-6alkylene-C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aOr R_2aIndependently substituted or unsubstituted;

each R_1bOr R_2bIndependently is absent, H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3alkylene-C_5-6Aryl radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1bOr R_2bIndependently substituted or unsubstituted;

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)NH-C_1-6Alkyl, C (O) N (C)_1-6Alkyl radical)₂、C(O)C_1-6Alkyl, S (O) C_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-NH-C_1-6Alkyl, -C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl radical, C_2-6alkenyl-OH, C_2-6Alkynyl, -C_2-6alkenyl-OH, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) OH, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently substituted or unsubstituted;

s is 0, 1,2,3, 4 or 5;

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently substituted or unsubstituted.

The present invention further provides a preferable embodiment of the compound of formula (1) or (I).

In some embodiments of formula (1), or formula (I), X₁Is CR_1aO, S or NR_1b。

In some embodiments of formula (1), or formula (I), R_1aIs H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_1aIs H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_1aIs H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S

In some embodiments of formula (1), or formula (I), R_1aIs H, F or methyl.

In some embodiments of formula (1), or formula (I), R_1bIs absent, H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3alkylene-C_5-6Aryl radical, C_3-6Heterocyclic radicalOr C_3-6A carbocyclic group; and each R_1bIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S. .

In some embodiments of formula (1), or formula (I), R_1bIs absent, H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylene-5-membered aryl, C_1-3An alkylene-6-membered aryl, a 3-membered heterocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 3-membered carbocyclyl, a 4-membered carbocyclyl, a 5-membered carbocyclyl, or a 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each of said heterocyclyl groups contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_1bIs absent, H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5 membered aryl, methylene-6 membered aryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered carbocyclyl, or 6 membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_1bIs absent, H, methyl or phenyl.

In some embodiments of formula (1), or formula (I), X₂Is CR_2aO, S or NR_2b。

In some embodiments of formula (1), or formula (I), R_2aIs H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radicalRadical, C (O) C_1-6Alkoxy radical, C_1-6alkylene-C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_2aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_2aIs H, F, Cl, Br, NH₂CN, OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) C_1-3Alkoxy radical, C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_2aIs H, F, Cl, Br, NH₂CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH₃、C(O)OCH₂CH₃、C(O)OCH₂CH₂CH₃、C(O)OCH(CH₃)₂、CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃、C(CH₃)₂OCH₂CH₃、C(CH₃)₂OCH₂CH₂CH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2aIndependently by F, Cl, Br, NH₂、OH、Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (1), or formula (I), R_2aIs H, F, Cl, CN, methyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

In some embodiments of formula (1), or formula (I), R_2aIs H, F, Cl, CN, methyl, CD₃Ethyl, isopropyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

In some embodiments of formula (1), or formula (I), R_2bIs absent, H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_2bIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_2bIs absent, H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and each of whichThe heterocyclic group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_2bIs absent, H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2bIndependently by F, Cl, Br, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R_2bIs absent or H.

In some embodiments of formula (1), or formula (I), R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、C(O)NH-C_1-3Alkyl, C (O) N (C)_1-3Alkyl radical)₂、C(O)C_1-3Alkyl, S (O) C_1-3Alkyl, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、-C_l-3alkylene-NH-C_1-3Alkyl, -C_l-3alkylene-N (C)_1-3Alkyl radical)₂、C_2-3Alkenyl radical, C_2-3alkenyl-OH, C_2-3Alkynyl, -C_2-3alkenyl-OH, -C_2-3alkynyl-OH, -C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) OH, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

R_3aindependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), R₃Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂CH₂N(CH₃)₂、CH₂N(CH₂CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Vinyl, propenyl, ethynyl, propynyl, propenyl, ethynyl, propynyl, prop,

-C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroarylA 3-membered heterocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 3-membered carbocyclyl, a 4-membered carbocyclyl, a 5-membered carbocyclyl, or a 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

In some embodiments of formula (1), or formula (I), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Vinyl group, ethynyl group,

-C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-9Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

In some embodiments of formula (1), or formula (I), s is 1,2,3, or 4.

In some embodiments of formula (1), or formula (I), each R is_3aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), each R is_3aIndependently H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH₂CH₂OH、CH(CH₃) OH or C (CH)₃)₂OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), R₃Is H, CH₃、C(O)NH₂、

In some embodiments of formula (1), or formula (I), R₃Is H, CH₃、C(O)NH₂、C(O)N(CH₃)₂、C(O)CH₃、C(O)OCH₃、

In some embodiments of formula (1), or formula (I), R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、C(O)NH-C_1-3Alkyl, C (O) N (C)_1-3Alkyl radical)₂、C(O)C_1-3Alkyl, S (O) C_1-3Alkyl, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

R_4aindependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Heterocyclyl or C_3-6A carbocyclic group; and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), R₄Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heteroarylCyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted.

In some embodiments of formula (1), or formula (I), each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), each R is_4aIndependently H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 8-membered heterocyclic group, 3-membered carbocyclic group, 4-membered carbocyclic group, 5-membered carbocyclic group or 6-membered carbocyclic group; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), each R is_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy,

Or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (1), or formula (I), wherein R is₄Is that

In some embodiments of formula (1), or formula (I), W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), W₁Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、CH₂CH₂OCH₂CH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each of said heteroaryl or heterocyclyl groupsContaining 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (1), or formula (I), W₁Is H, F, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、

And each W₁Independently by F, Cl, NH₂OH, methyl or methoxy substituted or unsubstituted.

In some embodiments of formula (1), or formula (I), W₁Is H, F, methyl, ethyl, propyl, methoxy, CH₂OCH₃、CH₂CH₂OCH₃、

In some embodiments of formula (1), or formula (I), W₁Is H, F, methyl, ethyl, propyl, methoxy, CH₂OCH₃、CH₂CH₂CF₃、CH₂CH₂OCH₃、

In some embodiments of formula (1), or formula (I), W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 substituents selected from N, O orA heteroatom of S.

In some embodiments of formula (1), or formula (I), W₂Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (1), or formula (I), W₂Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (1), or formula (I), W₂Is H,

And each W₂Independently F, Cl, methyl or methoxy, or unsubstituted.

In some embodiments of formula (1), or formula (I), W₂Is H,

In some embodiments of formula (1), the compound is of formula (2):

wherein,

X₁is O, S or NR_1b；

R_1bIs H halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-3alkylene-C_5-6An aryl group;

R₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) C_1-6Alkoxy radical, C_1-6alkylene-C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)N(C_1-6Alkyl radical)₂、C(O)OC_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

each R_3aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o);

R₄is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

each R_4aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Heterocyclyl or C_3-6A carbocyclic group; and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, -C_1-6alkylene-C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein eachEach said heteroaryl or heterocyclyl group containing 1,2,3 or 4 heteroatoms selected from N, O or S;

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

z is H, or deuterium.

In some embodiments of formula (1), or formula (I), the compound is formula II:

wherein,

X₁is O, S or NR_1b；

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical,C(O)NH₂、S(O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, -C_1-6alkylene-C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

The present invention further provides some preferred embodiments with respect to the compounds of formula (2), or formula (II).

In some embodiments of formula (2), or formula (II), R_1bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylene-5-membered aryl or C_1-3Alkylene-6-membered aryl.

In some embodiments of formula (2), or formula (II), R_1bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5 memberedAryl or methylene-6 membered aryl.

In some embodiments of formula (2), or formula (II), R_1bIs H, methyl or phenyl.

In some embodiments of formula (2), or formula (II), R₂Is H, F, Cl, Br, I, NH₂CN, OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) C_1-3Alkoxy radical, C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₂Independently by F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (2), or formula (II), R₂Is H, F, Cl, NH₂CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH₃、C(O)OCH₂CH₃、C(O)OCH₂CH₂CH₃、C(O)OCH(CH₃)₂、CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₂CH₃、CH₂CH₂OCH₃,C(CH₃)₂OCH₃、C(CH₃)₂OCH₂CH₃、C(CH₃)₂OCH₂CH₂CH₃5-or 6-membered heteroaryl; and each R₂Independently by F, Cl, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (2), or formula (II), R₂Is H, F, Cl, CN, methyl, methoxyBasic, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

In some embodiments of formula (2), or formula (II), R₂Is H, F, Cl, CN, methyl, CD₃Ethyl, isopropyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

In some embodiments of formula (2), or formula (II), R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、S(O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、-C_l-3alkylene-N (C)_1-3Alkyl radical)₂、-C_2-3alkynyl-OH, -C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

In some embodiments of formula (2), or formula (II), R₃Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂N(CH₂CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Ethynyl, propynyl, propargyl,

-C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

In some embodiments of formula (2), or formula (II), s is 1,2,3, or 4.

In some embodiments of formula (2), or formula (II), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂AcetyleneA base,

CH₂OCH₃、C(CH₃)₂OCH₃、CH₂OCH₂OH、C(CH₃)₂OCH₂OH、C(CH₃)₂OCH₂CH₂OH、C(CH₃)₂OCH₂CH₂CH₂OH、C(CH₃)₂-(OCH₂)₂-OH、C(CH₃)₂-(OCH₂CH₂)₂-OH、C(CH₃)₂-(OCH₂)₃-OH、C(CH₃)₂-(OCH₂CH₂)₃-OH、C(CH₃)₂-(OCH₂)₄-OH、C(CH₃)₂-(OCH₂CH₂)₄-OH、CH₂OCH₂OCH₃、C(CH₃)₂OCH₂OCH₃、C(CH₃)₂OCH₂CH₂OCH₃、C(CH₃)₂OCH₂CH₂CH₂OCH₃、C(CH₃)₂-(OCH₂)₂-OCH₃、C(CH₃)₂-(OCH₂CH₂)₂-OCH₃、C(CH₃)₂-(OCH₂)₃-OCH₃、C(CH₃)₂-(OCH₂CH₂)₃-OCH₃、C(CH₃)₂-(OCH₂)₄-OCH₃、C(CH₃)₂-(OCH₂CH₂)₄-OCH₃、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

In some embodiments of formula (2), or formula (II), each R is_3aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (2), or formula (II), each R is_3aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH₂CH₂OH、CH(CH₃) OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (2), or formula (II), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、

In some embodiments of formula (2), or formula (II), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、C(O)OCH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、

In some embodiments of formula (2), or formula (II), R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (2), or formula (II), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, S (O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted.

In some embodiments of formula (2), or formula (II), each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl;and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (2), or formula (II), each R is_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 8-membered heterocyclic group, 3-membered carbocyclic group, 5-membered carbocyclic group or 6-membered carbocyclic group; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (2), or formula (II), each R is_4aIndependently of each other H, F, Cl, NH₂OH, methyl,

Or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (2), or formula (II), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, S (O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、

In some embodiments of formula (2), or formula (II), W₁Is H, F, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (2), or formula (II), W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、CH₂CH₂OCH₂CH₃、CH(CH₃)OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (2), or formula (II), W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, CH₂OCH₃、CH₂CH₂OCH₃、

In some embodiments of formula (2), or formula (II), W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, CH₂OCH₃、CH₂CH₂CF₃、CH₂CH₂OCH₃、

In some embodiments of formula (2), or formula (II), W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (2), or formula (II), W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (2), or formula (II),W₂is H, F, Cl, methyl, methoxy,

In some embodiments of formula (1), the compound is of formula (3):

wherein,

X₂is O, S or NR_2b；

R_2bIs H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6An alkoxy group;

R₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、S(O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, -C_1-6Alkylene oxideradical-C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

z is H, or deuterium.

In some embodiments of formula (1), formula (I), the compound is formula III:

wherein,

X₂is O, S or NR_2b；

R₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or SAn atom;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

The present invention further provides some preferred embodiments with respect to the compounds of formula (3), or formula (III).

In some embodiments of formula (3), or formula (III), R_2bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3An alkoxy group.

In some embodiments of formula (3), or formula (III), R_2bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula (3), or formula (III), X₂Is O, S or NH.

In some embodiments of formula (3), or formula (III), R₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (3), or formula (III), R₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), R₁Is H, F or methyl.

In some embodiments of formula (3), or formula (III), R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

5 membered heteroAryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (3), or formula (III), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), R_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (3), or formula (III), R_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula (3), or formula (III), R₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH、

In some embodiments of formula (3), or formula (III), R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (3), or formula (III), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (3), or formula (III), R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), R₄Is H,F、Cl、NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH, or

In some embodiments of formula (3), or formula (III), R₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH、

In some embodiments of formula (3), or formula (III), W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (3), or formula (III), W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), W₁Is H, F, Cl, methyl, methoxy,

In some embodiments of formula (3), or formula (III), W₁Is H, F, Cl, methyl, methoxy, CH₂CH₂CF₃、

In some embodiments of formula (3), or formula (III), W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (3), or formula (III), W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (3), or formula (III), W₂Is H, F, Cl, NH₂OH, methyl, methoxy,

In some embodiments of formula (1), the compound is of formula (4):

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

each R_4aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Heterocyclyl or C_3-6A carbocyclic group; and wherein each said heterocyclyl contains a 1,2,3 or 4 heteroatom selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or SAn atom;

z is H, or deuterium.

In some embodiments of formula (I), or formula (4), the compound is formula IV:

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group comprises 1,2,3 or 4And a heteroatom selected from N, O or S.

The present invention further provides some preferred embodiments with respect to the compounds of formula (4), or formula (IV).

In some embodiments of formula (4), or formula (IV), R_2bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3An alkoxy group.

In some embodiments of formula (4), or formula (IV), R_2bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula (4), or formula (IV), X₂Is S or NH.

In some embodiments of formula (4), or formula (IV), R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

A 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (4), or formula (IV), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl,A 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (4), or formula (IV), R_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (4), or formula (IV), R_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula (4), or formula (IV), R₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH or

In some embodiments of formula (4), or formula (IV), R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (4), or formula (IV), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (4), or formula (IV), each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (4), or formula (IV), R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O.

In some embodiments of formula (4), or formula (IV), R₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH or

In some embodiments of formula (4), or formula (IV), W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl(ii) a And each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (4), or formula (IV), W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (4), or formula (IV), W₁Is H, F, Cl, methyl, methoxy,

In some embodiments of formula (4), or formula (IV), W₁Is H, F, Cl, methyl, methoxy, CH₂CH₂CF₃、

In some embodiments of formula (4), or formula (IV), W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl,A 4-membered, 5-membered, or 6-membered carbocyclic group; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (4), or formula (IV), W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (4), or formula (IV), W₂Is H, F, Cl, NH₂OH, methyl, methoxy,

In some embodiments of formula (1), the compound is of formula (5):

wherein,

X₁is CR_1aO, S or NR_1b；

R_1aIs H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

R_1bis H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1bIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

R₄is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radicalBase, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

Two R_4aTogether with the carbon atom to which they are attached form c (o);

z is H, or deuterium.

In some embodiments of formula (1), or formula (I), the compound is formula V:

wherein,

X₁is CR_1aO, S or NR_1b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₂is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains a 1,2,3 or 4 heteroatom selected from N, O or S.

The present invention further provides some preferred embodiments with respect to the compounds of formula (5), or formula (V).

In some embodiments of formula (5), or formula (V), R_1aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), R_1aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 substituents selected from N orA heteroatom of O.

In some embodiments of formula (5), or formula (V), R_1bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), R_1bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), X₁Is CH, O, S or NH.

In some embodiments of formula (5), or formula (V), R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), R_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (5), or formula (V), R_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of formula (5), or formula (V), R₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH or

In some embodiments of formula (5), or formula (V), R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroAryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

In some embodiments of formula (5), or formula (V), R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), R₄Is H, F, Cl, NH₂OH, methyl, methoxy、CH₂OH、C(CH₃)₂OH or

In some embodiments of formula (5), or formula (V), W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), W₁Is H, F, Cl, methyl, methoxy,

In some embodiments of formula (5), or formula (V), W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

In some embodiments of formula (5), or formula (V), W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

In some embodiments of formula (5), or formula (V), W₂Is H, F, Cl, NH₂OH, methyl, methoxy,

With respect to compounds of formula (1), formula (I), formula (2), formula (II), formula (3), formula (III), formula (4), formula (IV), formula (5), or formula (V), the present invention further provides some preferred embodiments:

1)2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

2)2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-hiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

3)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

4)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

5)2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol;

6)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

7)5- (2- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one;

8)5- (6- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one;

9)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

10)2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol;

11)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

12)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

13)2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol;

14)4- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -2-methylbut-3-yn-2-ol;

15)4- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -2-methylbut-3-yn-2-ol;

16) n- (3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) propyl) -3-methoxy-N-methyl- [1,2,4] triazol [4,3-b ];

17) (2S,3R) -2- ((1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethyl) amino) -3-hydroxybutanoic acid isopropyl ester;

18)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

19)2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

20)2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

21)2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

22)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

23)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

24)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] -pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

25)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

26)6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-3-carboxylic acid ethyl ester

27)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [3,2-b ] indol-2-yl) propan-2-ol;

28)2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol;

29)2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol;

30)2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol;

31) (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (2-hydroxypropan-2-yl) pyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridin-1 (4H) -yl) (phenyl) methanone;

with respect to formula (1), formula (I), formula (2), formula (II), formula (3), formula (III), formula (4), formula (IV), formula (5), or formula (V), the present invention further provides some preferred embodiments:

the present invention also provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient. In the composition, the weight ratio of said compound to said adjuvant ranges from about 0.0001 to about 10.

The invention also provides a combination product comprising a compound as described herein, and one or more other therapeutically active agents.

The invention further provides the use of a pharmaceutical composition of formula (1), formula (I), formula (2), formula (II), formula (3), formula (4), formula (IV), formula (5), or formula (V).

The invention further provides the use of a pharmaceutical composition as described herein in the manufacture of a medicament. In some embodiments, the use in the manufacture of a medicament for a disease or condition characterized by a bromodomain inhibitor. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myeloid Leukemia (AML). In some embodiments, the cancer is selected from acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers. In some embodiments, the disease or disorder is acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute kidney disease or disorder, chronic kidney disease or disorder, male infertility.

In some embodiments, the medicaments so prepared are useful for treating or preventing cancer, cancer metastasis, cardiovascular disease, immunological disease, or ocular disease.

The invention further provides the use of at least one compound as described herein for the preparation of a medicament. In some embodiments, for use in treating a disease or disorder characterized by a bromodomain inhibitor. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myeloid Leukemia (AML). In some embodiments, the cancer is selected from acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers. In some embodiments, the disease or disorder is selected from the group consisting of acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute kidney disease or disorder, chronic kidney disease or disorder, male infertility.

In some embodiments, the medicaments thus prepared may be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immunological disease or ocular disease.

At least one compound described herein for use in treating cancer, preventing cancer metastasis, or treating cardiovascular disease, immune disease, or ocular disease.

Use of at least one compound for the manufacture of a medicament for use as a BET inhibitor.

A method of treating a patient having a disorder mediated by BET activity, comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder mediated by BET activity is cancer.

In some embodiments, the indication mediated by BET activity is rage (noonan) syndrome, leopard (leopard) syndrome, juvenile myelomonocytic leukemia, liver cancer, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, neuroblastoma, anaplastic large cell lymphoma, and glioblastoma.

A method of treating a patient having a disease or disorder characterized by a bromodomain inhibitor, the method comprising administering to the patient a therapeutically effective amount of at least one compound as defined in any one of claims 1-152, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers. In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML). In some embodiments, the cancer is selected from the group consisting of acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers. In some embodiments, the disease or disorder is acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute kidney disease or disorder, chronic kidney disease or disorder, male infertility.

At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament.

A compound described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of cancer.

A method of treating cancer selected from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers in a mammal, comprising administering to a mammal in need of such treatment an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

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

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

The term "alkylene" means a difunctional group obtained by the removal of one hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH)₂-, ethylene (i.e., -CH)₂-CH₂-or-CH (CH)₃) -) and propylene (i.e., -CH₂-CH₂-CH₂-、-CH(-CH₂-CH₃) -or-CH₂-CH(CH₃)-)。

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

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

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

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

The term "heterocycle" as used herein, unless otherwise specified, refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to eight membered and is fully saturated or has one or more unsaturations. Included in this definition are a plurality of degrees of substitution, preferably one, two or three degrees of substitution.

Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazole.

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

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

The term "carbonyl (acyl), ═ O or oxo (oxo)" refers to the group c (O).

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

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

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

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

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

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

The stereochemistry at certain positions is not shown in the above formula. The present invention includes all stereoisomers of formula (la) and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. The products of such steps may be mixtures of stereoisomers during the synthetic steps used to prepare such compounds, or during the use of racemic or epimeric steps known to those skilled in the art.

The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms of the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuteriumAnd tritium. Isotopes of hydrogen can be represented as¹H (hydrogen) is selected from the group consisting of,²h (deuterium) and³h (tritium). They are also generally indicated by D for deuterium and T for tritium. In this application, CD₃Represents a methyl group in which all hydrogen atoms are deuterium.

When a tautomer of a compound of formula (la) is present, the present invention includes any possible tautomer, pharmaceutically acceptable salt thereof, and mixture thereof, unless otherwise specified.

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

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

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

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

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

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

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

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

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

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders and the like. In addition, the composition may be in a form suitable for use in a transdermal device. These formulations may be prepared by conventional processing methods using the compounds of formula (la) or pharmaceutically acceptable salts thereof of the present invention. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.

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

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

Typically, dosage levels of about 0.01mg/kg to about 150mg/kg body weight per day are useful for treating the above-mentioned conditions, or about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the Central Nervous System (CNS) can be effectively treated by administering about 0.01 to 50mg of the compound per kilogram of body weight per day, or about 0.5mg to about 3.5g per patient per day.

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

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

Preparation method

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

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

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

General routes for preparing the compounds of the invention are depicted in schemes 1-4, wherein R₁、R₂、R₃、R₄、W₁And W₂The substituents are defined herein as before or are functional groups that can be converted to the desired final substituents.The substituent Hal is halogen and L is a leaving group, such as halide or OH which can be readily converted to a leaving group (e.g. triflate or tosylate). M is a suitable coupling ligand such as a boronic acid, boronic ester or stannane for a suitable catalyst.

The compound of formula II can be synthesized by reference to the method shown in scheme 1. It will be appreciated that any compound of formula II may be prepared by appropriate selection of reagents having appropriate substituents. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art.

Scheme 1

A general route to the compounds of the present invention is depicted in scheme 1, wherein R is₂、R₃、R₄、X₁、W₁And W₂Substituents have been previously described herein or can be converted to functional groups of the desired final substituent. Hal is a halide and L is a leaving group, such as a halide or OH which can be readily converted to a leaving group (e.g. triflate or tosylate). M is a suitable coupling ligand, for example a boronic acid, boronic ester or stannane, which is used as a suitable catalyst. As shown in scheme 1, Suzuki coupling of 1 with an aromatic heterocycle 2 gives a functionalized intermediate 3. Reductive cyclization of Cadogan 3 can provide functionalized tricycles 4. Mitsunobu coupling of alkylating agent 5 with 4 using triphenylphosphine and diisopropylazodicarboxylic acid (DIAD) affords 7. Alternatively, 7 may be generated in a displacement reaction between 4 and alkylating agent 6 in the presence of a base (such as cesium carbonate), where L is a leaving group, such as halide, mesylate or triflate. Suzuki coupling of 7 with 8 (where M is a suitable coupling ligand, e.g. boronic acid, boronic ester) can give 9. Alternatively, intermediate 9 can be synthesized using Stille reaction conditions between 7 and 8 (where M is stannane). Bromination of 9 in the presence of a suitable reagent (e.g., NBS) can provide 10, and subsequent treatment of 10 by a coupling reaction with 11 using suitable coupling conditions can produce a compoundSubstance II.

The general route for compound III shown in the present invention is outlined in scheme 2, wherein R₁、R₃、R₄、X₂、X₆、W₁And W₂Substituents have been described above or functional groups that can be converted to the desired final substituent. Hal is a halide and L is a leaving group such as a halide or OH which can be readily converted to a leaving group such as triflate or tosylate. M is a suitable coupling ligand, for example a boronic acid, boronic ester or stannane, which is used as a suitable catalyst.

Scheme 2

The general route for compound IV illustrated in the present invention is outlined in scheme 3, wherein R₃、R₄、X₂、W₁And W₂Substituents are described previously herein or functional groups that can be converted to the desired final substituent. Hal is a halide and L is a leaving group such as a halide or OH which can be readily converted to a leaving group such as triflate or tosylate. M is a suitable coupling ligand such as a boronic acid, boronic ester or stannane using a suitable catalyst.

Scheme 3

The general route for compound V illustrated in the present invention is outlined in scheme 4, wherein R₃、R₄、X₁、W₁And W₂Substituents have been previously described herein or functional groups that can be converted to the desired final substituent. Hal is a halide and L is a leaving group such as a halide or OH which can be readily converted to a leaving group such as triflate or tosylate. M is a suitable coupling ligand, for example a boronic acid, boronic ester or stannane, which is used as a suitable catalyst.

Scheme 4

Examples

The following examples are provided to better illustrate the invention. Unless otherwise expressly indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

B₂Pin₂: pinacol ester diborate; DAST: diethylaminosulfur trifluoride; DCM: dichloromethane; DIEA: n, N-diisopropylethylamine; DMAC: dimethylacetamide; DMF: n, N-dimethylformamide; DMSO, DMSO: dimethyl sulfoxide; dmbpy: 4,4 '-dimethyl-2, 2' -bipyridine; dtbpy: 4,4' -di-tert-butylbipyridine; EtOAc: ethyl acetate; EtOH: ethanol; h or hr: hours; KOAc (Koac): potassium acetate; [ Ir (COD) acid (OMe)]2: bis (1, 5-cyclooctadiene) dimethoxydiiridium; MeMgBr: methyl magnesium bromide; MeOH: methanol; NMP: n-methyl-2-pyrrolidone; TBAI: tetrabutylammonium iodide; TEA: triethylamine; THF: tetrahydrofuran; TFA: trifluoroacetic acid; xantphos: dimethyl bis diphenylphosphine xanthene; min: the method comprises the following steps of (1) taking minutes; rt or r.t.: room temperature; RT: a retention time; TLC: thin layer chromatography; Pre-TLC: preparing thin layer chromatography; pd (dppf) Cl₂: [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride; pd (PPh)₃)₄: tetrakis (triphenylphosphine) palladium (0); PdCl₂(pph₃)₂: bis (triphenylphosphine) palladium (II) chloride.

Preparation of intermediates

Unless otherwise indicated, starting materials for the preparation of intermediates and examples are commercially available.

Intermediate 1 and intermediate 2

(3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (enantiomer a, intermediate 1)

And

(3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (enantiomer b, intermediate 2)

In N₂Next, three iodine crystals were added to a suspension of Mg (24.3g, 1.00mol) in THF (500mL), and pure 4-bromotetrahydro-2H-pyran (100g, 607mmol) was added dropwise through an additional funnel, during which time the internal temperature was controlled below 45 ℃. The reaction mixture was stirred at ambient temperature for an additional 2 hours. The reaction mixture was cooled to-30 ℃ and then a solution of 3-fluoropyridine-2-carbaldehyde (50.3g, 402mmol) in THF (300mL) was added dropwise through an additional funnel, during which time the internal temperature was maintained between-20 ℃ and-30 ℃. After 1 hour, the reaction mixture was filtered through a thin pad of celite. Adding saturated NH into the filtrate₄Aqueous Cl (100mL) solution separated into two layers. Anhydrous Na for organic phase₂SO₄Dried, collected by filtration and washed with EtOAc (200 mL). The filtrate was concentrated on a rotary evaporator. Purifying the crude compound by reverse phase chromatography using 40% to 50% MeCN/H₂O elution gave the racemic compound (52g, 61% yield) which was separated by chiral prep SFC to give enantiomer a, (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 1, 25.1g, yield 29.6%) and enantiomer b, (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 2, 25.3g, 29.7%).

Enantiomer a (intermediate 1): LC-MS [ M + H ]]⁺Chiral chromatography reports RT 12.25min (column: Chiralpak AY-H (ADH0CE-VC 0010.46 × 25 cm; mobile phase: 90/10/0.1 n-hexane/EtOH/DEA; flow rate: 1.0 mL/min).¹H NMR(400MHz,DMSO-d₆)δ8.42(dd,J＝3.20,1.32Hz,1H),7.66(ddd,J＝9.8,8.36,1.12Hz,1H),7.35–7.42(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),2.01-2.12(m,1H),1.82(dd,J＝13.3,1.52Hz,1H),1.24-1.38(m,1H),1.12-1.24(m,1H),1.00(dd,J＝12.9,1.34,1H)。

Enantiomer b (intermediate 2): LC-MS [ M + H ]]⁺Chiral chromatography reports RT 13.57min (column: Chiralpak AY-H (ADH0CE-VC 0010.46 × 25 cm; mobile phase: 9)0/10/0.1 n-hexane/EtOH/DEA; flow rate: 1.0 mL/min).¹H NMR(400MHz,DMSO-d₆)δ8.42(dd,J＝3.2,1.35Hz,1H),7.66(ddd,J＝1.12,8.4,9.8Hz,1H),7.35–7.42(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),1.12–1.24(m,1H),1.00(dd,J＝12.9,1.34,1H)。

Intermediates 3 to 7

The intermediates in table 1 were prepared using the same method as the racemates of intermediates 1 and 2:

TABLE 1

Example 1

2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylic acid ethyl ester

In N₂Next, to a solution of ethyl 5-bromothiophene-2-carboxylate (6.51g,27.7mmol) in 1, 4-dioxane (100mL) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborane) (8.55g,33.7mmol), Pd (dppf) Cl₂DCM (1.14g,1.40mmol) and KOAc (8.26g, 84.2 mol). The mixture was evacuated and charged with N₂Refill and repeat the process 3 times the resulting mixture is refluxed for 20 hours the reaction is quenched with water, extracted with EtOAc (3 × 200mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title intermediate as a black oil (6.00g, 76% yield) which is used directly in the next step LC-MS [ M + H ] M + H]⁺＝283。

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) thiophene-2-carboxylic acid ethyl ester

To a solution of ethyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) thiophene-2-carboxylate (6.00g,28.1mmol) in 1, 4-dioxane (100mL) and water (20mL) under nitrogen was added 2, 5-dibromo-3-nitropyridine (7.69g,27.3mmol), Pd (dppf) Cl₂DCM (1.01g, 1.24mmol), and K₂CO₃(10.29g, 84.4 mol). Mixing the mixture with N₂Flow purge 3 min, connect condenser, at N₂Under atmosphere, then heated to reflux and stirred for 3 hours the reaction mixture was cooled to room temperature, poured into water (300mL) and extracted with EtOAC (3 × 200 mL.) the collected organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure the residue obtained was purified by silica gel chromatography eluting with 0-30% EtOAC in n-hexane to give the title compound (3.03g, 32% yield) as a pale yellow solid LC-MS [ M + H ] LC-MS [ M + H]⁺＝357。

And step 3: 6-bromo-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid ethyl ester

In N₂A mixture of ethyl 5- (5-bromo-3-nitrobenzyl-2-yl) thiophene-2-carboxylate (2.01g,6.12mmol) and DPPE (2.92g, 7.34mmol) in 1, 2-dichlorobenzene (15mL) was heated to 160 ℃ with protection and stirred for 24 hours then the reaction mixture was slowly cooled to room temperature and a light brown solid generated from the solution the solid was collected by filtration and washed with EtOAc (2 × 5mL) to give the desired crude title intermediate (1.48g, 75% yield) as a pale yellow solid LC-MS [ M + H ] M]⁺＝325。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid ethyl ester

In N₂To 6-bromo-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]1, 4-dimethyl-5- (tristinnanyl) -1H-1,2, 3-triazole (2.59g, 6.69mmol) [ Seefeld, MA, etc. ] is added to a solution of pyridine-2-carboxylic acid ethyl ester (1.45g, 4.46mmol)) in 1, 4-dioxane (20 mL). PCT international application, 2008, WO2008098104]、Pd(dppf)Cl₂DCM (316mg, 0.452mmol) and DIEA (1.73g, 13.4 mmol). Mixing the mixture with N₂Purging for 3 min, oil bath at 120 deg.C with stirring and condensingN of the device₂The reaction mixture was poured into water (100mL) and extracted with EtOAc (2 × 100mL), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered, the collected filtrate was concentrated on a rotary vacuum evaporator, the resulting residue was purified by silica gel chromatography using 0-50% EtOAc in DCM to give the desired title compound (120mg, 8% yield) as a yellow solid, LC-MS [ M + H ] M]⁺＝342。

And 5: 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid ethyl ester

At room temperature, 6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4H-thieno [2',3':4,5] is added in batches]Pyrrolo [3,2-b]To a solution of pyridine-2-carboxylic acid ethyl ester (120mg, 0.281mmol) in THF (10ml) was added NaH (60% in oil, 34.2mg, 0.841 mmol). The resulting mixture is stirred under N₂Stirred under atmosphere for 10 minutes. The reaction mixture was cooled to 0 ℃ in an ice-water bath and then N₂Bromobenzyl (96.2mg, 0.562mmol) was added dropwise under an atmosphere. The reaction mixture was then slowly warmed to room temperature and stirring was continued for 2 hours. The reaction was quenched with water and extracted with EtOAc (100 mL). After separation, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (90mg, 75% yield) as a yellow solid. LC/MS [ M + H ]]⁺＝432。

Step 6: 2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

In N₂MeMgBr (3M in THF, 3.0mL, 9.00mmol) was slowly added dropwise to 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] at-30 ℃ over 10min]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid ethyl ester in THF. After addition, the reaction was slowly warmed to room temperature and stirred for 2 hours. Adding saturated NH₄The reaction was quenched with aqueous Cl and extracted with EtOAc (120 mL). The collected organic layer was washed with brine, dried over anhydrous sodium sulfateDried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give the desired title compound (100mg, 26% yield). LC-MS [ M + H ]]⁺＝418.¹H-NMR(400MHz,DMSO-d₆)δ9.24(s,1H),7.97(s,1H),7.23-7.33(m,5H),6.60(s,1H),5.88(s,2H),5.53(bs,1H),4.30(s,3H),2.33(s,3H),1.30(s,6H)。

Example 2

2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5-bromo-2- (1-ethoxyvinyl) -3-nitropyridine

To a solution of 2, 5-dibromo-3-nitropyridine (50.1g, 177mmol) in 1, 4-dioxane (1.0L) were added tributyl (1-ethoxyvinyl) stannane (64.1g, 177mmol) and CsF (53.9g, 355 mmol). The suspension mixture is treated with N₂Purge for 3 min, then add Pd (PPh)₃)₄(10.3g, 8.87 mmol). The mixture was evacuated and N was used₂Backfilling and repeating this sequence 3 times. In N₂The mixture was heated to reflux under a condenser for 16 hours. After the reaction mixture was cooled to room temperature, it was poured into water (1.0L) and extracted with EtOAc (2.5L). The collected organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 0-5% EtOAc in n-hexane to give the desired intermediate 5-bromo-2- (1-ethoxyvinyl) -3-nitropyridine as a yellow oil. (19.4g, 40% yield). LC-MS [ M + H ]]⁺＝273。

Step 2: 2-bromo-1- (5-bromo-3-nitropyridin-2-yl) ethan-1-one

N-bromosuccinimide (15.2g, 85.6mmol) was slowly added portionwise over 10 minutes at room temperature to a solution of 5-bromo-2- (1-ethoxyvinyl) -3-nitropyridine (19.1g, 85.6mmol) in THF (400mL) and water (70 mL). After addition, the reaction mixture is placed in a chamberStirring for 2 h. With saturated NaHCO₃The reaction was quenched and extracted with EtOAc (400 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-3% EtOAc in n-hexane to give the expected intermediate 2-bromo-1- (5-bromo-3-nitropyridin-2-yl) ethan-1-one (17.6g, 64% yield) as a yellow solid, LC-MS [ M + H ] M]⁺＝324。

And step 3: 5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-amine

A mixture of 2-bromo-1- (5-bromo-3-nitropyridin-2-yl) ethan-1-one (17.6g, 54.3mmol), thiourea (6.2g, 81.5mmol) and DIEA (14.0g, 109mmol) in EtOH (400mL) was heated to 80 ℃ and stirred for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in n-hexane to give the title compound (12.8g, 79% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝301。

And 4, step 4: n- (5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-yl) acetamide

A mixture of 5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-amine (12.6g, 41.9mmol) and DIEA (10.9g, 83.8mmol) in acetic anhydride (200mL) was heated to 30 deg.C and stirred for 18 h. A large amount of solid precipitated from the reaction mixture. The yellow solid was collected by filtration and washed with N-hexane to give N- (5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-yl) acetamide (11.7g, 82% yield). LC-MS [ M + H ]]⁺＝343。

And 5: n- (6-bromo-4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-yl) acetamide

In N₂A mixture of N- (5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-yl) acetamide (11.6g, 31.1mol), triethyl phosphite (20mL) in xylene (100mL) was heated to 150 ℃ under atmosphere and stirred for 16 h. The reaction mixture was then slowly cooled to room temperature. The reaction precipitated crystals which were collected by filtration to give the title compound (3.51g, crude product) as a light grey solid. LC-MS [ M + H ]]⁺＝311。

Step 6: 6-bromo-4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-amine

To the N- (6-bromo-4H-thiazolo [5',4':4, 5)]Pyrrolo [3,2-b]Pyridin-2-yl) acetamide (10.1g, 32.5mmol) to a mixture of EtOH (120mL) was added 12N HCl (40 mL). The resulting reaction mixture was heated to 90 ℃ and stirred for 16 h. The reaction mixture was then slowly cooled to room temperature. Crystals precipitated from the reaction system, which were collected by filtration to give the title compound (9.77g, 99% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝269。

And 7: 2, 6-dibromo-4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridine

6-bromo-4H-thiazolo [5',4':4,5] is reacted at 5 ℃ over 10 minutes]Pyrrolo [3,2-b]Pyridin-2-amine (1.05g, 3.70mmol) in H₃PO₄(85%, 8mL) of the suspension concentrated HNO was added dropwise₃(2.5 mL). The resulting solution was cooled to 2 ℃ and NaNO was added slowly over 30 minutes₂(330mg, 4.78mol) of H₂O (2.5mL) solution. The resulting solution was stirred between 0-5 ℃ C for 1 hour. Mixing the stirred CuSO₄·5H₂O (0.650g, 2.31mmol) and NaBr (1.18g, 11.5mmol) in H₂The O (4mL) solution was cooled to 6 deg.C and then the red diazo solution was added slowly over 90 minutes. The resulting green effervescent solution was stirred at 0-7 ℃ for at least 6 hours and then allowed to warm to room temperature overnight. With saturated NaHCO₃The reaction was quenched. The resulting solid was collected by filtration and washed with MeOH to give the title compound (1.04g, 84% yield) as a gray solid. LC-MS [ M + H ]]⁺＝335。

And 8: 4-benzyl-2, 6-dibromo-4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridine

2, 6-dibromo-4H-thiazolo [5',4':4,5]Pyrrolo [3,2-b]Pyridine (260mg, 0.776mmol), (bromomethyl) benzene (120mg, 0.702mmol), and Cs₂CO₃A mixture of (762mg, 2.34mmol) in DMF (20mL) was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (60 mL). The collected organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAC in n-hexane to give the titleCompound (120mg, 0.284mmol, 36% yield) as a pale yellow solid. LC-MS [ M + H ]]⁺＝423。

And step 9: 4-benzyl-6-bromo-2- (prop-1-en-2-yl) -4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridine

To 4-benzyl-2, 6-dibromo-4H-thiazolo [5',4':4,5]Pyrrolo [3,2-b]Pyridine (400mg, 0.946mmol) in DMF (20mL) and water (10mL) was added K₃PO₄(403mg, 1.90 mol). With N₂Purge the mixture for 2 minutes, then at N₂Adding Pd (dppf) Cl₂DCM (80.1mg, 0.0982 mmol). In N₂The mixture was heated to 100 ℃ and stirred under an atmosphere for 16 h. The reaction mixture was then cooled to room temperature. And extracted with EtOAc (500 mL). The collected organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-30% EtOAC in n-hexane to give the title compound (278mg, 0.726mmol, 76% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝384。

Step 10: 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (prop-1-en-2-yl) -4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridine

To 4-benzyl-6-bromo-2- (prop-1-en-2-yl) -4H-thiazolo [5',4':4,5]Pyrrolo [3,2-b]Pyridine (90.2mg, 0.235mmol) in dioxane (8mL) was added (1, 4-dimethyl-5- (stannyl) -1H-1,2, 3-triazole (226mg, 0.585mmol) and DIEA (89.2mg, 0.690mmol)₂Purge for 2min, then add PdCl₂(pph₃)₂(316mg, 0.450 mmol). The reaction mixture was stirred under reflux in an oil bath at 120 ℃ for 16 hours and then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (40 mL). The organic phase obtained is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure on a rotary evaporator. The residue was purified by silica gel chromatography using 0-50% EtOAc in DCM to give the title compound (50.1mg, 54% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝401。

Step 11: 1- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethanone

Osmium tetroxide (3.0ml, 0.1mmol/ml, 0.3mmol) was slowly added dropwise to 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (prop-1-en-2-yl) -4H-thiazolo [5',4':4, 5: -2, 5: -1)]Pyrrolo [3,2-b]Pyridine (80.2mg, 0.200mmol) in 1, 4-dioxane (10 ml). In N₂The mixture was stirred under atmosphere for 1 hour. To the reaction mixture was added dropwise an aqueous solution of sodium iodate (65.3mg, 0.330mmol) and stirred for 1 h. With saturated Na₂S₂O₃The reaction was quenched with aqueous solution and extracted with EtOAc (40 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure on a rotary evaporator. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give the title compound (30.2mg, 37% yield). LC-MS [ M + H ]]⁺＝403。

Step 12: 2- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5',4':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

MeMgBr (1.0mL, 3.0mmol, 3M in THF) was slowly added to 1- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5',4':4,5] over 1 min at-30 deg.C]Pyrrolo [3,2-b]Pyridin-2-yl) ethanone (120mg, 0.298mmol) in THF (10 mL). After addition, the reaction was stirred at room temperature for 2 h. With saturated NH₄The reaction was quenched with aqueous Cl. Extract with EtOAc (20 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure on a rotary evaporator. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give the title compound (30.1mg, 24% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝418。

Example 3

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid ethyl ester

To 6-bromo-4H-thieno [2',3':4,5] at room temperature]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid ethyl ester (from step 3 of example 1, 800mg, 2.46mmol), (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 6, 0.60g, 2.84mmol) and triphenylphosphine (1.56g, 5.95mmol) in dry toluene (20mL) was added dropwise a solution of diisopropyl azodicarboxylate (1.19g, 5.88mmol) in THF (5 mL). In N₂The resulting solution was refluxed for 16H under atmosphere then the reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 100mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered the filtrate was concentrated under reduced pressure the resulting residue was purified by silica gel chromatography using 0-30% EtOAc in n-hexane to give the title compound (101mg, 8% yield) as a pale yellow solid LC-MS: [ M + H ] solution]⁺＝519。

Step 2: ethyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

To 6-bromo-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine-2-carboxylic acid ethyl ester (101mg, 0.195mmol) in DMF (2mL) was added 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (117mg, 0.303mmol), tetrakis (triphenylphosphine) palladium (23.2mg, 0.0201mmol), CuI (11.0mg, 0.0578mmol) and TEA (41mg, 0.056mL, 0.406 mmol). The mixture was degassed, flushed with nitrogen, and the sequence was repeated 3 times. In N₂The resulting mixture was heated to 110 ℃ and stirred for 3 hours under atmosphere, the mixture was cooled to room temperature, diluted with water (50mL) and extracted with EtOAc (3 × 50mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified by Prep-TLC using 80% EtOAc in n-hexane to giveThe title compound (66.1mg, 65% yield) was a light yellow solid. LC-MS: [ M + H ]]⁺＝535。

And step 3: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described in example 1, step 6, after purification by silica gel chromatography using 0-6% MeOH in DCM, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Ethyl pyridine-2-carboxylate (56.2mg, 0.105mmol) was converted to the expected product as an off-white solid (10.3mg, 19% yield). LC-MS: [ M + H ]]⁺＝521.¹H-NMR(400MHz,CDCl₃)δ8.63(s，1H),8.53(s，1H),8.39(s，1H),7.80-7.75(m,2H),7.59(s,1H),5.78(d,J＝11.0Hz,1H),5.71(s,1H),4.03(s,3H),3.83(d,J＝9.44Hz,1H),3.73(d,J＝11.2Hz,1H),3.32-3.16(m,3H),2.31(s,3H),1.61(s,6H),1.49-1.31(m,2H),1.30–1.15(m,1H),0.98–0.85(m,1H)。

Example 4

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5-bromo-3-nitro-2- (thiophen-3-yl) pyridines

To a solution of 2, 5-dibromo-3-nitropyridine (5.00g, 17.8mmol) in EtOH (20mL), water (27mL), and toluene (30mL) under a nitrogen atmosphere was added thiophen-3-ylboronic acid (2.39g, 18.7mol) and Na₂CO₃(5.68g, 53.6 mol). Mixing the mixture with N₂Purge for 2min, then add tetrakis (triphenylphosphine) palladium (1.04g, 0.900 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to room temperature and extracted with EtOAc (100 mL). The collected organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressureConcentrating under reduced pressure. The resulting residue was purified by silica gel chromatography using 0-5% EtOAc in hexanes to give the title compound (3.84g, 76% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝286。

Step 2: 6-bromo-8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine

A mixture of 5-bromo-3-nitro-2- (thiophen-3-yl) pyridine (3.80g, 13.3mmol), DPPE (6.92g, 17.4mmol) in 1, 2-dichlorobenzene (50mL) was degassed, flushed with nitrogen, and the sequence repeated 3 times. The resulting mixture was heated to 165 ℃ and stirred for 5 hours. The reaction mixture was then slowly cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-30% EtOAc in n-hexane to give the title compound (2.01g, 60% yield) as a pale yellow solid. LC-MS [ M + H ]]⁺＝254。

And step 3: 6-bromo-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine

Reacting 6-bromo-8H-thieno [3',2':4,5]Pyrrolo [3,2-b]A solution of pyridine (1.01g, 4.00mmol), phenyl (tetrahydro-2H-pyran-4-yl) methanol (Kyoto pharmaceutical Co., Ltd., 0.93g, 4.84mmol) and triphenylphosphine (2.12g, 8.08mmol) in dry toluene (20mL) was degassed and flushed with nitrogen and the sequence repeated three times. A solution of diisopropyl azodicarboxylate (4.02g, 19.9mmol) in THF (10ml) was added dropwise at room temperature, and the resulting solution was refluxed for 16 hours. The reaction was then extracted with EtOAc (50mL), washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with 0-20% EtOAc in n-hexane to give the title compound (1.49g, 87% yield) as a white solid. LC-MS [ M + H ]]⁺＝428。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine

To 6-bromo-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5]Pyrrolo [3,2-b]Pyridine (1.49g, 3.49mmol) in DMF (20mL) was added 1,4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (2.04g, 5.28mmol), tetrakis (triphenylphosphine) palladium (406mg, 0.351mmol), CuI (170mg, 0.893mmol), and TEA (711mg, 7.03 mmol). The mixture was degassed and flushed with nitrogen and the sequence was repeated 3 times. The resulting mixture is stirred under N₂The reaction mixture was cooled to room temperature, diluted with water (100mL) and extracted with EtOAc (3 × 100mL), the collected organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated the residue was purified by silica gel chromatography using 0-100% EtOAc in n-hexane to give the title compound (1.32g, 85% yield) as a yellow solid LC-MS [ M + H ] M + H]⁺＝444。

And 5: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine

N-bromosuccinimide (0.651g, 3.66mmol) was added in small portions to 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8 (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4, 5-triazol-5-yl) over 10 minutes at room temperature]Pyrrolo [3,2-b]Pyridine (1.32g, 2.98mmol) in THF (10mL) and water (6 mL). After the addition, the reaction mixture was stirred at room temperature for 2 hours. With saturated NaHCO₃The reaction was quenched and the resulting mixture was extracted with EtOAc (100 mL). The collected organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-3% MeOH in DCM to give the title compound (0.761g, 49% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝523。

Step 6: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (1-ethoxyvinyl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine

To a solution of 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5]Pyrrolo [3,2-b]To a solution of pyridine (300mg, 0.575mmol) in 1, 4-dioxane (6mL) were added tributyl (1-ethoxyvinyl) -stannane (256mg, 0.707mmol), cesium fluoride (176mg, 1.16mmol) and tetrakis (triphenylphosphine) palladium (2)11mg, 0.183 mmol). The mixture was degassed and flushed with nitrogen and the sequence was repeated 3 times. The resulting mixture is stirred under N₂Heat to reflux under atmosphere for 16 hours. After cooling to room temperature, the solvent was removed on a rotary evaporator to give the crude title compound as a pale yellow oil (293mg, 99% yield). LC-MS [ M + H ]]⁺＝514。

And 7: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

To crude 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (1-ethoxyethylene) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4, 5: -1-ethyloxyethylene)]Pyrrolo [3,2-b]Pyridine (293mg, 0.570mmol) in THF (5mL) and water (2mL) was added 2N HCl (1 mL). The mixture was stirred at ambient temperature for 2 hours. Then saturated NaHCO₃The reaction was quenched with aqueous solution and the mixture was extracted with EtOAc (100 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (110mg, 40% over two steps) as an off-white solid. LC-MS [ M + H ]]⁺＝486。

And 8: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

In analogy to the procedure described in example 1, step 6, 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] in THF (3mL) was used]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (110mg, 0.226mmol) was converted to the title compound as an off-white solid (40mg, 35% yield). LC-MS: [ M + H ]]⁺＝502.¹H-NMR(400MHz,CDCl₃)δ8.35(d,J＝1.6Hz,1H),7.66(d,J＝1.6Hz,1H),7.45-7.43(m,3H),7.36-7.29(m,3H),5.14(d,J＝10.8Hz,1H),4.03-3.95(m,2H),3.94(s,3H),3.55-3.47(m,2H)。

Example 5

2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Step 1: 1- (3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

In N₂To 6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) -methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine (step 3, 964mg, 2.18mmol from example 18) in 1, 4-dioxane (30mL) was added tributyl (1-ethoxyvinyl) -stannane (1.74g, 4.81mmol), tetrakis (triphenylphosphine) palladium (252mg, 0.218mmol), CsF (662mg, 4.36 mmol). The reaction mixture was refluxed under nitrogen for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure on a rotary evaporator to give a pale yellow solid.

To a solution of this solid in THF (30mL) was added 2N HCl (3mL) at room temperature and stirred for 2 hours. The reaction was then quenched with saturated NaHCO₃Quench, extract with EtOAc (100mL), wash with brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by silica gel chromatography using 0-3% MeOH in DCM to give the title compound (0.76g, 1.88mmol, 86% yield) as a white solid. LC-MS [ M + H ]]⁺＝405。

Step 2: 1- (2-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) -methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

N-bromosuccinimide (169mg, 0.955mmol) is slowly added to 1- (3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5', over 10 minutes at room temperature]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (320mg, 0.792mmol) in THF (10mL) and water (50 mL). After addition, the reaction was stirred at room temperature for 2 hours. With saturated NaHCO₃The reaction was quenched with aqueous solution and the mixture was extracted with EtOAc (50 mL). The extract was washed with brine and dried over anhydrous sodium sulfateDried and concentrated. The residue was purified by silica gel chromatography using 0-40% EtOAc in n-hexane to give the title compound (351mg, 0.703mmol, 92% yield) as a white solid. LC-MS [ M + H ]]⁺＝484。

And step 3: 1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

To 1- (2-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) -methyl) -4H-thieno [2',3':4,5] under nitrogen]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (351mg, 0.725mmol) in DMF (20mL) was added 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (723mg, 1.87mmol), tetrakis (triphenylphosphine) palladium (62.2mg, 0.0538mmol) and DIEA (253mg, 1.96). The mixture was evacuated, back-filled with nitrogen and the process was repeated three times. The reaction mixture was sealed, stirred at 110 ℃ for 36h, then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (373mg, 0.747mmol, 84% yield) as a white solid. LC-MS [ M + H ]]⁺＝500。

And 4, step 4: 2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

In analogy to the procedure described in example 1, step 6, 1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5 ':4]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (134mg, 0.268mmol) was converted to the title compound (109mg, 78% yield) as a white solid. LC-MS [ M + H ]]⁺＝516。¹H-NMR(400MHz,DMSO-d₆)δ8.55(s,1H),8.18(s,1H),7.61-7.63(d,2H),7.36-7.40(t,2H),7.28-7.31(t,2H),5.68-5.71(d,1H),3.93(s,3H),3.89-3.91(m,1H),3.76-3.78(m,1H),3.48-3.53(m,2H),3.23-3.30(m,2H),2.28(s,3H),2.22(s,1H),1.75-7.77(m,1H),1.50(s,6H),1.34-1.36(m,1H),0.85-0.90(m,1H)。

Example 6

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

6-bromo-3-methyl-4H-thieno [2',3':4,5, 6-bromo-3-methyl-4H-thieno [2',3':4,5] was synthesized in analogy to the procedure described in step 1 of example 3]Pyrrolo [3,2-b]Pyridine (from step 2 of example 18, 840mg, 3.16mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (734mg, 3.48mmol) were converted to the title compound (1.24g, 85% yield) as an off-white solid. LC-MS [ M + H ]]⁺＝460。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In analogy to the procedure described in example 3, step 2, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (1.23g,2.67mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (1.24g,3.20mmol) were converted to the title compound (1.22g, 96% yield). LC-MS [ M + H ]]⁺＝477。

And step 3: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoro-pyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure similar to that described in step 2 of example 5, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Conversion of pyridine (600mg,1.26mmol) to the title compoundThe title compound (608mg,1.10mmol, 87% yield). LC-MS [ M + H ]]⁺＝556。

And 4, step 4: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

Following a procedure analogous to that described in example 5, step 1, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (605mg,1.09mmol) was converted to the title compound (349mg,0.674mmol, 62% yield). LC-MS [ M + H ]]⁺＝519。

And 5: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) - (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (1.02g,2.04mmol) was converted to the title compound (0.661g, 63% yield) as a white solid. LC-MS [ M + H ]]⁺＝535.¹H-NMR(400MHz,DMSO-d₆)δ8.47-8.48(d,1H),8.38(s,1H),8.30(s,1H),7.39-7.44(m,1H),7.31-7.35(m,1H),6.15-6.17(d,2H),3.97(s,3H),3.85-3.89(d,1H),3.25-3.51(m,3H),2.91(s,3H),2.32(s,3H),1.82(s,6H),1.26-1.47(m,4H)。

Example 7

5- (2- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one

Step 1: 2-methoxy-3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

In N₂To 5-bromoTo a solution of (E) -2-methoxy-3-methylpyridine (5.01g,24.9mmol) in dioxane (50mL) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborane) (9.48g,37.3mol) and potassium acetate (4.88g,49.8 mol). The mixture was evacuated, back-filled with nitrogen and the process was repeated three times. Adding Pd (PPh)₃)₄(1.44g,1.25 mmol). The resulting mixture was purged with a stream of nitrogen for 2 minutes, then heated to 80 ℃ and stirred for 8 h. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc (100 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAC in hexanes to give the title compound (5.01g, 20.1mmol, 80% yield). LC-MS [ M + H ]]⁺＝250。

Step 2: 3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one

A mixture of 2-methoxy-3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (1.51g,6.06mmol), p-toluenesulfonic acid (5.20g,30.2mol), and lithium chloride (1.31g,31.1mmol) in DMF (30mL) was heated to 140 ℃ and stirred for 2.5 h. The reaction mixture was then slowly cooled to room temperature, poured into water and extracted with EtOAC (50 mL). The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.800g, 57% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝236。

And step 3: 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one

To a solution of 3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.801g,3.39mmol) and cesium carbonate (2.20g,6.78mmol) in dioxane (20ml) was added iodomethane (0.961g,6.78mmol) at room temperature. The resulting solution was refluxed for 3 h. The reaction was then slowly cooled to room temperature, poured into water and extracted with EtOAc (50 mL). The collected organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.741g, 87% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝250。

And 4, step 4: 1, 3-dimethyl-5- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) pyridin-2 (1H) -one

In N₂To 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine (from step 3, 0.692g,1.62mmol of example 9) in dioxane (25mL) and water (10mL) was added 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.481g,1.92mol), Pd (dppf) Cl₂(100mg,0.121mmol) and Na₂CO₃(3.70g,3.49 mmol). Vacuumizing the mixture, and backfilling N₂And this process was repeated three times. In N₂The resulting reaction mixture was heated to 90 ℃ and stirred for 5h under an atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30-100% EtOAc in hexanes to give the title compound (50.2mg, 7% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝470。

And 5: 5- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one

Following a procedure analogous to that in step 2 of example 5, 1, 3-dimethyl-5- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-6-yl) pyridin-2 (1H) -one (50.1mg,0.107mmol) was converted to the title compound (57.3mg, 97% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝549。

Step 6: 5- (2-acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one

Following a procedure analogous to that in step 1 of example 5,5- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one (54.1mg,0.0985mmol) was converted to the title compound (40.2mg, 80% yield) asA white solid. LC-MS [ M + H ]]⁺＝512。

And 7: 5- (2- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one

Following a procedure analogous to that in step 6 of example 1,5- (2-acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one (37.2mg,0.0728mmol) was converted to the title compound (21.2mg, 55% yield) as a white solid. LC-MS [ M + H ]]⁺＝528。¹H NMR(400MHz,DMSO)δ8.52(s,1H),8.45(s,1H),8.09(d,J＝2.20Hz,1H),7.89(s,1H),7.66(d,J＝7.41Hz,2H),7.51(s,1H),7.33(s,2H),7.24(t,J＝7.30Hz,1H),5.66(s,1H),5.61(d,J＝11.32Hz,1H),3.89(d,J＝10.64Hz,2H),3.76(t,J＝14.56Hz,2H),3.58(s,3H),3.33(s,1H),3.22(d,J＝8.62Hz,2H),2.16(s,3H),1.61(d,J＝6.56Hz,6H),1.23(s,2H)。

Example 8

5- (6- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one

Step 1: 5- (6-acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one

In N₂To 1- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]To a solution of pyridin-6-yl) ethan-1-one (from step 2, 330mg, 0.704mmol of example 10) in dioxane (5mL) and water (2mL) was added 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (from step 3, 210mg, 0.840mol of example 7), Pd (dppf) Cl₂(100mg,0.121mmol) and K₃PO₄(297mg, 1.40 mmol). Vacuumizing the mixture, and backfilling N₂And repeating the process three timesNext, the process is carried out. The resulting mixture was heated to 90 ℃ and stirred for 20 h. The reaction mixture was then poured into water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator, and the residue was purified by silica gel chromatography using 30-100% EtOAc in hexanes to give the title compound (90.1mg, 25% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝512。

Step 2: 5- (6- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one

Following a procedure analogous to that in step 6 of example 1,5- (6-acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (90.2mg,0.176mmol) was converted to the title compound (12.3mg, 13% yield) as a white solid. LC-MS [ M + H ]]⁺＝528。¹H NMR(400MHz,DMSO)δ8.49(s,1H),8.29(s,1H),8.15(d,J＝1.24Hz,1H),7.98(s,1H),7.89(s,1H),7.66(d,J＝7.56Hz,2H),7.34(t,J＝7.48Hz,2H),7.24(t,J＝7.20Hz,1H),5.57(d,J＝11.32Hz,1H),5.24(s,1H),3.90(d,J＝10.56Hz,1H),3.78(d,J＝10.12Hz,1H),3.56(s,3H),3.46(t,J＝10.38Hz,1H),3.38(s,1H),3.25(d,J＝10.58Hz,1H),2.50(s,2H),2.14(s,3H),1.57(s,6H),1.21(d,J＝9.92Hz,2H)。

Example 9

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5-bromo-2- (thiophen-2-yl) -3-nitropyridines

In N₂Next, to a solution of 2, 5-dibromo-3-nitropyridine (6.21g,22.0mmol) in dioxane (100mL) and water (80mL) was added thiophen-2-ylboronic acid (2.51g,19.6mmol), Pd (dppf) Cl₂(0.801g,0.979mmol) and K₂CO₃(9.01g,65.3mmol)。Vacuumizing the mixture, and backfilling N₂And this process was repeated three times. In N₂Next, the resulting mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in hexanes to give the title compound (4.51g, 81% yield). LC-MS [ M + H ]]⁺＝284。

Step 2: 6-bromo-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂A mixture of 5-bromo-3-nitro-2- (thiophen-2-yl) pyridine (6.21g,21.9mmol), DPPE (10.4g,26.1mmol) in 1, 2-dichlorobenzene (50mL) was heated to 180 ℃ and stirred for 4 h. The reaction was slowly cooled to room temperature. The solvent was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 0-30% EtOAC in n-hexane to give 6-bromo-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (3.01g, 55% yield) as a white solid. LC-MS [ M + H ]]⁺＝252。

And step 3: 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂At room temperature, to 6-bromo-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Diisopropyl azodicarboxylate (2.02g,10.0mmol) was added to a solution of pyridine (1.26g,5.01mmol), phenyl (tetrahydro-2H-pyran-4-yl) methanol (Kyoto pharmaceutical Co., Ltd., 1.92g,10.0mmol), and triphenylphosphine (2.62g,10.0mmol) in dry toluene (20 mL). In N₂Next, the resulting solution was refluxed for 2 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (1.25g, 59%) as a white solid. LC-MS [ M + H ]]⁺＝428。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂Next, 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] was added to the solution in a single-necked flask]Pyrrolo [3,2-b]To a solution of pyridine (1.01g,2.36mmol) in DMF (20mL) was added 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (2.30g,5.88mmol), tetrakis (triphenylphosphine) palladium (262mg,0.227mmol), CuI (86.0mg,0.447mmol) and TEA (500mg,4.54 mmol). Vacuumizing the mixture, and backfilling N₂And this process was repeated three times. The resulting mixture was stirred at 85 ℃ for 3h and then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (945mg, 90% yield) as a white solid. LC-MS [ M + H ]]⁺＝444。

And 5: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

N-bromosuccinimide (0.432g,2.43mmol) was added in small portions to 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] at room temperature over 10min]Pyrrolo [3,2-b]Pyridine (0.722g,1.63mmol) in THF (20mL) and water (10 mL). After addition, the reaction was stirred at room temperature for 2 h. With saturated NaHCO₃The reaction was quenched and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-3% MeOH in DCM to give the title compound (0.761g, 90%) as a white solid. LC-MS [ M + H ]]⁺＝522。

Step 6: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

In N₂Then, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H thieno [2',3':4,5 ':4]Pyrrolo [3,2-b]To a solution of pyridine (0.761g,1.46mmol) in 1, 4-dioxane (20mL) was added tributyl (1-ethoxyvinyl) -stannane(0.834g,2.31mmol), tetrakis (triphenylphosphine) palladium (88.0mg,0.0761mmol), cesium fluoride (465mg,3.06 mmol). The mixture was refluxed for 20 h. The solvent was then concentrated under reduced pressure to give a pale yellow solid.

To a solution of the solid in THF (10mL) was added 2N HCl (2mL) at room temperature and stirred for 2 h. Then saturated NaHCO was used₃The reaction was quenched and extracted with EtOAc (100mL), and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5%]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (0.341g, 45% yield) as a white solid. LC-MS [ M + H ]]⁺＝486。¹H-NMR(400MHz,DMSO-d₆)δ8.48(s,1H),8.39(d,1H),7.64(m,3H),7.32(t,2H),7.25(t,1H),5.62(d,1H),4.02(m,3H),3.87(s,1H),3.78(d,1H),3.44(m,1H),3.28(m,2H),1.63(d,6H),1.43(m,2H),1.23(d,1H),1.16(d,2H)。

And 7: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5: 4) was followed in analogy to the procedure in step 6 of example 1]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (300mg,0.617mmol) gave the title compound (100mg, 32% yield) as a white solid. LC-MS [ M + H ]]⁺＝502。¹H-NMR(400MHz,DMSO-d₆)δ8.45(s,1H),8.36(d,J＝1.44Hz,1H),7.66(s,1H),7.67-7.62(m,2H),7.34-7.28(m,2H),7.28-7.23(m,1H),5.73(s,1H),5.61(d,J＝11.3Hz,1H),4.00(s,3H),3.91-3.82(m,1H),3.81-3.72(m.1H),3.49-3.40(m,1H)3.32-3.28(m,1H),2.28(s,3H),1.64(s,3H),1.63(s,3H),1.51-1.36(m,2H),1.35-1.27(m,1H),1.261.12(m,2H)。

Example 10

2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Step 1: 1- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

Following a procedure analogous to that in step 6 of example 9, 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (from step 3 of example 9, 2.01g, 4.70mmol) was converted to the title compound (0.802g, 44% yield) as a white solid. LC-MS [ M + H ]]⁺＝391。

Step 2: 1- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

Following a procedure analogous to that in step 5 of example 9, 1- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (0.801g,2.05mmol) was converted to the title compound (0.732g,1.56mmol, 76% yield) as a white solid. LC-MS [ M + H ]]⁺＝469。

And step 3: 1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

In N₂To 1- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-6-yl) ethan-1-one (0.731g,1.56mmol) in dioxane (20mL) was added 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (1.52g,3.94mmol), Pd (PPh)₃)Cl₂(112mg,0.153mmol) and DIEA (600mg,4.68 mmol). Vacuumizing the mixture, and backfilling N₂And this process was repeated three times. In N₂The resulting mixture was refluxed for 24h, then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (450mg, 59)% yield) as a white solid. LC-MS [ M + H ]]⁺＝486。

And 4, step 4: 2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Following a procedure analogous to that in step 6 of example 1, 1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (450mg,0.926mmol) was converted to the title compound (401mg, 86% yield) as a white solid. LC-MS [ M + H ]]⁺＝502。¹H-NMR(400MHz,DMSO-d₆)δ8.56(s,1H),8.40(s,1H),8.04(s,1H),7.65(d,2H),7.31(m,2H),7.24(t,1H),5.66(d,1H),4.14(s,3H),3.88(d,1H),3.77(s,1H),3.39(d,1H),3.32-3.29(m,4H),1.56(d,6H),1.49(s,3H),1.35(d,1H),1.19(d,2H)。

Example 11

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

At 0 ℃ N₂To a solution of 6-bromo-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine (from step 2, 1.51g, 5.99mmol of example 9), (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (1.26g,5.97mmol) and triphenylphosphine (1.82g,18.0mmol) in dry THF (30mL) was added DTAD (2.76g,12.0 mmol). After addition, the reaction was stirred at room temperature for 20 h. The reaction mixture was then poured into water and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (2.21g, 81% yield) as a white solid。LC-MS[M+H]⁺＝446。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure analogous to that in step 3 of example 10, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] in dioxane (30mL) was added]Pyrrolo [3,2-b]Pyridine (2.2g,5.0mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (2.9g,7.5mmol) were converted to the title compound (1.10g, 48% yield) as a white solid. LC-MS [ M + H ]]⁺＝463。

And step 3: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure analogous to that in example 9, step 5, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (1.10g,2.36mmol) was converted to the title compound (1.21g, 94% yield) as a white solid. LC-MS [ M + H ]]⁺＝541。

And 4, step 4: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

Following a procedure analogous to that in step 6 of example 9, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (672mg,1.24mmol) and tributyl (1-ethoxyvinyl) -stannane (674mg,1.87mmol) were converted to the title compound (503mg, 80% yield) as a white solid. LC-MS [ M + H ]]⁺＝505。

And 5: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 6 analogous to example 1 is followedThe step (1) is to mix 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (150mg,0.297mmol) was converted to the title compound (20.3mg, 13% yield) as a white solid. LC-MS [ M + H ]]⁺＝521。

¹H-NMR(400MHz,DMSO-d₆)δ8.59(d,1H),8.49(m,1H),8.41(d,1H),7.71(d,1H),7.48(dt,1H),7.39(s,1H),6.06(d,1H),4.02(s,3H),3.84(d,1H),3.73(d,1H),3.38(m,1H),3.25(m,2H),2.30(s,3H),1.56(t,6H),1.51(m,2H),1.38(m,1H),1.35(d,2H)。

Example 12

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5-bromo-2- (furan-2-yl) -3-nitropyridine

In N₂Next, to a solution of 2, 5-dibromo-3-nitropyridine (11.3g,40.1mmol) in dioxane (120mL) and water (50mL) was added furan-2-ylboronic acid (4.91g,43.8mmol), Pd (dppf) Cl₂(1.64g,2.01mmol) and K₂CO₃(16.1g,120 mmol). Vacuumizing the mixture, and backfilling N₂And this process was repeated three times. In N₂The resulting mixture was refluxed for 5 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc (100mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAC in hexanes to give the title compound (5.91g, 55% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝269。

Step 2: 6-bromo-4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridine

5-bromo-2- (furan-2-yl) -3-nitropyridine (6.30g,23.4mmol) was converted to the title compound (2.61g, 46% yield) following a procedure analogous to that in step 2 of example 4, except that the reaction was at 180 ℃) It is a white solid. LC-MS [ M + H ]]⁺＝237。

And step 3: 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂At room temperature, to 6-bromo-4H-furo [2',3':4,5 ')]Pyrrolo [3,2-b]To a solution of pyridine (1.2g,5.06mmol), phenyl (tetrahydro-2H-pyran-4-yl) methanol (1.92g,10.0mmol) and triphenylphosphine (1.92g,10.0mmol) in dry THF (20mL) was added diisopropyl azodicarboxylate (2.02g,10.0 mmol). In N₂Next, the resulting solution was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into water, extracted with EtOAc (50mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (1.10g, 53%) as a white solid. LC-MS [ M + H ]]⁺＝411。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure analogous to that in step 4 of example 9, 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5]Pyrrolo [3,2-b]Pyridine (1.00g,2.43mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (1.42g,3.65mmol) were converted to the title compound (1.01g, 98% yield) as a white solid. LC-MS [ M + H ]]⁺＝428。

And 5: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure analogous to that in example 9, step 5, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5]Pyrrolo [3,2-b]Pyridine (0.551g,1.28mmol) was converted to the title compound (501mg, 77% yield) as a white solid. LC-MS [ M + H ]]⁺＝506。

Step 6: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

Following a procedure analogous to that in step 6 of example 9, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine (0.512g,0.981mmol) and tributyl (1-ethoxyvinyl) -stannane (0.6g,1.96mmol) were converted to the title compound (172mg, 35% yield) as a white solid. LC-MS [ M + H ]]⁺＝470。

And 7: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4, 5: 4) methyl) -1, was prepared according to a procedure similar to that in step 6 of example 1]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (170mg,0.362mmol) was converted to the title compound (24.2mg, 14% yield) as a white solid. LC-MS [ M + H ]]⁺＝486。¹H-NMR(400MHz,DMSO-d₆)δ8.42(s,1H),8.34(s,1H),7.60(d,3H),7.28(m,2H),7.16(s,1H),5.53(d,1H),4.02(m,3H),3.83(m,1H),3.78(d,1H),3.39(m,1H),3.28(m,2H),2.30(s,3H),1.58(d,6H),1.39(m,2H),1.23(d,1H),1.17(d,2H)。

Example 13

2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Step 1: 1- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

Following a procedure analogous to that in example 9, step 6, 6-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5]Pyrrolo [3,2-b]Pyridine (from step 3 of example 12, 1.01g, 2.44mmol) and tributyl (1-ethoxyvinyl) -stannane (1.32g,3.66mmol)Conversion to the title compound (452mg, 49% yield) as a white solid. LC-MS [ M + H ]]⁺＝375。

Step 2: 1- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

Following a procedure analogous to that in example 12, step 5, 1- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4, 5)]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (252mg,0.674mmol) was converted to the title compound (151mg, 50% yield) as a white solid. LC-MS [ M + H ]]⁺＝453。

And step 3: 1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) ethan-1-one

In N₂To 1- (2-bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-6-yl) ethan-1-one (0.151g,0.331mmol) in dioxane (20mL) was added with 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (0.19g, 0.501 mmol), Pd (PPh)₃)₄(38mg,0.03mmol) and CuI (13mg,0.07mmol) and TEA (67mg,0.66 mmol). Vacuumizing the mixture, and backfilling N₂And the process was repeated three times. The resulting mixture was stirred at 85 ℃ for 3h and then cooled to room temperature. The reaction mixture was poured into water, extracted with EtOAc (50mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give 1 of the title compound (150mg, 96% yield) as a white solid. LC-MS [ M + H ]]⁺＝470。

And 4, step 4: 2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

1- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4, 5) was used in a similar manner to that in step 6 of example 1]Pyrrolo [3,2-b]Pyridin-6-yl) ethan-1-one (150mg,0.319mmol) was converted to the title compound (8.1mg, 5% yield) It is a white solid. LC-MS [ M + H ]]⁺＝486。¹H-NMR(400MHz,DMSO-d₆)δ8.49(t,1H),8.30(s,1H),7.75(s,1H),7.63(d,2H),7.28(m,3H),5.71(s,1H),5.54(d,1H),4.27(s,3H),3.88(m,3H),3.42(d,2H),3.12(m,2H),1.55(d,6H),1.44(m,2H),1.29(d,1H),1.24(d,2H)。

Example 14

4- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -2-methylbut-3-yn-2-ol

To the reaction solution of 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5 ':4]Pyrrolo [3,2-b]Pyridine (from step 5, 102mg, 0.195mmol of example 9), 2-methylbut-3-yn-2-ol (51.0mg,0.606mmol), Et₃N(40.1mg,55μL,0.396mmol)、PPh₃Pd (PPh) was added to a solution of (11.0mg,0.0419mmol) and CuI (5.1mg,0.0268mmol) in DMF (3mL)₃)₂Cl₂(14.2mg,0.0194 mmol). The mixture was degassed and flushed 3 times with nitrogen and stirred at 120 ℃ for 4 h. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl (50mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM and then further purified by Prep-HPLC to give the title compound (41.1mg, 41% yield) as an off-white solid. LC-MS (ES)⁺):[M+H]⁺＝526。¹H-NMR(600MHz,CDCl₃)δ9.36(s,1H),7.65(s,1H),7.43(s,1H),7.38-7.37(m,2H),7.35-7.32(m,2H),7.30-7.29(m,1H),5.16(d,J＝10.8Hz,1H),4.03-4.00(m,1H),3.93-3.92(m,1H),3.92(s,3H),3.49-3.40(m,2H),2.94-2.89(m,1H),2.30(s,3H),1.69(s,6H),1.51-1.44(m,2H),1.41-1.36(m,2H),1.31-1.26(m,1H)。

Example 15

4- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -2-methylbut-3-yn-2-ol

To a solution of 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5 ':4]Pyrrolo [3,2-b]Pyridine (from step 5 of example 12, 150mg, 0.296mmol), 2-methylbut-3-yn-2-ol (30.1mg,0.358mmol), Et₃To a solution of N (91.2mg, 125. mu.L, 0.901mmol) and CuI (6.1mg,0.0320mmol) in DMF (5mL) was added Pd (PPh)₃)₂Cl₂(21.2mg,0.0290 mmol). The mixture was degassed and flushed with nitrogen, and the sequence was repeated three times. The resulting mixture was stirred at 120 ℃ for 16h in a preheated oil bath. The reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl (50mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM and then further purified using Prep-HPLC to give the title compound (3.2mg, 2% yield) as an off-white solid. LC-MS [ M + H ]]⁺＝510。

Example 16

N- (3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) propyl) -3-methoxy-N-methyl- [1,2,4] triazol [4,3-b ] pyridazin-6-amine

Step 1: 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) propan-1-ol

To the solution of 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) propan-2-ol (step from example 9)7,230mg,0.458mmol) and propane-1, 3-diol (10mL) in CHCl₃To the solution (10mL) was added p-TsOH (80.2mg,0.466 mmol). The mixture was degassed and flushed with nitrogen, and the sequence was repeated three times. The resulting reaction mixture was stirred at 50 ℃ for 16 h. The mixture was cooled to room temperature and extracted with dilute water (50mL) and with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% EtOAc in hexanes to give the title compound (240mg, 93% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝560。

Step 2: 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) propyl 4-methylbenzenesulfonate

To the reaction mixture of 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5:)]Pyrrolo [3,2-b]Pyridin-2-yl) propan-2-yl) oxy) propan-1-ol (240mg,0.429mmol), TsCl (123mg,0.645mmol) and Et₃DMAP (3.1mg,0.0254mmol) was added to a solution of N (125. mu.L, 0.896mmol) in DCM (5 mL). The mixture was degassed and flushed with nitrogen, and the sequence was repeated three times. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water (50mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (320mg, crude) as a pale yellow solid. LC-MS: [ M + H ]]⁺＝714。

And step 3: 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) -N-methylpropan-1-amine

To the reaction mixture of 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5:)]Pyrrolo [3,2-b]Pyridin-2-yl) propan-2-yl) oxy) propyl 4-methylbenzenesulfonate (309mg,0.433mmol) in dioxane (10mL) was added to a solution of methylamine in EtOH (33%, 10 mL). Mixing the obtained extractsThe mixture was stirred at 70 ℃ for 16 h. The mixture was cooled to room temperature, diluted with water (50mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give the title compound (200mg, 81% yield) as a light yellow solid in two steps. LC-MS: [ M + H ]]⁺＝573。

And 4, step 4: n- (3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-yl) oxy) propyl) -3-methoxy-N-methyl- [1,2,4] triazol [4,3-b ] pyridazin-6-amine

To the reaction mixture of 3- ((2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5:)]Pyrrolo [3,2-b]Pyridin-2-yl) propan-2-yl) oxy) -N-methylpropan-1-amine (90.2mg,0.157mmol) and 6-chloro-3-methoxy- [1,2,4]Triazole [4,3-b ]]Pyridazine (31.2mg,0.169mmol) [ Bradbury, R.et al.J.Med.chem.,2016,59(17), pp 7801-7817-]To a solution of DIEA (60. mu.L, 0.344mmol) in EtOH (2mL) was added. The mixture was stirred at 90 ℃ for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% MeOH in DCM and then further purified by Prep-HPLC to give the title compound (14.2mg, 12% yield) as a light yellow solid. LC-MS: [ M + H ]]⁺＝721。¹H-NMR(400MHz,DMSO-d₆)δ8.47(s,1H),8.38(s,1H),7.99(s,1H),7.74(s,1H),7.73-7.52(m,2H),7.43-7.08(m,5H),5.63(d,J＝11.4Hz,1H),3.99(s,3H),,3.71(s,3H),3.85-3.61(m,4H),3.60-3.30(m,4H),3.54(s,3H),3.00(s,3H),2.02-1.97(m,3H)，1.92-1.65(m,2H),1.68(s,6H),1.55-1.12(m,1H)。

Example 17

(2S,3R) -2- ((1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethyl) amino) -3-hydroxybutanoic acid isopropyl ester

Step 1: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-ol

To the solution of 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (6,147 mg,0.302mmol from example 9) in MeOH (5mL) was added NaBH₄(11.2mg,0.296 mmol). The mixture was stirred at room temperature for 16 h. The reaction was then quenched with water (20mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (150mg, 100% yield) as a pale yellow solid. LC-MS: [ M + H ]]⁺＝488。

Step 2: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethylmethanesulfonate

To the solution of 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazole-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-ol (150mg,0.307mmol) in DCM (5mL) was added Et₃N (90. mu.L, 0.645 mmol). The mixture was cooled to 0 ℃ and MsCl (36. mu.L, 0.465mmol) was added dropwise. The mixture was stirred at 0 ℃ for 30min and the reaction mixture was used as such.

And step 3: (2S,3R) -2- ((1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethyl) amino) -3-hydroxybutanoic acid isopropyl ester

To the mixture was added isopropyl L-threonine (200mg,1.24mmol) and Et₃N (85. mu.L, 0.607mmol) in DCM (5mL) was added dropwise 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) Ethyl methanesulfonate (170mg,0.307mmol) in DCM (5 mL). The mixture was stirred at room temperature for 48 h. The mixture was concentrated under reduced pressure. Tong (Chinese character of 'tong')The residue was purified by Prep-TLC and Prep-HPLC to give the title compound (30.2mg, 16% three step yield) as an off-white solid. LC-MS: [ M + H ]]⁺＝631。¹H-NMR(600MHz,DMSO-d₆)δ8.45(s,1H),8.38(s,1H),7.73(s,1H),7.66-7.66(m,2H),7.33-7.31(m,2H),7.26-7.24(m,1H),5.61(d,J＝11.4Hz,1H),4.82-4.78(m,2H),4.29-4.23(m,1H),4.00(s,3H),3.88-3.84(m,2H),3.79-3.77(m,1H),3.44-3.41(m,1H),3.36-3.33(m,2H),3.24-3.19(m,2H),2.30(s,3H),1.45(d,J＝6.6Hz,3H),1.42-1.18(m,4H),1.14(d,J＝6.0Hz,3H),1.11(d,J＝6.6Hz,3H),1.02(d,J＝6.0Hz,3H)。

Example 18

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5-bromo-2- (4-methylthiophen-2-yl) -3-nitropyridine

Following a procedure analogous to that described in example 19, step 2, 5-dibromo-3-nitropyridine (150g,53.2mmol) and (4-methylthiophen-2-yl) boronic acid (7.55g,53.2mol) were converted to the title compound (14.1g, 88.7%) as a light yellow solid. LC-MS [ M + H ]]⁺＝297。

Step 2: 6-bromo-3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂Next, 5-bromo-2- (4-methylthiophen-2-yl) -3-nitropyridine (13.8g,46.6mmol), PPh₃A mixture of (25.2g,96.1mmol) in 1, 2-dichlorobenzene (150mL) was heated to 140 ℃ and stirred for 24 h. The reaction mixture was then slowly cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-30% EtOAc in hexanes to give the title compound (6.21g, 53% yield) as a white solid. LC-MS [ M + H ]]⁺＝265。¹H-NMR(400MHz,DMSO-d₆)δ8.38(s,1H),8.07(s,1H),8.44(s,1H),2.49(s,3H)。

And step 3: 6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂Reacting at room temperature for 15min to obtain 6-bromo-3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine (11.8g,6.80mmol), phenyl (tetrahydro-2H-pyran-4-yl) methanol (1.57g,8.16mmol) and triphenylphosphine (3.75g,14.3mmol) in dry THF (100mL) was added dropwise diisopropyl azodicarboxylate (2.89g,14.3 mmol). The resulting solution was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (2.43g, 81% yield) as a white solid. LC-MS [ M + H ]]⁺＝441。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

In N₂To 6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine (1.01g,2.30mmol) in DMF (20mL) was added 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (1.85g,4.77mmol), tetrakis (triphenylphosphine) palladium (262mg,0.227mmol), CuI (86.2mg,0.453mmol), and TEA (0.69mL,4.54 mmol). Charging the resulting mixture with N₂2min and stirred in a preheated oil bath at 85 ℃ for 3 h. The reaction mixture was cooled to room temperature and poured into H₂O and extracted with EtOAc (100 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (941mg, 90% yield) as a white solid. LC-MS [ M + H ]]⁺＝458。

And 5: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure analogous to that described in step 2 of the synthesis of example 5, 6- (1, 4-dimethyl-1H-1, 2, 3-triaza was addedOxazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (0.93g,2.03mmol) was converted to the title compound (981mg, 90% yield) as a white solid. LC-MS [ M + H ]]⁺＝537。

Step 6: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

Following a procedure similar to that described in example 9, step 6, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (980mg,1.83mmol) and tributyl (1-ethoxyvinyl) -stannane (1.45g,4.03mmol) were converted to the title compound (623mg, 68% yield) as a white solid. LC-MS [ M + H ]]⁺＝500。

And 7: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (1.02g,2.04mmol) was converted to the title compound (663mg, 63% yield) as a white solid. LC-MS [ M + H ]]⁺＝516。¹H-NMR(400MHz,DMSO-d₆)δ8.34(s,1H),8.10(s,1H),7.58-7.60(d,2H),7.33-7.36(t,2H),7.24-7.28(t,2H),5.72-5.75(d,1H),3.87(s,3H),3.44-3.49(t,2H),3.22-3.28(t,2H),2.81(s,3H),2.19(s,3H),2.73-1.77(d,1H),1.66(s,6H),1.33-4.45(m,4H)。

Example 19

2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: (4-chloro-5- (methoxyacyl) thiophen-2-yl) boronic acid

For 10min at-78 deg.C, N₂LDA (2.0M in THF, 33.1mL,66.3mmol) was added dropwise to a stirred solution of methyl 3-chlorothiophene-2-carboxylate (10.0g,56.6mmol) in THF (200mL) under an atmosphere. The resulting solution was stirred for 30 minutes at which time trimethylborate (23.5g, 125mmol) was added dropwise. The solution was stirred for 1h and then warmed to 0 ℃. The reaction was quenched dropwise with 100mL of 2N HCl and allowed to warm to ambient temperature with stirring. The mixture was extracted three times with EtOAc (200mL), and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator to give a semi-solid. Purification by silica gel chromatography (0-7% MeOH/DCM) gave the title compound (9.24g, 74% yield).

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) -3-bromothiophene-2-carboxylic acid methyl ester

In N₂To a solution of 2, 5-dibromo-3-nitropyridine (7.04g,25.0mmol) in 1, 4-dioxane (100mL) and water (25mL) was added (4-chloro-5- (methoxyacyl) thiophen-2-yl) boronic acid (4.51g,20.5mmol), Pd (dppf) Cl under a stream of air₂(1.34g,1.64mmol), and K₃PO₄(8.73g,41.1 mmol). The reaction mixture is treated with N₂Purge for 2min, heat to 60 ℃ and stir for 2 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-7% EtOAc in hexanes to give the title compound (3.36g, 43% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝376。

And step 3: 6-bromo-3-chloro-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂A mixture of methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-chlorothiophene-2-carboxylate (3.36g,8.96mmol), DPPE (4.18g,10.1mmol) in 1, 2-dichlorobenzene (50mL) was heated to 150 ℃ and stirred for 2 h. The reaction mixture was then cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-30% EtOAc in n-hexane to afford the titled compoundCompound (852mg, 28% yield) as a white solid. LC-MS [ M + H ]]⁺＝345。

And 4, step 4: 6-bromo-3-chloro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 3 of example 4, 6-bromo-3-chloro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid (306mg,0.890mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol (191mg,0.995mmol) were converted to the title compound (403mg, 87% yield) as a white solid. LC-MS [ M + H ]]⁺＝519。

And 5: 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 4 of synthetic example 9, 6-bromo-3-chloro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (276mg,0.533mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (267mg,0.693mmol) were converted to the title compound (257mg, 91% yield) as a white solid. LC-MS [ M + H ]]⁺＝536。

Step 6: 2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

In analogy to the procedure described in example 1, step 6, 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (50.2mg,0.0938mmol) was converted to the title compound and purified by silica gel chromatography using 0-6% MeOH in DCM to give 2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5%]Pyrrolo [3,2-b]Pyridin-2-yl) propan-2-ol (32.2mg, 64% yield) as a white solid. LC-MS [ M + H ]]⁺＝536.¹H-NMR(400MHz,DMSO-d₆)δ8.41(s,1H),8.21(s,1H),7.65-7.67(d,2H),7.34-7.37(t,2H),7.28(m,1H),6.26-6.29(d,1H),6.20(s,1H),3.89(s,3H),3.77-3.80(m,2H),3.45-3.48(m,2H),3.24-3.27(m,1H),2.20(s,3H),1.71-1.79(m,1H),1.73(s,6H),1.31-1.36(m,2H),1.01-1.04(d,1H)。

Example 20

2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-chloro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3-chloro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (3,606 mg,1.75mmol from example 19) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (432mg,2.05mmol) were converted to the desired product. The crude product was purified by silica gel chromatography using 0-30% EtOAc in hexanes to give the title compound (783mg, 83% yield) as a white solid. LC-MS [ M + H ]]⁺＝538。

Step 2: 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 2 of example 3, 6-bromo-3-chloro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (657mg,1.22mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (612mg,1.59mmol) were converted to the title compound (603mg, 89% yield) as a white solid. LC-MS [ M + H ]]⁺＝555。

And step 3: 2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

In analogy to the procedure described in example 1, step 6, 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (353mg,0.636mmol) was converted to the title compound (305mg, 86% yield) as a white solid. LC-MS [ M + H ] ]⁺＝555。

¹HNMR(400MHz,DMSO-d₆)δ8.59-8.60(d,1H),8.45(s,1H),8.28(s,1H),7.72-7.77(m,1H),7.49-7.54(m,1H),6.66-6.68(d,1H),6.20(s,1H),3.93(s,3H),3.82-3.84(d,1H),3.73-3.75(d,1H),3.35-3.44(m,3H),2.20(s,3H),1.73(s,6H),1.62-1.66(d,1H),1.35-1.38(m,2H),0.79-0.82(d,1H)。

Example 21

2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-chloro-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3-chloro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (from step 3,719mg,2.08mmol of example 19) and (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (513mg,2.48mmol) were converted to the title compound (968mg, 87% yield) as a white solid. LC-MS [ M + H ]]⁺＝534。

Step 2: 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in example 3, step 2, 6-bromo-3-chloro-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl)) Methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (522mg,0.979mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (492mg,1.27mmol) were converted to the title compound (475mg, 88% yield) as a white solid. LC-MS [ M + H ]]⁺＝551。

And step 3: 2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

In analogy to the procedure described in example 1, step 6, 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (402mg,0.731mmol) was converted to the title compound (334mg, 83% yield) as a white solid. LC-MS [ M + H ]]⁺＝551。

¹H-NMR(400MHz,DMSO-d₆)δ8.62-8.63(d,1H),8.41(s,1H),7.98(s,1H),7.61-7.63(d,2H),7.31-7.34(m,1H),6.42-6.45(d,1H),6.21(s,1H),3.84(s,3H),3.82-3.84(d,1H),3.73-3.75(d,1H),3.35-3.45(m,2H),3.16-3.22(m,1H),2.20(s,3H),2.10(s,3H),1.73(s,6H),1.37-1.48(m,2H),0.61-0.64(d,1H)。

Example 22

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5- (dibutyl (pentyl) stannyl) -3-fluorothiophene-2-carboxylic acid methyl ester

For 10min at-78 deg.C, N₂LDA (2.0M in THF, 20.1mL,40.20mmol) was added dropwise to a stirred solution of methyl 3-fluorothiophene-2-carboxylate (5.03g,31.4mmol) in THF (200mL) under an atmosphere. The resulting solution was stirred for 1 hour, at which time dibutyl chloro (pentyl) stannane (6.20g,33.0mmol) was added dropwise. The solution was stirred for 0.5 hour, then warmed to room temperature and stirred furtherFor the outer 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (100mL) with stirring. The mixture was extracted three times with EtOAc (600 mL). The combined organic solutions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give an oil. Purification by silica gel chromatography eluting with 0-2% EtOAc/n-hexane afforded the title compound (12.3g,22.0mmol, 84% yield).

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylic acid methyl ester

In N₂Next, to a solution of 2, 5-dibromo-3-nitropyridine (18.0g,63.8mmol) in 1, 4-dioxane (300mL) was added methyl 5- (dibutyl (pentyl) stannyl) -3-fluorothiophene-2-carboxylate (14.5g,31.4mmol), Pd (pph)₃)₄(5.81g,5.03mmol), and CsF (10.5g,69.4 mmol). The reaction mixture is treated with N₂Purging for 5min, then at N₂Then, the mixture was stirred at 110 ℃ for 12 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (500 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in n-hexane to give the title compound (3.69g,9.84mmol, 33% yield). LC-MS [ M + H ]]⁺＝361。

And step 3: 6-bromo-3-fluoro-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylate (3.69g,10.2mmol) was converted to the title compound (1.12g,3.27mmol, 32% yield) following a procedure similar to that described in synthetic example 1, step 3, except at 150 ℃, using 0-35% EtOAc in n-hexane, purified by silica gel chromatography to give a white solid after purification. LC-MS: [ M + H ]]⁺＝329。

And 4, step 4: 6-bromo-3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3-fluoro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (415mg,1.37mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol (318mg,1.66mmol) were converted to the title compound (620mg,1.23mmol, 90%Yield), purified by silica gel chromatography using 0-25% EtOAc in n-hexane as a white solid. LC-MS [ M + H ]]⁺＝503。

And 5: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 4 of example 1, 6-bromo-3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (620mg,1.23mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (617mg,1.60mmol) were converted to the title compound (517mg,0.996mol, 81% yield) which was purified by silica gel chromatography using DCM with 0-4% MeOH as a white solid. LC-MS [ M + H ]]⁺＝520。

Step 6: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (510mg,0.98mmol) was converted to the desired compound (428mg,0.825mmol, 84% yield) and purified by silica gel chromatography using 0-6% MeOH in DCM to give a white solid after purification. LC-MS [ M + H ]]⁺＝520。¹H-NMR(400MHz,DMSO-d₆)δ8.52(s,1H),8.44(s,1H),7.57-7.59(d,2H),7.33-7.37(m,2H),7.25-7.29(m,1H),5.98(s,1H),5.58-5.60(d,1H),4.00(s,3H),3.74-3.88(m,2H),3.37-3.43(m,1H),3.17-3.27(m,2H),3.28(s,3H),1.64(s,6H),1.52-1.55(d,1H),1.34-1.43(m,2H),0.61-0.64(d,1H)。

Example 23

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3-fluoro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (from step 3,230mg,0.700mmol of example 22) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (183mg,0.867mmol) were converted to the title product (302mg,0.580mmol, 83% yield) which was purified by chromatography on silica gel using 0-30% EtOAc in n-hexane as a white solid. LC-MS [ M + H ]]⁺＝522。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 2 of synthetic example 3, 6-bromo-3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (502mg,0.964mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (687mg,1.78mmol) were converted to the title compound (350mg,0.651mmol, 93% yield) which was purified by silica gel chromatography using 0-4% MeOH in DCM as a white solid. LC-MS [ M + H ]]⁺＝539。

And step 3: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described for step 6 in the synthesis of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (263mg,0.49mmol) was converted to the title compound (192mg,0.357mmol, 73% yield) which was purified by silica gel chromatography using 0-7% MeOH in DCM as a white solid. LC-MS [ M + H ]]⁺＝539。¹H-NMR(400MHz,DMSO-d₆)δ8.54(s,1H),8.45(s,1H),8.42(s,1H),7.72-7.77(m,1H),7.47-7.51(m,1H),5.97(s,1H),5.91-5.94(d,1H),3.98(s,3H),3.75-3.84(m,2H),3.33-3.39(m,2H),3.23-3.28(m,2H),2.26(s,3H),1.64(s,6H),1.55-1.58(d,1H),1.29-1.35(m,1H),0.96-0.98(d,1H)。

Example 24

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] -pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3-fluoro-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (from step 3,202mg,0.614mmol of example 22) and (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 6,156mg,0.739mmol) were converted to the title compound (274mg,0.525mmol, 86% yield) which was purified by silica gel chromatography using 0-30% EtOAc in n-hexane as a white solid. LC-MS [ M + H ]]⁺＝522。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 2 of example 3, 6-bromo-3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (278mg,0.533mmol) in DMF (10mL) and 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (528mg,1.37mmol) was converted to the title compound (263mg,0.489mmol, 92% yield) which was purified by silica gel chromatography with DCM using 0-4% MeOH as a white solid. LC-MS [ M + H ]]⁺＝539。

And step 3: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in example 1, step 6, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (263mg,0.489mmol) was converted to the title compound (187mg,0.348mmol, 71% yield) which was purified by silica gel chromatography using 0-7% MeOH in DCM to give a white solid after purification. LC-MS [ M + H ]]⁺＝539。

¹H-NMR(400MHz,DMSO-d₆)δ8.56(s,1H),8.50(s,1H),8.45(s,1H),7.72-7.77(m,1H),7.65-7.68(m,1H),5.95(s,1H),5.66-5.59(d,1H),4.01(s,3H),3.76-3.85(m,2H),3.35-3.389(m,1H),3.23-3.25(m,2H),3.28(s,3H),1.63(s,6H),1.40-1.45(m,2H),1.24-1.28(m,1H),1.10-1.13(d,1H)。

Example 25

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: (4-methoxy-5- (methoxyacyl) thiophen-2-yl) boronic acid

Following a procedure analogous to that described for step 1 of the synthesis of example 19, methyl 3-methoxythiophene-2-carboxylate (5.03g,29.2mmol) was converted to the title compound (5.62g,26.0mmol, 89% yield) and purified by chromatography on silica eluting with 0-4% MeOH in DCM. LC-MS [ M + H ]]⁺＝217。

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) -3-methoxythiophene-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 2 in the synthesis of example 19, (4-methoxy-5- (methoxyacyl) thiophen-2-yl) boronic acid (8.32g,38.5mmol) and 2, 5-dibromo-3-nitropyridine (11.2g,39.8mmol) was converted to the title compound (3.25g,8.74mmol, 27% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝373。

And step 3: 6-bromo-3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 2 of the synthesis of example 18, methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-methoxythiophene-2-carboxylate (3.25g,8.71mmol) was converted to the title compound (1.32g,3.88mmol, 44% yield) using 0-35% EtOAc in n-hexane and purified by silica gel chromatography to give 6-bromo-3-methoxy-4H-thieno [2',3':4,5] as a white solid]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester. LC-MS [ M + H ]]⁺＝341。

And 4, step 4: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 1 of the synthesis of example 3, 6-bromo-3-methoxy-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (308mg,0.906mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (222mg,1.05mmol) were converted to the title compound (442mg,0.828mmol, 92% yield) which was purified by silica gel chromatography using 0-35% EtOAc in n-hexane as a white solid. LC-MS [ M + H ]]⁺＝534。

And 5: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 2 in the synthesis of example 3, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (403mg,0.755mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (728mg,1.88mmol) were converted to the title compound (390mg,0.709mmol, 94% yield) which was purified by silica gel chromatography using 0-4% MeOH in DCM as a white solid. LC-MS [ M + H ]]⁺＝551。

Step 6: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described for step 6 in the synthesis of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (463mg,0.840mmol) was converted to the title compound (380mg,0.691mmol, 82% yield) which was purified by silica gel chromatography using 0-7% MeOH in DCM to give a white solid after purification. LC-MS [ M + H ]]⁺＝551。¹H-NMR(400MHz,DMSO-d₆)δ8.54(s,1H),8.41(s,1H),8.31(s,1H),7.75-7.80(m,1H),7.49-7.53(m,1H),6.06-6.09(d,1H),5.99(s,1H),4.01(s,3H),3.97(s,3H),3.70-383(m,2H),3.33-3.36(m,2H),3.17-3.22(m,1H),2.24(s,3H),1.66-1.68(d,6H),1.51-1.54(d,1H),1.24-1.44(m,2H),0.75-0.78(d,1H)。

Example 26

6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-3-carboxylic acid ethyl ester

Step 1: 5-bromo-2-methylthiophene-3-carboxylic acid ethyl ester

N-bromosuccinimide (6.53g,36.7mmol) was slowly added dropwise to a solution of ethyl 2-methylthiophene-3-carboxylate (5.07g,32.5mmol) in DMF (60mL) and acetic acid (40mL) over 10min at room temperature. After addition, the reaction was stirred at room temperature for 12 h. With saturated NaHCO₃The reaction was quenched with aqueous solution and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-3% EtOAc in hexanes to give the title compound (7.17g,20.6mmol, 94% yield) as a white solid. LC-MS [ M + H ]]⁺＝249。

Step 2: 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-3-carboxylic acid ethyl ester

To a solution of ethyl 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-3-carboxylate (7.73g,32.5mmol) in dioxane (200mL), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborane) (16.7g,65.9mol), and potassium acetate (6.75g,68.8mmol) was added Pd (dppf) Cl₂(1.19g,1.65 mmol). Vacuumizing the mixture, and backfilling N₂And this sequence was repeated three times. The resulting mixture was heated to 80 ℃ for 12 h. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc (200 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in n-hexane to give the title compound 8.06g, 27.2mmol, 88% yield.

And step 3: 5- (5-bromo-3-nitropyridin-2-yl) -2-methylthiophene-3-carboxylic acid ethyl ester

In N₂To a solution of 2, 5-dibromo-3-nitropyridine (11.3g,39.9mmol) in 1, 4-dioxane (200mL) and water (50mL) was added ethyl 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-3-carboxylate (8.86g,32.5mmol), Pd (dppf) Cl under a stream of air₂(3.45g,4.22mmol), and K₃PO₄(14.2g,66.9 mmol). In N₂Next, the reaction mixture was heated to 80 ℃ for 12 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (500 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in hexanes to give the title compound (1.75g,4.73mmol, 15% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝371。

And 4, step 4: 6-bromo-2-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-3-carboxylic acid ethyl ester

In analogy to the procedure described for example 1, ethyl 5- (5-bromo-3-nitropyridin-2-yl) -2-methylthiophene-3-carboxylate (1.39g,3.74mmol) was converted to the title compound (825mg,2.44mmol, 65% yield) according to the procedure described for example 1 step 3, purified by silica gel chromatography using 0-10% EtOAc in n-hexane, purifiedThis was followed by a white solid. LC-MS [ M + H ]]⁺＝339。

And 5: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-3-carboxylic acid ethyl ester

Following a procedure analogous to that described for step 1 in the synthesis of example 3, 6-bromo-2-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-3-carboxylic acid ethyl ester (400mg,1.18mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (296mg,1.40mmol) were converted to the title compound (463mg,0.872mmol, 74% yield) which was purified by silica gel chromatography using 0-20% EtOAc in n-hexane as a white solid. LC-MS [ M + H ]]⁺＝532。

Step 6: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-3-carboxylic acid ethyl ester

Following a procedure analogous to that described for step 2 in the synthesis of example 3, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-3-carboxylic acid ethyl ester (463mg,0.87mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (796mg,2.06mmol) were converted to the title compound. The residue was purified by silica gel chromatography using 0-4% MeOH in DCM to give 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-3-carboxylic acid ethyl ester (293mg,0.535mmol, 71% yield) as a white solid. LC-MS [ M + H ]]⁺＝549。

Example 27

2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Step 1: 5-Nitro-6- (thien-2-yl) nicotinic acid methyl ester

In N₂To a solution of methyl 6-chloro-5-nitronicotinate (8.23g,38.0mmol) in DMF (50mL) under a stream of air was added tributyl (thien-2-yl) stannane (16.6g,44.4mmol), Pd (PPh)₃)₂Cl₂(1.42g,2.02mmol), cesium fluoride (13.9g,91.4 mmol). In N₂The mixture was stirred at reflux for 20h under an atmosphere. The reaction mixture was then cooled to room temperature and extracted with EtOAc (100 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 5-10% EtOAC in hexanes to give the title compound (2.85g,10.8mmol, 28%) as a yellow solid. LC-MS: [ M + H ]]⁺＝265。

Step 2: 4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

Methyl 5-nitro-6- (thiophen-2-yl) nicotinate (2.85g,10.8mmol) was converted to the title compound (1.32g,5.69mmol, 53% yield) following a procedure similar to that described in step 3of example 1, except that the reaction was carried out at 180 ℃, purified by silica gel chromatography using 0-30% EtOAC in n-hexane, as a yellow solid after purification. LC-MS (ES)⁺)：[M+H]⁺＝233。

And step 3: 2-bromo-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

N-bromosuccinimide (472mg,2.03mmol) was slowly added dropwise to 4H-thieno [2',3':4,5, 10min at room temperature]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (501mg,2.81mmol) in THF (20 mL). After addition, the reaction was stirred at room temperature for 2 h. With saturated NaHCO₃The reaction was quenched with aqueous solution and extracted with EtOAc (100 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-3% MeOH in DCM to give the title compound (472mg,1.52mmol, 75% yield) as a white solid. LC-MS [ M + H ]]⁺＝311。

And 4, step 4: 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

In N₂To 2-bromo-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (472mg,1.52mmol) in DMF (20mL) was added with 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (880mg,2.28mmol), Pd (PPh)₃)₂Cl₂(110mg,0.150mmol) and DIEA (1.40mL,7.97 mmol). Mixing the mixture with N₂Purge for 2 minutes at N₂Stirred at 120 ℃ for 20h under atmosphere and then cooled to room temperature. The reaction mixture is poured into H₂O (100mL) and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (390mg,1.19mmol, 78% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝328。

And 5: 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

Following a procedure similar to that described in example 3, step 1,2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (190mg,0.581mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (202mg,0.957mmol) were converted to the title compound. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (96.1mg,0.185mmol, 30% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝521。

Step 6: 2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Following a procedure analogous to that described in example 1, step 6, 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (96.1mg,0.185mmol) was converted to the title compound (47.2mg,0.0908mmol, 49%) as a white solid. LC-MS [ M + H ]]⁺＝521。¹H-NMR(400MHz,DMSO-d₆)δ8.57(t,2H),8.38(d,1H),7.88(s,1H),7.72(m,1H),7.48(m,1H),6.06(d,1H),4.13(d,3H),3.86(m,1H),3.74(d,1H),3.36(d,2H),3.24(m,2H),2.40(d,3H),1.56(s,6H),1.55(s,2H),1.41(d,1H),1.24(d,1H)。

Example 28

2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Step 1: 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

Following a procedure similar to that described in step 3of example 18, 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (from step 4,150mg,0.459mmol of example 27) and (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (147mg,0.697mmol) were converted to the title compound (64.2mg,0.123mmol, 27% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝521。

Step 2: 2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

Following a procedure analogous to that described in example 1, step 6, 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-6-carboxylic acid methyl ester (64.0mg,0.123mmol) was converted to the title compound (14.3mg,0.0275mmol, 22% yield) as a white solid. LC-MS [ M + H ]]⁺＝521。¹H-NMR(400MHz,DMSO-d₆)δ8.68(t,1H),8.56(t,1H),8.47(d,1H),8.03(s,1H),7.74(m,2H),5.84(d,1H),4.16(d,3H),3.86(m,1H),3.74(d,1H),3.36(d,2H),3.25(m,2H),2.43(d,3H),1.58(s,6H),1.56(s,2H),1.36(d,1H),1.24(d,1H)。

Example 29

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure similar to that described in step 3of example 18, 6-bromo-3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (543mg,2.04mmol) and (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (512mg,2.47mmol) were converted to the title compound (568mg,1.25mmol, 61% yield) as a white solid. LC-MS [ M + H ]]⁺＝456。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure similar to that described in step 4 of example 18, except that the reaction was carried out at 80 ℃, 6-bromo-3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (392mg,0.862mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (1.52g,3.94mmol) were converted to the title compound (280mg,1.84mmol, 70%) as a white solid. LC-MS [ M + H ]]⁺＝473。

And step 3: 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine

Following a procedure similar to that described in step 2 of example 5, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine (276mg,0.58mmol) was converted to the title compound (114mg,0.207mmol, 36% yield) as a white solid. LC-MS[M+H]⁺＝551。

And 4, step 4: 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) ethan-1-one

Following a procedure similar to that described in example 6, step 4, 2-bromo-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5 ':4]Pyrrolo [3,2-b]Pyridine (114mg,0.207mmol) was converted to the title compound (54.2mg,0.105mol, 51%) as a white solid. LC-MS [ M + H ]]⁺＝515。

And 5: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in example 6, step 1, 1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ((3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridin-2-yl) ethan-1-one (54.2mg,0.105mmol) was converted to the title compound (6.2mg,0.0117mmol, 11% yield) as a white solid. LC-MS [ M + H ]]⁺＝531。¹H-NMR(400MHz,DMSO-d₆)δ8.47-8.48(d,1H),8.38(s,1H),8.30(s,1H),7.39-7.44(m,1H),7.31-7.35(m,1H),6.15-6.17(d,2H),3.97(s,3H),3.85-3.89(d,1H),3.25-3.51(m,3H),2.91(s,3H),2.32(s,3H),1.82(s,6H),1.61(s,3H),1.26-1.47(m,4H),1.0–0.85(m,1H)。

Example 30

2- (1-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester

In N₂At room temperature, to B₂Pin₂(6.82g,26.9mmol), dtbpy (2.12g,7.90mmol) and [ Ir (cod) (ome)]₂(882mg,1.33mmol) in THF (60mL) was added methyl 1H-pyrrole-2-carboxylate (2.88g,23.0 mmol). The resulting solution was refluxed for 2 h. The reaction was then cooled to room temperature and poured into H₂O (50mL) and extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in hexanes to give the title compound (3.74g,14.9mmol, 65% yield) as a white solid. LC-MS [ M + H ]]⁺＝252。

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester

In N₂To a solution of 2, 5-dibromo-3-nitropyridine (7.82g,27.7mmol) in THF (100mL) and water (80mL) under a stream of air was added methyl 5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylate (3.74g,0.015mol), Pd (dppf) Cl₂(1.78g,2.20mmol), and K₃PO₄(9.58g,45.2 mmol). The resulting mixture was purged with a stream of nitrogen for 2 minutes, warmed to reflux and stirred for 5 h. The reaction mixture was then cooled to room temperature and poured into H₂O (200mL), extracted with EtOAc (2 × 100 mL). The collected organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAC in hexanes to give the title compound (3.20g,9.82mmol, 67% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝326。

And step 3: 1-benzyl-5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester

To a solution of methyl 5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylate (552mg,1.69mmol) in DMF (10ml) was added (bromomethyl) benzene (358mg,2.09mmol) and K₂CO₃(687mg,4.97 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into H₂O and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography using 0-10% EtOAc in n-hexaneThe residue was digested to give the title compound (669mg,1.61mmol, 95% yield) as a pale yellow solid. LC-MS [ M + H ]]⁺＝416。

And 4, step 4: 1-benzyl-6-bromo-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In analogy to the procedure described for step 3of the synthesis of example 1, except that the reaction was carried out at 180 ℃ for 4H, 1-benzyl-5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester (669mg,1.60mmol) was converted to the title compound (486mg,1.26mmol, 79% yield) as yellow solid. LC-MS [ M + H ]]⁺＝386。

And 5: 1-benzyl-6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 1 of the synthesis of example 3, 1-benzyl-6-bromo-1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (486mg,1.26mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (510mg,2.41mmol) were converted to the title compound (567mg,0.984mmol, 77% yield) as a white solid. LC-MS [ M + H ]]⁺＝577。

Step 6: 1-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described for step 2 in the synthesis of example 3, except that the reaction was carried out at 85 ℃ for 3H, 1-benzyl-6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (86.1mg,0.149mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (138mg,0.357mmol) were converted to the title compound (56.2mg,0.0945mmol, 65% yield) as a white solid. LC-MS [ M + H ]]⁺＝594。

And 7: 2- (1-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described for step 6 of the synthesis of example 1, 1-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (55.1mg,0.0929mmol) was converted to the title compound (28.2mg,0.0476mmol, 51% yield) as a white solid. LC-MS [ M + H ]]⁺＝594。

Examples 31 to 33

The compounds in table 2 were synthesized as described in example 9:

TABLE 2

Examples 34 to 35

2- (4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol (enantiomer a) and

2- (4- ((3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-B ] pyridin-2-yl) propan-2-ol (enantiomer B)

Step 1: (5- (Methoxyacyl) -4-methylthiophen-2-yl) boronic acid

In N₂Next, LDA (2.0M in THF, 34.5mL,68.9mmol) was added dropwise to a stirred solution of methyl 3-methylthiophene-2-carboxylate (7.13g,45.7mmol) in THF (100mL) at-78 ℃ over 10 min. The resulting solution was stirred for 30 minutes at which time trimethyl borate (11.0g,58.4mmol) was added dropwise. The solution was stirred for 1 hour and then warmed to 0 ℃. The reaction was quenched by the addition of 70mL HCl (2N) and allowed to warm to ambient temperature with stirring. The mixture was extracted 3 times with EtOAc (200mL) and the combined organic layers were dried over anhydrous sodium sulfateFiltered and concentrated in vacuo to give a semi-solid. Purification by silica gel chromatography with 0-7% MeOH/DCM gave the title compound (8.31g, 91% content). LC-MS [ M + H ]]⁺＝201。

Step 2: 5- (5-bromo-3-nitropyridin-2-yl) -3-methylthiophene-2-carboxylic acid methyl ester

In N₂To a solution of 2, 5-dibromo-3-nitropyridine (17.3g,61.2mmol) in 1, 4-dioxane (200mL) and water (50mL) was added (5- (methoxyacyl) -4-methylthiophen-2-yl) boronic acid (9.35g,46.8mmol), Pd (dppf) Cl under a stream of air₂(4.58g,5.61mmol), and K₃PO₄(21.5g,101 mmol). In N₂Purge for 2 minutes, then heat to 60 ℃ in a preheated oil bath and stir for 12 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the title compound (8.85g,24.8mmol, 53% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝357。

And step 3: 6-bromo-3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂A mixture of methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-methylthiophene-2-carboxylate (6.77g,18.0mmol) and DPPE (8.70g,21.8mmol) in 1, 2-dichlorobenzene (50mL) was heated to 150 ℃ and stirred under atmosphere for 2 h. The reaction mixture was then cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-30% EtOAc in hexanes to give the title compound (1.87g,5.75mmol, 31% yield) as a white solid. LC-MS [ M + H ]]⁺＝325。

And 4, step 4: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Reacting 6-bromo-3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Dried methyl pyridine-2-carboxylate (807mg,2.48mmol), (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 1,561mg,2.66mmol) and triphenylphosphine (1.68g,6.40mmol)A solution of dry THF (20mL) was degassed and flushed with nitrogen three times. Diisopropyl azodicarboxylate (1.54g,7.61mmol) was added dropwise at room temperature and the resulting solution was stirred for 2 h. The reaction mixture was then poured into H₂O (50mL) and extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in n-hexane to give the title compound (1.12g, 87% yield) as a white solid. LC-MS [ M + H ]]⁺＝518。

And 5: 4- ((3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

To 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine-2-carboxylic acid methyl ester (1.57g,3.03mmol) in DMF (30mL) was added 1-methyl-4- (methyl-d 3) -5- (tributyltin-yl) -1H-1,2, 3-triazole (3.74g,9.60mmol), tetrakis (triphenylphosphine) palladium (0.491g,0.425mmol), CuI (167mg,0.877mmol) and TEA (0.762g,1.05mL,7.67mmol), using nitrogen, the resulting mixture was degassed three times, sealed and stirred at 110 ℃ for 2H, the reaction mixture was cooled to room temperature, diluted with water (100mL) and extracted with EtOAc (3 × 100mL), after separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated using 0-100% EtOAc residue in hexane to afford the title compound (1.29g, 79% yield) as a yellow solid]⁺＝538。

Step 6: 2- (4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described for step 6 in the synthesis of example 1,4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (424mg,0.788mmol) was converted to the title compound(242mg,0.451mmol, 57% yield) as a white solid. LC-MS [ M + H ]]⁺＝538。¹H NMR(400MHz,DMSO-d6)δ8.59(d,J＝4.6Hz,1H),8.37(d,J＝1.7Hz,1H),8.24(s,1H),7.81–7.71(m,1H),7.51(dt,J＝8.6,4.4Hz,1H),6.13(d,J＝10.7Hz,1H),5.79(s,1H),3.93(s,3H),3.83(d,J＝8.0Hz,1H),3.73(d,J＝8.7Hz,1H),3.47–3.33(m,2H),3.20(t,J＝11.0Hz,1H),2.82(s,3H),1.65(s,6H),1.59(s,1H),1.44(s,1H),1.31(d,J＝7.7Hz,1H),0.72(d,J＝12.0Hz,1H)。

Example 35 was prepared following the same procedure described in example 34, except intermediate 2 was used in step 4, to give the other enantiomer B as a white solid. LC-MS [ M + H ]]⁺＝538。¹H NMR(400MHz,DMSO-d6)δ8.59(d,J＝4.6Hz,1H),8.37(s,1H),8.24(s,1H),7.81–7.70(m,1H),7.52(dd,J＝8.4,4.3Hz,1H),6.13(d,J＝11.6Hz,1H),5.79(s,1H),3.93(s,3H),3.83(d,J＝8.9Hz,1H),3.73(d,J＝9.6Hz,1H),3.38(d,J＝10.1Hz,2H),3.20(t,J＝11.6Hz,1H),2.82(s,3H),1.65(s,6H),1.59(s,1H),1.43(s,1H),1.31(d,J＝12.2Hz,1H),0.72(d,J＝12.5Hz,1H)。

Example 36

(S) -2- (6- (3, 5-dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: (S) -6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂At 0 deg.C, adding 6-bromo-3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (from step 3of example 35, 200mg,0.615mmol), (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (Kyowa pharmaceutical Co., Ltd., 127mg,0.661mmol) and triphenylphosphine (416mg,1.58mmol) in dry toluene (10mL) was added DIAD (382mg,1.89 mmol). After addition, the reaction was heated to 110 ℃ for 2 h. Then, the reaction was slowly cooled to room temperature and the reaction mixture was poured inWater and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (136mg,0.272mmol, 43.9% yield) as a white solid. LC-MS [ M + H ]]⁺＝500。

Step 2: (S) -6- (3, 5-Dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂To (S) -6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] under a gas stream]Pyrrolo [3,2-b]To a solution of pyridine-2-carboxylic acid methyl ester (136mg,0.272mmol) in dry 1, 4-dioxane (4ml) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (74.1mg,0.331mmol), pd (dppf) Cl₂(16.2mg,0.0221mmol)、K₃CO₄(113mg,0.819mmol) and water (1 ml). The reaction mixture is treated with N₂Purge 2min, cap, heat to 100 ℃ and stir for 2 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-4% EtOAc in hexanes to give the title compound (106mg,0.206mmol, 78% yield) as a white solid. LC-MS [ M + H ]]⁺＝516。

And step 3: (S) -2- (6- (3, 5-dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

(S) -6- (3, 5-Dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] following a procedure similar to that described in step 6 of example 1]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (106mg,0.206mmol) was converted to the title compound (5.1mg, 5% yield) as an off-white solid. LC-MS: [ M + H ]⁺]＝516。¹H NMR(400MHz,DMSO-d6)δ8.26(d,J＝1.4Hz,1H),7.92(s,1H),7.60(d,J＝7.1Hz,2H),7.35(s,2H),7.26(t,J＝7.3Hz,1H),5.73(s,2H),3.87(d,J＝8.9Hz,1H),3.77(d,J＝8.1Hz,1H),3.49(t,J＝10.9Hz,1H),3.24(d,J＝11.5Hz,1H),2.81(s,3H),2.55–2.51(m,1H),2.36(s,3H),2.17(s,3H),1.77(d,J＝12.3Hz,1H),1.66(s,6H),1.45(s,1H),1.32(d,J＝11.1Hz,1H),0.93(d,J＝12.2Hz,1H)。

Example 37

2- (6- (3, 5-dimethylisoxazol-4-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 37 was prepared using the same procedure described in example 36, except that intermediate 1 was used in step 1, to give the title compound (32.0mg) as an off-white solid. LC-MS: [ M + H ]]⁺＝535。¹H NMR(400MHz,DMSO-d6)δ8.60(d,J＝4.6Hz,1H),8.28(d,J＝1.6Hz,1H),8.10(s,1H),7.75-7.72(m,1H),7.51-7.49(m,1H),6.12(d,J＝11.2Hz,1H),5.75(s,1H),3.84(d,J＝8.8Hz,1H),3.73(d,J＝8.5Hz,1H),3.37-3.35(m,2H),3.19-3.17(m,1H),2.82(s,3H),2.39(s,3H),2.21(s,3H),1.65(s,6H),1.67-1.64(m,1H),1.41-1.39(m,2H),1.29-1.27(m,1H)。

Example 38

(S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 4- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 2 of the synthesis of example 19, 2, 5-dibromo-3-nitropyridine (10.9g,53.2mmol) and (4-fluoro-5- (methoxyacyl) thiophen-3-yl) boronic acid (5.28g,25.88mol) were converted to the title compound as a light yellow solid (4.48g,12.4mmol, 48%). LC-MS [ M + H ]]⁺＝361。

Step 2: 6-bromo-3-fluoro-8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂Next, a mixture of methyl 4- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylate (1.94g,5.37mmol), DPPE (3.45g,8.65mmol) in toluene (40mL) was heated to 100 ℃ and stirred for 12 h. The reaction mixture was then slowly cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-25% EtOAc in hexanes to give the title compound (0.671g,2.04mmol, 38% yield) as a white solid. LC-MS [ M + H ]]⁺＝329。

And step 3: (S) -6-bromo-3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 4 of example 19, 6-bromo-3-fluoro-8H-thieno [3',2':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (218mg,0.66mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (191mg,0.99mmol) were converted to the title compound (230mg,0.46mmol, 69% yield) as a white solid. LC-MS [ M + H ]]⁺＝503。

And 4, step 4: (S) -methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

Following a procedure analogous to that described for step 3 in the synthesis of example 5, (S) -6-bromo-3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (230mg,0.46mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (425mg,1.10mmol) were converted to the title compound (196mg,0.38mmol, 82% yield) as a white solid. LC-MS [ M + H ]]⁺＝520。

And 5: (S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8-carboxylic acid was prepared in a similar manner to that described in step 6 of example 1(phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (273mg,0.53mmol) was converted to the title compound (95mg, 38% yield) as an off-white solid. LC-MS: [ M + H ]]⁺＝520.¹H NMR(400MHz,DMSO-d6)δ8.58(d,J＝1.8Hz,1H),8.46(d,J＝1.8Hz,1H),7.64(d,J＝7.2Hz,2H),7.38(t,J＝7.4Hz,2H),7.30(t,J＝7.3Hz,1H),5.90(s,1H),5.72(d,J＝11.3Hz,1H),4.07–3.98(m,3H),3.84(dd,J＝15.9,12.6Hz,2H),3.43-3.40(m,1H),3.34(d,J＝11.9Hz,1H),3.03(d,J＝5.7Hz,1H),2.34–2.25(m,3H),1.61(s,6H),1.40–1.33(m,1H),1.20-118(m,2H),0.89-0.86(m,1H)。

Example 39

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3',2':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 39 was prepared according to the procedure described for example 38 except intermediate 1 was used instead of (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol in step 3 to give the title compound (56mg) as an off-white solid. LC-MS: [ M + H ]]⁺＝539.¹H NMR(400MHz,DMSO-d6)δ8.60(s,2H),8.49(s,1H),7.76(s,1H),7.53(s,1H),6.12(s,1H),5.81(s,1H),4.05(s,3H),3.79(d,J＝36.0Hz,2H),3.34(s,1H),3.22(s,2H),2.33(s,3H),1.57(d,J＝21.9Hz,6H),1.45(s,3H),0.82(s,1H)。

Example 40

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 3of example 18, 6-bromo-3-methyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (from step 3,216mg,0.66mmol of example 34) and 4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butan-1-ol (intermediate 7,182mg,0.82mmol) were converted to the title compound (294mg,0.56mmol, 84% yield) as a white solid. LC-MS [ M + H ]]⁺＝530。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 3of example 5, 6-bromo-3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (294mg,0.55mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (294mg,0.77mmol) were converted to the title compound (198mg,0.36mmol, 65% yield) as a white solid. LC-MS [ M + H ]]⁺＝547。

And step 3: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4,4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (198mg,0.36mmol) was converted to the title compound (91mg, 46% yield) as an off-white solid. LC-MS: [ M + H ]]⁺＝547。¹H NMR(400MHz,DMSO-d6)δ8.59(d,J＝4.6Hz,1H),8.38(s,1H),7.78–7.67(m,1H),7.58-7.50(m,2H),6.62(dd,J＝7.6,7.8Hz,1H),5.81(s,1H),3.85(s,3H),2.95-2.86(m,1H),2.78-2.65(m,2H),2.12(s,3H),2.10–1.96(m,2H),1.65(s,6H),1.28-1.18(m,2H)。

EXAMPLE 41

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

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

In N₂Down to NiI₂(1.74g,5.56mmol)、Zn(6.43g,98.3mmol)、MgCl₂(7.64g,80.2mmol), TBAI (23.1g,62.6mmol) and dmbpy (1.45g,7.88mmol) in DMAC (150mL) was added methyl 3-bromothiophene-2-carboxylate (10.3g,46.4mmol) and 4-methylbenzenesulfonic acid d₃-methyl ester (15.97g,84.4mmol) in DMAC (20 mL). After addition, the reaction was stirred at rt for 16 h. The reaction mixture was extracted with EtOAc (500 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-2% EtOAc in hexanes to give methyl 3- (methyl-d 3) thiophene-2-carboxylate (4.88g,30.69mmol, 66% yield) as a colorless oil. LC-MS [ M + H ]]⁺＝160。

Step 2: (5- (Methoxyacyl) -4- (methyl-d 3) thiophen-2-yl) boronic acid

Methyl 3- (methyl-d 3) thiophene-2-carboxylate (2.40g,15.1mmol) was converted to the title compound (2.41g,11.87mmol, 79% yield) following a procedure analogous to that described for step 1 in the synthesis of example 19.

And step 3: 5- (5-bromo-3-nitropyridin-2-yl) -3- (methyl-d 3) thiophene-2-carboxylic acid methyl ester

Following a procedure analogous to that described in example 19, step 2, 5-dibromo-3-nitropyridine (5.25g,18.64mmol) and (5- (methoxyacyl) -4- (methyl-d 3) thiophen-2-yl) boronic acid (2.41g,11.87mmol) were converted to the title compound (2.31g,6.42mmol, 55% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝360。

And 4, step 4: 6-bromo-3- (methyl-d 3) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂Next, methyl 5- (5-bromo-3-nitropyridin-2-yl) -3- (methyl-d 3) thiophene-2-carboxylate (2.21g,6.14mmol), P (OEt)₃(5.02g,43.26mmol) inA mixture of xylenes (25mL) was heated to 135 ℃ and stirred for 2 h. The reaction mixture was then cooled to room temperature. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography using 0-30% EtOAc in n-hexane to give 6-bromo-3- (methyl-d 3) -4H-thieno [2',3':4, 5%]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (642mg,1.96mmol, 32% yield) as a white solid. LC-MS [ M + H ]]⁺＝328。

And 5: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-3- (methyl-d 3) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (287mg,0.87mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 1,231mg,1.09mmol) were converted to the title compound (403mg, 89% yield) as a white solid. LC-MS [ M + H ]]⁺＝521。

Step 6: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 4 of example 1, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (467mg,0.87mmol) and 1-methyl-4- (methyl) -5- (tributyltin-yl) -1H-1,2, 3-triazole (1.07g,2.76mmol) were converted to the title compound (383mg,0.71mmpl, 82% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝538。

And 7: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d 3) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (313mg,0.58mmol) was converted to the title compound (137mg,0.26mmol, 44% yield) as a white solid. LC-MS [ M + H ]]⁺＝538。¹H NMR(400MHz,DMSO-d6)δ8.59(d,J＝4.52Hz,1H),8.37(d,J＝1.2Hz,1H),8.24(s,1H),7.79-7.72(m,1H),7.7.55-7.48(m,1H),6.12(d,J＝11.0Hz,1H),5.80(s,1H),3.93(s,3H),3.82(d,J＝8.2Hz,1H),3.72(d,J＝8.68Hz,1H),3.48-3.32(m,3H),3.32-3.15(m,1H)，2.20(s,3H),1.65(s,6H),1.62-1.54(m,1H),1.48-1.35(m,1H),1.34-1.20(m,1H)。

Example 42

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 5- (5-bromo-3-nitropyridin-2-yl) -1-methyl-1H-pyrrole-2-carboxylic acid methyl ester

To a solution of methyl 5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylate (0.68g,2.09mmol) from step 2 of example 30 in DMF (15ml) was added CH₃I (352mg,2.48mmol) and K₂CO₃(0.55g,3.98 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then extracted with EtOAc (50mL), the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the title compound (677mg,1.99mmol, 95% yield) as a light yellow solid. LC-MS [ M + H ]]⁺＝340。

Step 2: 6-bromo-1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

5- (5-bromo-3-nitropyridin-2-yl) -1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (677mg,1.99mmol) was converted to the title compound following a procedure similar to that described in step 3of example 1 except that the reaction was carried out at 180 ℃ for 4H. The crude product was purified by silica gel chromatography using 0-20% EtOAc in n-hexane to afford the titled compoundCompound (484mg,1.57mmol, 79% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝308。

And step 3: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 1 of example 3, 6-bromo-1-methyl-1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (200mg,0.65mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (252mg,1.19mmol) were converted to the title compound. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the title compound (198mg,0.40mmol, 62% yield) as a white solid. LC-MS [ M + H ]]⁺＝501。

And 4, step 4: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 2 of example 3, except that the reaction was carried out at 85 ℃ for 3H, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (111mg,0.22mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (354mg,0.92mmol) were converted to the title compound. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the title compound (55mg,0.11mmol, 50% yield) as a white solid. LC-MS [ M + H ]]⁺＝518。

And 5: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure analogous to that described in example 1, step 6, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (55mg,0.11mmol) was converted to the title compound. Use ofThe residue was purified by silica gel chromatography with 0-6% MeOH in DCM to give the title compound (13mg,0.0251mmol, 23% yield) as a white solid. LC-MS [ M + H ]]+＝518。¹H NMR(400MHz,DMSO-d6)δ8.55(d,J＝4.64Hz,1H),8.27(d,J＝7.04Hz,2H),7.71–7.63(m,1H),7.44(dt,J＝8.52,4.48Hz,1H),6.08(s,1H),5.89(d,J＝10.9Hz,1H),5.26(s,1H),4.19(s,2H),4.02(s,3H),3.83(d,J＝10.9Hz,1H),3.74(d,J＝9.56Hz,1H),3.41–3.34(m,1H),3.30–3.17(m,3H),2.67(t,J＝1.68Hz,1H),2.31(s,3H),2.00(s,1H),1.55(d,J＝15.7Hz,6H),1.23(s,2H)。

Example 43

(S) -2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 43 was prepared according to the procedure described for example 19. LC-MS [ M + H ]]⁺＝536。¹H-NMR(400MHz,DMSO-d₆)δ8.41(s,1H),8.21(s,1H),7.67(d,2H),7.37-7.34(m,2H),7.28-7.26(m,1H),6.28(d,1H),6.20(s,1H),3.89(s,3H),3.80-3.77(m,2H),3.48-3.45(m,2H),3.27-3.24(m,1H),2.20(s,3H),1.71-1.79(m,1H),1.73(s,6H),1.36-1.31(m,2H),1.03(d,1H)。

Example 44

2- (3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol (enantiomer A)

The compound of example 44, LC-MS [ M + H ], was prepared as described in example 20, except that intermediate 1 (enantiomer a) replaced the racemate in step 1 of example 20]⁺＝555。¹HNMR(400MHz,DMSO-d₆)δ8.59(d,1H),8.45(s,1H),8.28(s,1H),7.77-7.72(m,1H),7.54-7.49(m,1H),6.68-6.66(d,1H),6.20(s,1H),3.93(s,3H),3.83(d,1H),3.74(d,1H),3.44-3.35(m,2H),2.20(s,3H),1.73(s,6H),1.64(d,1H),1.38-1.35(m,3H),0.82-0.79(m,1H)。

Example 45

(S) -2-methyl-4- (6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) but-3-yn-2-ol

The compound of example 45 was prepared according to the procedure described for example 14. LC-MS (ES +): [ M + H ]]⁺＝529。¹H-NMR(600MHz,CDCl₃)δ9.36(s,1H),7.65(s,1H),7.43(s,1H),7.38-7.37(m,2H),7.35-7.32(m,2H),7.30-7.29(m,1H),5.16(d,J＝10.8Hz,1H),4.03-4.00(m,1H),3.93-3.92(m,1H),3.92(s,3H),3.49-3.40(m,2H),2.94-2.89(m,2H),1.69(s,6H),1.51-1.44(m,1H),1.41-1.36(m,2H),1.31-1.26(m,1H)。

Example 46

2- (6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 46 was prepared according to the procedure described for example 12. LC-MS (ES +): [ M + H ]]⁺＝489。¹H-NMR(400MHz,DMSO-d₆)δ8.42(s,1H),8.34(s,1H),7.60-7.58(m,3H),7.28-7.19(m,2H),7.16(s,1H),5.53(d,1H),4.02(s,3H),3.83(d,1H),3.78(d,1H),3.39-3.37(m,1H),3.28-26(m,2H),1.58(s,6H),1.39-1.37(m,2H),1.23-1.20(m,1H),1.17-1.15(m,2H)。

Example 47

2- (4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -6- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 47 was prepared according to the procedure described for example 11. LC-MS (ES +): [ M + H ]]⁺＝524。¹H-NMR(400MHz,DMSO-d₆)δ8.60(d,1H),8.49-8.48(m,1H),8.41(d,1H),7.71-7.69(m,1H),7.48-7.42(m,1H),7.39(s,1H),6.07(d,1H),4.02(s,3H),3.85(d,1H),3.73(d,1H),3.38-3.37(m,1H),3.25-3.32(m,2H),1.56(s,6H),1.51-1.49(m,2H),1.38-1.36(m,1H),1.35-1.32(m,2H)。

Example 48

(S) -2- (2- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

The compound of example 48 was prepared according to the procedure described for example 10. LC-MS (ES +): [ M + H ]]⁺＝505.¹H-NMR(400MHz,DMSO-d₆)δ8.56(s,1H),8.40(s,1H),8.04(s,1H),7.65-7.62(m,2H),7.31-7.29(m,2H),7.24-7.21(m,1H),5.66(d,1H),4.14(s,3H),3.88(d,1H),3.77-3.76(m,1H),3.39(d,1H),3.32-3.30(m,2H),1.56(s,6H),1.49-1.47(m,2H),1.35-1.32(m,1H),1.19-1.17(m,2H)。

Example 49

(S) -2- (3-methyl-2- (1-methyl-4- (methyl-d 3) -1H-1,2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

The compound of example 49 was prepared according to the procedure described for example 10. LC-MS (ES +): [ M + H ]]⁺＝519。¹H-NMR(400MHz,DMSO-d₆)δ8.55(s,1H),8.18(s,1H),7.62-7.60(m,2H),7.38-7.36(m,2H),7.29-7.26(m,1H),5.79(s,1H),5.69(d,1H),3.93(s,3H),3.91-3.89(m,1H),3.78-3.76(m,1H),3.53-3.48(m,2H),3.30-3.27(m,1H),2.22(s,3H),1.77-1.75(m,2H),1.50(s,6H),1.36-1.34(m,1H),0.90-0.85(m,1H)。

Example 50

(S) -5- (6- (2-hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one

The compound of example 50 was prepared according to the procedure described for example 8. LC-MS [ M + H ]]⁺＝528.¹H NMR(400MHz,DMSO)δ8.49(s,1H),8.29(s,1H),8.15(d,J＝1.24Hz,1H),7.98(s,1H),7.89(s,1H),7.66-7.64(m,2H),7.34-7.31(m,2H),7.24-7.22(m,1H),5.57(d,J＝11.32Hz,1H),5.24(s,1H),3.90-3.88(m,1H),3.78-3.76(m,1H),3.56(s,3H),3.40-3.38(m,2H),3.25-3.24(m,1H),2.50-2.48(m,2H),2.14(s,3H),1.57(s,6H),1.21-1.19(m,2H)。

Example 51

(S) -2- (2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-6-yl) propan-2-ol

The compound of example 51 was prepared according to the procedure described for example 5. LC-MS [ M + H ]]⁺＝516。¹H-NMR(400MHz,DMSO-d₆)δ8.55(s,1H),8.18(s,1H),7.62-7.60(m,1H),7.38-7.30(m,4H),5.72(s,1H),5.70(d,1H),3.93(s,3H),3.89-3.91(m,1H),3.76-3.78(m,1H),3.53-3.48(m,2H),3.30-3.23(m,1H),2.38(s,3H),2.27(s,3H),2.22-2.20(m,1H),1.75-7.77(m,1H),1.50(s,6H),1.36-1.34(m,1H),0.90-0.85(m,1H)。

Example 52

(S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 52 was prepared according to the procedure described for example 22. LC-MS [ M + H ]]⁺＝520。¹H-NMR(400MHz,DMSO-d₆)δ8.52(s,1H),8.44(s,1H),7.59-7.57(m,2H),7.37-7.33(m,2H),7.29-7.25(m,1H),5.98(s,1H),5.59(d,1H),4.00(s,3H),3.83-3.79(m,2H),3.43-3.37(m,1H),3.28(s,3H),3.27-3.17(m,3H),1.64(s,6H),1.52-1.55(d,1H),1.34-1.43(m,2H)。

Example 53

(R) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

The compound of example 53, LC-MS [ M + H ], was prepared according to the procedure described in example 9]⁺＝502。¹H-NMR(400MHz,DMSO-d₆)δ8.45(s,1H),8.36(d,J＝1.44Hz,1H),7.66(s,1H),7.67-7.62(m,2H),7.34-7.28(m,2H),7.28-7.23(m,1H),5.73(s,1H),5.61(d,J＝11.3Hz,1H),4.00(s,3H),3.91-3.82(m,1H),3.81-3.72(m.1H),3.49-3.40(m,1H),3.32-3.28(m,1H),2.28(s,3H),1.64(s,3H),1.63(s,3H),1.51-1.36(m,2H),1.35-1.27(m,1H),1.26-1.12(m,2H)。

Example 54

(S) -methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methoxy-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

Step 1: (S) -6-bromo-3-methoxy-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Reacting 6-bromo-3-methoxy-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]A solution of pyridine-2-carboxylic acid methyl ester (from step 3,300mg,0.88mmol of example 25), (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (208mg,1.08mmol) and triphenylphosphine (561mg,2.14mmol) in dry THF (20mL) was degassed and flushed with nitrogen three times. Diisopropyl azodicarboxylate (457mg,2.26mmol) was added dropwise at room temperature and the resulting solution was stirred for 2 h. The reaction was then extracted with EtOAc (50mL), washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-40% EtOAc in n-hexane to give (S) -6-bromo-3-methoxy-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (403mg, 89% yield) as a white solid. LC-MS [ M + H ]]⁺＝515。

Step 2: (S) -methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methoxy-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

Following a procedure analogous to that described in step 2 of example 3, (S) -6-bromo-3-methoxy-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (403mg,0.78mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (728mg,1.88mmol) were converted to the title compound (390mg, 94% yield) as a yellow solid. LC-MS [ M + H ]]⁺＝532。¹H NMR(400MHz,DMSO-d6)δ8.52(d,J＝1.4Hz,1H),8.47(s,1H),7.64(d,J＝7.5Hz,2H),7.35-7.32(m,2H),7.27-7.25(m,1H),5.85(d,J＝11.4Hz,1H),4.23(s,3H),3.96(s,3H),3.90(s,3H),3.86(d,J＝8.9,1H),3.79(d,J＝9.2Hz,1H),3.45-3.42(m,1H),3.32(s,1H),3.28-3.25(m,1H),2.26(s,3H),1.66-1.62(m,1H),1.39–1.26(m,2H),1.17–1.08(m,1H)。

Example 55

(S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 3-Ethylthiophene-2-carboxylic acid methyl ester

In N₂Next, tributyl (ethylene) stannane (17.33g,54.65mmol), CsF (14.03g,92.63mmol), Pd (PPh) and methyl 3-bromothiophene-2-carboxylate (10.03g,45.37mmol) were added to a solution of dioxane (150mL)₃)₄(5.26g,4.55 mmol). Vacuumizing the mixture, and backfilling N₂And this sequence was repeated three times. In N₂The mixture was then refluxed for 16h using a condenser. After the reaction mixture was cooled to room temperature, it was poured into water (100L) and extracted with EtOAc (3 × 100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the desired intermediate, methyl 3-ethylenethiophene-2-carboxylate, as a yellow oil (4.19g, 47% yield). LC-MS [ M + H ]]⁺＝169。¹H NMR(400MHz,CDCl₃)δ7.61(dd,J＝17.6,10.8Hz,1H),7.40(d,J＝5.2Hz,1H),7.32(d,J＝5.2Hz,1H),5.72(dd,J＝18.0,1.6Hz,1H),5.44(dd,J＝11.2,1.2Hz,1H),3.88(s,3H)。

Step 2: 3-Ethylthiophene-2-carboxylic acid methyl ester

In N₂Next, to a solution of methyl 3-vinylthiophene-2-carboxylate (4.13g,24.55mmol) in MeOH (40mL) and EtOAc (20mL) was added 10% wet Pd/C (0.45 g). Vacuumizing the mixture, and backfilling H₂And this sequence was repeated three times. At H₂The mixture was stirred at room temperature with a condenser for 16 h. The reaction mixture was diluted with EtOAc (50L) and filtered. The filter cake was washed with EtOAc (3 × 100 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the desired intermediate, methyl 3-ethylthiophene-2-carboxylate, as a yellow oil (2.80g, 67% yield). LC-MS [ M + H ]]⁺＝171。¹H NMR(400MHz,CDCl₃)δ7.40(d,J＝4.8Hz,1H),6.98(d,J＝5.2Hz,1H),3.86(s,3H),3.04(q,J＝7.6Hz,2H),1.24(t,J＝7.6Hz,3H)。

And step 3: (4-Ethyl-5- (methoxyacyl) thiophen-2-yl) boronic acid

Following a procedure analogous to that described in example 19, step 1, methyl 3-ethylthiophene-2-carboxylate (2.76g,16.21mmol) was converted to the title compound (2.33g) as a yellow solid. LC-MS [ M + H ]]⁺＝215。

And 4, step 4: 5- (5-bromo-3-nitropyridin-2-yl) -3-ethylthiophene-2-carboxylic acid methyl ester

In N₂Next, to a solution of (4-ethyl-5- (methoxyacyl) thiophen-2-yl) boronic acid (2.33g,10.89mmol) in EtOH (10mL), toluene (16mL) and water (16mL) was added tetrakis (triphenylphosphine) palladium (1.22g,1.06mmol), Na₂CO₃(3.48g,32.83mol) and 2, 5-dibromo-3-nitropyridine (3.40g,12.06 mmol). Vacuumizing the mixture, and backfilling N₂And this sequence was repeated three times. In N₂The mixture was then refluxed for 16h using a condenser. The reaction was cooled to room temperature, poured into water (50mL) and treated with EtOA_C(3 × 50mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-ethylthiophene-2-carboxylate as a light yellow solid (1.70g, 14% two step yield). LC-MS [ M + H ]]⁺＝343。¹H NMR(400MHz,CDCl₃)δ8.80(d,J＝2.0Hz,1H),8.12(d,J＝2.0Hz,1H),7.21(s,1H),3.89(s,3H),3.00(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H)。

And 5: 6-bromo-3-ethyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂Next, methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-ethylthiophene-2-carboxylate (1.70g,4.58mmol), P (OEt)₃A mixture (5.36g,32.26mmol) in xylene (20mL) was heated to 140 ℃ and stirred for 16 h. The reaction was then slowly cooled to room temperature and purified by silica gel chromatography using 0-20% EtOAc in n-hexane to afford 6-bromo-3-ethyl-4H-thieno [2',3':4, 5%]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester as a pale yellow solid (352mg, 23% yield). LC-MS [ M + H ]]⁺＝339。¹H NMR(400MHz,DMSO-d₆)δ12.24(s,1H),8.48(d,J＝2.0Hz,1H),8.17(d,J＝2.0Hz,1H),7.21(s,1H),3.86(s,3H),3.22(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H)。

Step 6: (S) -6-bromo-3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

To 6-bromo-3-ethyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]To a solution of pyridine-2-carboxylic acid methyl ester (352mg,1.04mmol) in dry toluene (8mL) were added (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (241mg,1.25mmol) and triphenylphosphine (548g,2.09 mmol). Vacuumizing the mixture, and backfilling N₂And the process was repeated three times. To the solution was added dropwise diisopropyl azodicarboxylate (445mg,2.20mmol) at room temperature. The resulting solution was refluxed for 16 h. The reaction was then poured into water (50mL) and extracted with EA (3 × 50mL), washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EA in n-hexane to give (S) -6-bromo-3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (391mg, 73% yield) as a pale yellow solid. LC-MS (ES)⁺)：[M+H]⁺＝513。

And 7: (S) -methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

To (S) -6-bromo-3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (299mg,0.58mmol) in dioxane (5mL) was added with 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (463mg,1.19mmol), Pd (dppf)₂Cl₂(85mg,0.12mmol) and DIPEA (234mg,1.81 mmol). Vacuumizing the mixture, and backfilling N₂And this process was repeated three times and then stirred at 120 ℃ for 16 h. The mixture was cooled to room temperature, diluted with water (50mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM and by Prep-HPLC to give (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-ethaneYl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (129mg, 42% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝530。

And 8: (S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-ethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] according to a procedure similar to that described in step 6 of example 1]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (125mg,0.24mmol) was converted to the title compound (58mg, 46% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺530。¹H-NMR(400MHz,DMSO-d₆)δ8.34(s,1H),7.94(s,1H),7.55-7.53(m,2H),7.37-7.34(m,2H),7.29-7.26(m,1H),5.55(d,J＝10.0Hz,1H),3.89-3.85(m,1H),3.83(s,3H),3.78-3.72(m,1H),3.51-3.38(m,1H),3.29-3.17(m,3H),2.14(s,3H),1.87-1.79(m,2H),1.66(s,6H),1.53-1.28(m,6H),0.98-0.88(m,1H)。

Example 56

(S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 3- (prop-1-en-2-yl) thiophene-2-carboxylic acid methyl ester

In N₂Next, to a solution of methyl 3-bromothiophene-2-carboxylate (10.05g,45.46mmol) in dioxane (100mL) and H₂Adding 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborane (12.09g,71.95mmol) and K into O (20mL) solution₂CO₃(13.22g,95.66mmol)、Pd(dppf)Cl₂(3.86g,4.73 mmol). Vacuumizing the mixture, and backfilling N₂And this sequence was repeated three times. In N₂The mixture was then refluxed for 16h using a condenser. In thatAfter the reaction mixture was cooled to room temperature, it was poured into water (100mL) and extracted with EtOAc (3 × 100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-8% EtOAc in hexanes to give the target intermediate, methyl 3- (prop-1-en-2-yl) thiophene-2-carboxylate, as a yellow oil (7.62g, 92% yield). LC-MS [ M + H ]]⁺＝183.¹H NMR(400MHz,CDCl₃)δ7.40(d,J＝5.2Hz,1H),6.93(d,J＝5.2Hz,1H),5.22-5.20(m,1H),5.01-5.00(m,1H),3.85(s,3H)。

Step 2: 3-isopropylthiophene-2-carboxylic acid methyl ester

In N₂Next, to a solution of methyl 3- (prop-1-en-2-yl) thiophene-2-carboxylate (7.62g,52.57mmol) in MeOH (100mL) and EtOAc (50mL) was added 10% wet Pd/C (1.88 g). Vacuumizing the mixture, and backfilling H₂And this sequence was repeated three times. At H₂The mixture was stirred at room temperature for 16h with a condenser. The reaction mixture was diluted with EtOAc (100L) and filtered. The filter cake was washed with EtOAc (3 × 100 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the desired intermediate, methyl 3-isopropylthiophene-2-carboxylate, as a yellow oil (7.62g, 99% yield). LC-MS [ M + H ]]⁺＝185。¹H NMR(400MHz,CDCl₃)δ7.40(d,J＝5.2Hz,1H),7.08(d,J＝5.2Hz,1H),4.01-3.94(m,1H),3.86(s,3H),1.25(s,3H),1.23(s,3H)。

And step 3: (4-isopropyl-5- (methoxyacyl) thiophen-2-yl) boronic acid

Following a procedure analogous to that described in example 19, step 1, methyl 3-isopropylthiophene-2-carboxylate (4.03g,21.87mmol) was converted to the title compound (5.26g, 100%) as a yellow solid. LC-MS [ M + H ]]⁺＝229。

And 4, step 4: 5- (5-bromo-3-nitropyridin-2-yl) -3-isopropylthiophene-2-carboxylic acid methyl ester

(4-isopropyl-5- (methoxyacyl) thiophen-2-yl) boronic acid (5.26g,21.87mmol and 2, 5-dibromo-3-nitropyridine (6.13g,21.75mmol) was converted to the title compound (1.47g, 18% bipartite) according to a procedure similar to that described in step 4 of example 55Step yield) as a pale yellow solid. LC-MS [ M + H ]]⁺＝385。¹H NMR(400MHz,CDCl₃)δ9.02(d,J＝2.0Hz,1H),8.83(d,J＝2.0Hz,1H),7.36(s,1H),3.86-3.80(m,4H),1.18(s,3H),1.16(s,3H)。

And 5: 6-bromo-3-isopropyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

In N₂Next, a reaction mixture of methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-isopropylthiophene-2-carboxylate (1.42g,3.69mmol), DPPE (2.63g,6.60mmol) in o-dichlorobenzene (30mL) was heated to 150 ℃ and stirred for 4 h. The reaction was then slowly cooled to room temperature and purified by silica gel chromatography using 0-10% EtOAc in n-hexane to afford 6-bromo-3-isopropyl-4H-thieno [2',3':4,5 ')]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester as a pale yellow solid (501mg, 38% yield). LC-MS [ M + H ]]⁺＝353.¹H NMR(400MHz,DMSO-d₆)δ11.91(s,1H),8.49(d,J＝2.0Hz,1H),8.10(d,J＝2.0Hz,1H),4.35-4.28(m,1H),3.86(s,3H),1.43(s,3H),1.41(s,3H)。

Step 6: (S) -6-bromo-3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 6 of example 55, 6-bromo-3-isopropyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (231mg,0.65mmol) and (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol (154mg,0.80mmol) were converted to the title compound (152mg, 45% yield) as a light yellow solid. LC-MS (ES)⁺)：[M+H]⁺＝527。

And 7: (S) -methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylate

Following a procedure analogous to that described in step 7 of example 55, (S) -6-bromo-3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (148mg,0.28mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (232mg,0.60mmol) were converted to the title compound (1)49mg, 96% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝544。

And 8: (S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] according to a procedure similar to that described in step 6 of example 1]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (102mg,0.19mmol) was converted to the title compound (28mg, 27% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝544。¹H-NMR(400MHz,DMSO-d₆)δ8.37(d,J＝1.2Hz,1H),7.63(s,1H),7.45-7.43(m,2H),7.36-7.32(m,2H),7.29-7.25(m,1H),5.79(d,J＝10.4Hz,1H),4.13-4.06(m,1H),3.93-3.85(m,1H),3.71(s,3H),3.30-3.65(m,1H),3.53-3.48(m,1H),3.26-3.13(m,1H),2.88-2.86(m,1H),2.13-2.07(m,1H),2.04(s,3H),1.67(s,3H),1.66(s,3H),1.59-1.57(m,2H),1.39-1.33(m,2H),1.18(d,J＝6.8Hz,6H)。

Example 57

2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Step 1: 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure similar to that described in step 6 of example 55, 6-bromo-3-isopropyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (from step 5,233mg,0.66mmol of example 56) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (intermediate 1,173mg,0.82mmol) were converted to the title compound (174mg, 48% yield) as a pale yellow solid. LC-MS (ES)⁺)：[M+H]⁺＝546。

Step 2: 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester

Following a procedure analogous to that described in step 7 of example 55, 6-bromo-4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Methyl pyridine-2-carboxylate (170mg,0.31mmol) and 1, 4-dimethyl-5- (tributyltin-yl) -1H-1,2, 3-triazole (253mg,0.65mmol) were converted to the title compound (147mg, 84% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝563。

And step 3: 2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol

Following a procedure similar to that described in step 6 of example 1, 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ((3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-isopropyl-4H-thieno [2',3':4,5]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (116mg,0.21mmol) was converted to the title compound (32mg, 28% yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝563。¹H-NMR(400MHz,DMSO-d₆)δ8.62(s,1H),8.50-8.46(m,2H),7.90-7.75(m,1H),7.59-7.46(m,1H),6.11(d,J＝10.8Hz,1H),5.79(s,1H),4.12-4.01(m,1H),4.01(s,3H),3.85-3.80(m,1H),3.62-3.59(m,1H),3.24-3.18(m,1H),2.92-2.90(m,1H),1.65(s,6H),1.62(s,3H),1.61-1.45(m,2H),1.25-1.18(m,2H),1.18(d,J＝6.3Hz,6H),0.93-0.78(m,1H)。

Example 58

(S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-N, N-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxamide

Step 1: (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid

To (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid methyl ester (step 7 from example 56, 38mg,0.070mmol) in THF (4mL) and H₂To the O (1mL) solution was added LiOH (12 mg). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the pH of the residue was adjusted to 7 with 1N aqueous HCl. The mixture was extracted with EtOAc (3 × 20ml) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (29mg, 78% yield) as a pale yellow solid. LC-MS (ES)⁺)：[M+H]⁺＝530。

Step 2: (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carbonyl chloride

To (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-2-carboxylic acid (29mg,0.055mmol) in DCM (2mL) was added (COCl)₂(2 mL). Mixing the mixture in N₂Reflux with a condenser for 2 hours under atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude compound (53mg) as a pale yellow solid which was used in the next step without further discharge.

And step 3: (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-N, N-dimethyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxamide

To (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-isopropyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2',3':4, 5)]Pyrrolo [3,2-b]Pyridine-2-carbonyl chloride (53mg,0.055mmol) in DCM (1mL) was added Et₃N (0.5mL) and dimethylamine (0.5mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified by Prep-HPLC to give the title compound (17mg, 39% three step yield) as an off-white solid. LC-MS (ES)⁺)：[M+H]⁺＝557。¹H-NMR(400MHz,DMSO-d₆)δ8.41(s,1H),8.00(s,1H),7.64-7.51(m,2H),7.44-7.34(m,2H),7.33-7.23(m,1H),5.69(d,J＝8.8Hz,1H),3.96-3.69(m,4H),3.56-3.37(m,2H),3.30-3.17(m,1H),3.03(s,6H),2.14(s,3H),1.90-1.78(m,2H),1.47(s,6H),1.37-1.56(m,3H),0.98-0.82(m,1H)。

Examples 59 to 67

The compounds in table 3 were synthesized analogously according to the above examples:

TABLE 3

Pharmacological testing

BRD4(BD1) binding assay

The assay was performed by Shanghai Ruizi Chemicals, Inc. using a homogeneous time-resolved fluorescence (HTRF) binding assay.

The experimental method comprises the following steps:

(1) the compounds in the Echo plates were diluted sequentially according to the plate map. The final proportion of DMSO was 0.1%.

(2) 0.02. mu.L of the above serially diluted compound solution at each concentration and vehicle DMSO were transferred to 384-well assay plates, respectively, by Echo.

(3) To the assay plate was added 10. mu.L of 2 × protein (BRD4(BD1) protein: 5 nM/well, # RD-11-157, available from Reaction Biology Corp) and a mixture of peptides (peptide mixture: 5 nM/well, #329934, available from Jill Biochemical Shanghai Co., LTD.).

(4) To the assay plate was added 10. mu.L of 2 × assay mix (assay mix: Anti-GST-EU3+ Cryptate (Cryptate) (0.25 nM/well, #62BDAPEH, purchased from Cisbio), SA-XL-665(0.625 nM/well, #62BDAPEH, purchased from Cisbio)), and shaken for 30 seconds.

(5) The assay plates were incubated at room temperature for 2 hours.

(6) The HTRF signal was read on Envision (Ex at 340nm, Em at 615nm and 665 nm).

(7) And (6) fitting a curve. Data were fitted in Excel to obtain inhibition values. Fitting data in GraphPad to obtain IC₅₀The value is obtained.

As a result:

BRD4(BD1) binding test results are shown in table 4 below:

TABLE 4 results of BRD4(BD1) binding tests

2. Cell proliferation assay

MTS assay protocol:

MV-4-11 cell proliferation assay was performed by MTS (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole, inner salt) assay. Briefly, 5% CO at 37 deg.C₂And MV-4-11 cells were cultured in 10% (v/v) FBS (fetal bovine serum) IMDM (Iscove's Modified Dubecco's Medium) medium at 95% humidity cells in the logarithmic growth phase were harvested and counted with a hemocytometer (hemocytometer) ensuring cell viability over 95% by trypan blue exclusion (trypan blue exclusion) MV-4-11 cell concentration was adjusted to 1.2 × 10 with complete medium⁵Add 100. mu.L of cell suspension (each cell concentration in triplicate) to a 96-well plate to a final cell density of 1.2 × 10⁴Individual cells/well. The next day, test compounds were dissolved in DMSO as stock solutions. 5 μ L of stock solution was dispensed into 1mL of media and 25 μ L of drug media was added to the 96-well plate. After serial dilution with medium, the final concentrations of the compounds were 0, 0.03, 0.1, 0.3, 1,3. 10, 30, 100 nM. The plates were cultured for 3 days and then examined by the MTS method. Immediately before adding to the cell-containing culture plate, pms (phenazinium methosulfate) solution was added to MTS solution (1: 20). mu.L of the combined MTS/PMS solution was pipetted into each well of a 96-well assay plate containing 100. mu.L of cells in culture. The plates were moistened with 5% CO at 37 deg.C₂Incubation for 1-4 hours in atmosphere. Using a microplate spectrophotometer (Envision)^RPeikinElmer) the absorbance at 490nm was recorded. Fitting data and obtaining IC Using GraphPad5.0₅₀The value is obtained.

As a result:

the results of the cell proliferation activity assay are shown in table 2 below:

TABLE 2 results of cell proliferation Activity assay

3. Immunoblot analysis

MV-4-11 cells were cultured in IMDM medium supplemented with 10% (v/v) FBS (fetal bovine serum). Cells were pretreated with 10nM compound for 16 h. Cells were collected and lysed in RIPA buffer (radioimmunoprecipitation assay buffer) containing protease inhibitors. Protein concentration was measured using BCA (bicinchoninic acid) assay according to the manufacturer's instructions. The samples (total protein 30. mu.g) were subjected to SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), and then the protein electrophoresis was transferred to a polyvinylidene fluoride membrane. Membranes were blocked in 5% BSA (bovine serum albumin) for 1h and then incubated with the appropriate primary antibody (1:1000 diluted in 2% BSA) overnight at 4 ℃. The membrane was then washed and incubated with secondary antibody (1:2000 diluted in 2% BSA) for 1h at room temperature. Protein bands were visualized by using an enhanced chemiluminescence detection system (Thermo Fisher Scientific). The primary antibody was an anti-c-MYC antibody (#5605, Cell Signaling Technology), the secondary antibody was an anti-rabbit IgG HRP-linked antibody (#7074, Cell Signaling Technology), and the internal reference protein was GAPDH (#5174, Cell Signaling Technology).

As a result:

the results of the immunoblot analysis are shown in table 6:

TABLE 6 results of immunoblot analysis

The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art. See, e.g., < Remington (REMINGTON): science and practice of pharmacy (edited by a. gennaro et al, 19 th edition, Mack publishing co., 1995). The compounds of formula (la) are generally effective over a wide dosage range.

For the examples, the daily dose will generally be in the range of about 0.025mg to about 200mg of the total daily dose, preferably 0.025mg to 150mg of the total daily dose, more preferably 0.025mg to 50mg of the total daily dose. In some cases dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage ranges are not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, individual patient response, and the severity of the patient's symptoms.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt or stereoisomer thereof:

one of which is

Is a single bond, and the other is

Is a double bond;

X₁is CR_1a、O、S、S(O)、S(O)₂Or NR_1b；

X₂Is CR_2aO, S or NR_2b；

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)NH-C_1-6Alkyl, C (O) N (C)_1-6Alkyl radical)₂、C(O)C_1-6Alkyl, C (O) OC_1-6Alkyl, S (O) C_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-NH-C_1-6Alkyl, -C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl radical, C_2-6alkenyl-OH, C_2-6Alkynyl, -C_2-6alkenyl-OH, -C_2-6alkynyl-OH,-C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) OH, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently substituted or unsubstituted;

s is 0, 1,2,3, 4 or 5;

z is H, or deuterium.

2. A compound of formula (1), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is of formula I:

one is

Is a single bond and the other

Is a double bond;

X₁is CR_1a、O、S、S(O)、S(O)₂Or NR_1b；

X₂Is CR_2aO, S or NR_2b；

s is 0, 1,2,3, 4 or 5;

3. A compound according to claim 1 or 2, wherein X₁Is CR_1aO, S or NR_1b。

4. A compound according to any one of claims 1-3, wherein R_1aIs H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

5. The compound according to any one of claims 1-4, wherein R_1aIs H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

6. The compound according to any one of claims 1 to 5, which isIn R_1aIs H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S.

7. The compound according to any one of claims 1-6, wherein R_1aIs H, F or methyl.

8. The compound according to any one of claims 1-7, wherein R_1bIs absent, H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3alkylene-C_5-6Aryl radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1bIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S.

9. The compound according to any one of claims 1-8, wherein R_1bIs absent, H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylene-5-membered aryl, C_1-3An alkylene-6-membered aryl, a 3-membered heterocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 3-membered carbocyclyl, a 4-membered carbocyclyl, a 5-membered carbocyclyl, or a 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each of said heterocyclyl groups contains 1,2 or 3 heteroatoms selected from N, O or S。

10. The compound according to any one of claims 1-9, wherein R_1bIs absent, H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5 membered aryl, methylene-6 membered aryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered carbocyclyl, or 6 membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.

11. The compound according to any one of claims 1-10, wherein R_1bIs absent, H, methyl or phenyl.

12. The compound according to any one of claims 1-11, wherein X₂Is CR_2aO, S or NR_2b。

13. The compound according to any one of claims 1-12, wherein R_2aIs H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) C_1-6Alkoxy radical, C_1-6alkylene-C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_2aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

14. The compound according to any one of claims 1-13, wherein R_2aIs H, F, Cl, Br, NH₂CN, OH, carboxyl, C_1-3Alkyl radical、C_1-3Alkoxy, C (O) C_1-3Alkoxy radical, C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

15. The compound according to any one of claims 1-14, wherein R_2aIs H, F, Cl, Br, NH₂CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH₃、C(O)OCH₂CH₃、C(O)OCH₂CH₂CH₃、C(O)OCH(CH₃)₂、CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃、C(CH₃)₂OCH₂CH₃、C(CH₃)₂OCH₂CH₂CH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2aIndependently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

16. The compound according to any one of claims 1-15, wherein R_2aIs H, F, Cl, CN, methyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

17. The compound according to any one of claims 1-15, wherein R_2aIs H, F, Cl, CN, methyl, CD₃Ethyl, isopropyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

or

18. The compound of any one of claims 1-17, wherein R_2bIs absent, H, F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_2bIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S.

19. The compound of any one of claims 1-18, wherein R_2bIs absent, H, F, Cl, Br, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S.

20. The compound of any one of claims 1-19, wherein R_2bIs absent, H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_2bIndependently by F, Cl, Br, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.

21. The compound of any one of claims 1-20, wherein R_2bIs absent or H.

22. The compound of any one of claims 1-21, wherein R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、C(O)NH-C_1-3Alkyl, C (O) N (C)_1-3Alkyl radical)₂、C(O)C_1-3Alkyl, S (O) C_1-3Alkyl, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、-C_l-3alkylene-NH-C_1-3Alkyl, -C_l-3alkylene-N (C)_1-3Alkyl radical)₂、C_2-3Alkenyl radical, C_2-3alkenyl-OH, C_2-3Alkynyl, -C_2-3alkenyl-OH, -C_2-3alkynyl-OH, -C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) OH, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

Two R_3aTogether with the carbon atom to which they are attached form c (o).

23. The compound of any one of claims 1-22, wherein R₃Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂CH₂N(CH₃)₂、CH₂N(CH₂CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Vinyl, propenyl, ethynyl, propynyl, propenyl, ethynyl, propynyl, prop,

-C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl radical)-C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted.

24. The compound of any one of claims 1-23, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Vinyl group, ethynyl group,

25. The compound of any one of claims 1-24, wherein s is 1,2,3, or 4.

26. The compound of any one of claims 1-25, wherein each R_3aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

27. The compound of any one of claims 1-26, wherein each R_3aIndependently H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH₂CH₂OH、CH(CH₃) OH or C (CH)₃)₂OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

28. The compound of any one of claims 1-27, wherein R₃Is H, CH₃、C(O)NH₂、

29. The compound of any one of claims 1-27, wherein R₃Is H, CH₃、C(O)NH₂、C(O)N(CH₃)₂、C(O)CH₃、C(O)OCH₃、

30. The compound of any one of claims 1-29, wherein R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、C(O)NH-C_1-3Alkyl, C (O) N (C)_1-3Alkyl radical)₂、C(O)C_1-3Alkyl, S (O) C_1-3Alkyl, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

Two R_4aTogether with the carbon atom to which they are attached form c (o).

31. The compound of any one of claims 1-30, wherein R₄Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

32. The compound of any one of claims 1-31, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH₂、C(O)CH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted.

33. The compound of any one of claims 1-32, wherein each R_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

34. The compound of any one of claims 1-33, wherein each R_4aIndependently H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 8-membered heterocyclic group, 3-membered carbocyclic group, 4-membered carbocyclic group, 5-membered carbocyclic group or 6-membered carbocyclic group; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

35. The compound of any one of claims 1-34, wherein each R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy,

Or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

36. The compound of any one of claims 1-35, wherein R₄Is that

37. The compound of any one of claims 1-36, wherein W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

38. The compound of any one of claims 1-37, wherein W₁Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、CH₂CH₂OCH₂CH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

39. The compound of any one of claims 1-38, wherein W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

40. The compound of any one of claims 1-39, wherein W₁Is H, F, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、

41. The compound of any one of claims 1-40, wherein W₁Is H, F, methyl, ethyl, propyl, methoxy, CH₂OCH₃、CH₂CH₂OCH₃、

42. The compound of any one of claims 1-40, wherein W₁Is H, F, methyl, ethyl, propyl, methoxy, CH₂OCH₃、CH₂CH₂CF₃、CH₂CH₂OCH₃、

43. The compound of any one of claims 1-42, wherein W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S.

44. The compound of any one of claims 1-43, wherein W₂Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂、OH. Carboxy, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

45. The compound of any one of claims 1-44, wherein W₂Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

46. The compound of any one of claims 1-45, wherein W₂Is H,

And each W₂Independently F, Cl, methyl or methoxy, or unsubstituted.

47. The compound of any one of claims 1-46, wherein W₂Is H,

48. The compound of claim 1, wherein the compound is of formula (2),

wherein,

X₁is O, S or NR_1b；

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、C(O)N(C_1-6Alkyl radical)₂、C(O)OC_1-6Alkyl, S (O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each of said heteroaryl groups isHeterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

z is H, or deuterium.

49. The compound according to any one of claims 1-48, wherein said compound is of formula II:

wherein,

X₁is O, S or NR_1b；

R₃is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, C (O) NH₂、S(O)₂C_1-6Alkyl, P (O) (C)_1-6Alkyl radical)₂、-C_l-6alkylene-OH, -C_l-6alkylene-NH₂、-C_l-6alkylene-N (C)_1-6Alkyl radical)₂、C_2-6Alkenyl, -C_2-6alkynyl-OH, -C_l-6alkylene-O-C_1-6Alkyl, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-OH、-C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-C_1-6Alkoxy, -C_1-6Alkylene- (O-C)_1-6Alkylene radical)_s-N(C_1-6Alkyl) -C_5-10Heteroaryl, -C_0-6alkylene-NH-C_1-6alkylene-C (O) -C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclic group, C_3-6A carbocyclic group; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

each R_4aIndependently of each other H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Heterocyclyl or C_3-6A carbocyclic group;and wherein each said heterocyclyl contains 1,2,3 or 4 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o);

50. The compound of claim 48, or 49, wherein R_1bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylene-5-membered aryl or C_1-3Alkylene-6-membered aryl.

51. The compound of any one of claims 48-50, wherein R_1bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5 membered aryl or methylene-6 membered aryl.

52. The compound of any one of claims 48-51, wherein R_1bIs H, methyl or phenyl.

53. The compound of any one of claims 48-52, wherein R₂Is H, F, Cl, Br, I, NH₂CN, OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) C_1-3Alkoxy radical, C_1-3alkylene-C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₂Independently by F, Cl, Br, I, NH₂、CN、OH、NO₂Carboxyl group, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

54. The compound of any one of claims 48-53, wherein R₂Is H, F, Cl, NH₂CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH₃、C(O)OCH₂CH₃、C(O)OCH₂CH₂CH₃、C(O)OCH(CH₃)₂、CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₂CH₃、CH₂CH₂OCH₃,C(CH₃)₂OCH₃、C(CH₃)₂OCH₂CH₃、C(CH₃)₂OCH₂CH₂CH₃5-or 6-membered heteroaryl; and each R₂Independently by F, Cl, NH₂OH, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl group contains 1,2 or 3 heteroatoms selected from N or O.

55. The compound of any one of claims 48-54, wherein R₂Is H, F, Cl, CN, methyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

56. The compound of any one of claims 48-54, wherein R₂Is H, F, Cl, CN, methyl, CD₃Ethyl, isopropyl, methoxy, CF₃、C(O)OCH₂CH₃、CH₂OH、CH₂OCH₃、

57. The compound of any one of claims 48-56, wherein R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, C (O) NH₂、S(O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, -C_l-3alkylene-NH₂、-C_l-3alkylene-N (C)_1-3Alkyl radical)₂、-C_2-3alkynyl-OH, -C_l-3alkylene-O-C_1-3Alkyl, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-OH、-C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-C_1-3Alkoxy, -C_1-3Alkylene- (O-C)_1-3Alkylene radical)_s-N(C_1-3Alkyl) -C_5-10Heteroaryl, -C_0-3alkylene-NH-C_1-3alkylene-C (O) -C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently byA plurality of R_3aSubstituted or unsubstituted.

58. The compound of any one of claims 48-57, wherein R₃Is H, F, Cl, Br, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH₂CH₂OH、C(CH₃)₂OH、CH₂NH₂、CH₂CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、CH₂N(CH₂CH₃)₂、C(CH₃)₂N(CH₃)₂、C(CH₃)₂N(CH₂CH₃)₂Ethynyl, propynyl, propargyl,

59. The compound of any one of claims 48-58, wherein s is 1,2,3, or 4.

60. The compound of any one of claims 48-59, wherein R₃Is H, F, Cl, NH₂OH, methylEthyl, isopropyl, methoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂An ethynyl group,

61. The compound of any one of claims 48-60, wherein each R_3aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

62. The compound of any one of claims 48-61, wherein each R_3aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH₂CH₂OH、CH(CH₃) OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

63. The compound of any one of claims 48-62, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, C (O) NH₂、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、

64. The compound of any one of claims 48-62, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, C (O) NH₂、C(O)N(CH₃)₂、C(O)CH₃、C(O)OCH₃、S(O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、CH₂NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N(CH₃)₂、

65. The compound of any one of claims 48-64, wherein R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂C_1-3Alkyl, P (O) (C)_1-3Alkyl radical)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

66. The compound of any one of claims 48-65, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, S (O)₂CH₃、P(O)(CH₃)₂、CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted.

67. The compound of any one of claims 48-66, wherein each R_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

68. The compound of any one of claims 48-67, wherein each R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 8-membered heterocyclic group, 3-membered carbocyclic group, 5-membered carbocyclic group or 6-membered carbocyclic group; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

69. The compound of any one of claims 48-68, wherein each R_4aIndependently of each other H, F, Cl, NH₂OH, methyl,

Or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

70. The compound of any one of claims 48-69, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, S (O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、

71. The compound of any one of claims 48-69, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, isopropyl, methoxy, S (O)₂CH₃、P(O)(CH₃)₂、CH₂OH、C(CH₃)₂OH、

72. The compound of any one of claims 48-71, wherein W₁Is H, F, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

73. The compound of any one of claims 48-72, wherein W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂CH₂OCH₃、CH₂CH₂OCH₂CH₃、CH(CH₃)OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

74. The compound of any one of claims 48-73, wherein W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, CH₂OCH₃、CH₂CH₂OCH₃、

75. The compound of any one of claims 48-73, wherein W₁Is H, F, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, CH₂OCH₃、CH₂CH₂CF₃、CH₂CH₂OCH₃、

76. The compound of any one of claims 48-75, wherein W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

77. The compound of any one of claims 48-76, wherein W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

78. The compound of any one of claims 48-77, wherein W₂Is H, F, Cl, methyl, methoxy,

79. The compound according to claim 1, wherein said compound is of formula (3):

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

each R_3aIndependently of each other H, halogen, NH₂、CN、OH、NO₂A carboxyl group、C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

z is H, or deuterium.

80. The compound of any one of claims 1-47, or 79, wherein the compound is of formula III:

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

81. The compound of claim 79, or 80, wherein R_2bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3An alkoxy group.

82. The compound of any one of claims 79-81, wherein R_2bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

83. The compound of any one of claims 79-82, wherein X₂Is O, S or NH.

84. The compound of any one of claims 79-83, wherein R₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₁Independently by F, Cl, Br, I, NH₂OH, carboxylBase, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

85. The compound of any one of claims 79-84, wherein R₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

86. The compound of any one of claims 79-85, wherein R₁Is H, F or methyl.

87. The compound of any one of claims 79-86, wherein R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

A 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 substituents selected fromN, O or S.

88. The compound of any one of claims 79-87, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

89. The compound according to any one of claims 79-88, wherein R_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

90. The compound of any one of claims 79-89, wherein R_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

91. The compound of any one of claims 79-90, wherein R₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH、

92. The compound of any one of claims 79-91, wherein R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

93. The compound of any one of claims 79-92, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

94. The compound of any one of claims 79-93, wherein each R_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

95. The compound of any one of claims 79-94, wherein R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heteroCyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O.

96. The compound of any one of claims 79-95, wherein R₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH, or

97. The compound of any one of claims 79-95, wherein R₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH、

98. The compound of any one of claims 79-97, wherein W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

99. The compound of any one of claims 79-98, wherein W is₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

100. The compound of any one of claims 79-99, wherein W₁Is H, F, Cl, methyl, methoxy,

101. The compound of any one of claims 79-99, wherein W₁Is H, F, Cl, methyl, methoxy, CH₂CH₂CF₃、

102. The compound of any one of claims 79-101, wherein W is₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

103. The compound of any one of claims 79-102, wherein W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl group contains 1,2 or 3 heteroatoms selected from N or O.

104. The compound of any one of claims 79-103, wherein W is₂Is H, F, Cl, NH₂OH, methyl, methoxy,

105. The compound according to claim 1, wherein said compound is of formula (4):

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

W₁is H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy, -C_1-6alkylene-C_1-6Alkoxy, 6-membered aryl, C_5-6Heteroaryl group, C_3-6Heterocyclyl orC_3-6A carbocyclic group; and each W₁Independently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 heteroatoms selected from N, O or S;

z is H, or deuterium.

106. The compound of any one of claims 1-47, or 105, wherein said compound is of formula IV:

wherein,

X₂is O, S or NR_2b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

107. The compound of claim 105, or 106, wherein R_2bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3An alkoxy group.

108. The compound of any one of claims 105-107, wherein R is_2bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

109. The compound of any one of claims 105-108, wherein X₂Is S or NH.

110. The compound of any one of claims 105-109, wherein R₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

111. The compound of any one of claims 105-110, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

112. The compound of any one of claims 105-111, wherein R is_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

113. The compound of any one of claims 105-112, wherein R is_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

114. The compound as claimed in any one of claims 105-113, wherein R is₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH or

115. The compound of any one of claims 105-114, wherein R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

116. The compound of any one of claims 105-115, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

117. The compound of any one of claims 105-116 wherein each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic groupHeterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

118. The compound of any one of claims 105-117, wherein R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O.

119. The compound of any one of claims 105-118, wherein R is₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH or

120. The compound as claimed in any one of claims 105-119, wherein W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

121. According to the rightThe compound of any one of claims 105-120, wherein W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

122. The compound as claimed in any one of claims 105-121, wherein W₁Is H, F, Cl, methyl, methoxy,

123. The compound as claimed in any one of claims 105-121, wherein W₁Is H, F, Cl, methyl, methoxy, CH₂CH₂CF₃、

124. The compound as claimed in any one of claims 105-123, wherein W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or notIs substituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

125. The compound as claimed in any one of claims 105-124, wherein W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

126. The compound as claimed in any one of claims 105-125, wherein W₂Is H, F, Cl, NH₂OH, methyl, methoxy,

127. The compound of claim 1, wherein said compound is of formula (5):

wherein,

X₁is CR_1aO, S or NR_1b；

R_1aIs H, halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_5-6Heteroaryl group, C_3-6Heterocyclyl or C_3-6A carbocyclic group; and each R_1aIndependently by halogen, NH₂、CN、OH、NO₂Carboxyl group, C_1-6Alkyl or C_1-6Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2,3 or 4 members selected fromN, O or S;

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

z is H, or deuterium.

128. The compound of any one of claims 1-47, or 127, wherein said compound is of formula V:

wherein,

X₁is CR_1aO, S or NR_1b；

s is 1,2,3 or 4;

Two R_3aTogether with the carbon atom to which they are attached form c (o);

Two R_4aTogether with the carbon atom to which they are attached form c (o);

129. A compound according to claim 127, or 128, wherein R_1aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

130. The compound of any one of claims 127-129 wherein R_1aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1aIndependently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein eachEach said heteroaryl or heterocyclyl group containing 1,2 or 3 heteroatoms selected from N or O.

131. The compound of any one of claims 127-130, wherein R_1bIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

132. The compound of any one of claims 127-131 wherein R_1bIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R_1bIndependently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

133. The compound of any one of claims 127-132, wherein X₁Is CH, O, S or NH.

134. The compound of any one of claims 127-133, wherein R is₃Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、C_1-3alkylene-OH, CH₂NH₂、CH(CH₃)NH₂、C(CH₃)₂NH₂、CH₂N(CH₃)₂、C(CH₃)₂N((CH₃)₂、

135. The compound of any one of claims 127-134, wherein R₃Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₃Independently by one or more R_3aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

136. The compound of any one of claims 127-135, wherein R_3aIs H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3alkylene-OH; or

Two R_3aTogether with the carbon atom to which they are attached form c (o).

137. The compound of any one of claims 127-136, wherein R_3aIs H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

138. The compound of any one of claims 127-137, wherein R₃Is H, F, Cl, NH₂OH, methyl, methoxy, C (CH)₃)₂OH or

139. The compound of any one of claims 127-138 wherein R₄Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, S (O)₂CH₃、P(O)(CH₃)₂、-C_l-3alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

140. The compound of any one of claims 127-139, wherein R₄Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OH、CH(CH₃)OH、C(CH₃)₂OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each R₄Independently by one or more R_4aSubstituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

141. The compound of any one of claims 127-140 wherein each R is_4aIndependently H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy group, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 8-membered heterocyclic group,a 3-membered, 4-membered, 5-membered or 6-membered carbocyclic group; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S; or

Two R_4aTogether with the carbon atom to which they are attached form c (o).

142. The compound as claimed in any of claims 127-141, wherein R_4aIndependently of each other H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and wherein each said heterocyclyl contains 1,2 or 3 heteroatoms selected from N or O.

143. The compound of any one of claims 127-142 wherein R₄Is H, F, Cl, NH₂OH, methyl, methoxy, CH₂OH、C(CH₃)₂OH or

144. The compound as claimed in any one of claims 127-143, wherein W₁Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, -C_1-3alkylene-C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N, O or S.

145. The compound as set forth in any one of claims 127-144,wherein W₁Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₃、C(CH₃)₂OCH₃5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₁Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

146. The compound of any one of claims 127-145 wherein W₁Is H, F, Cl, methyl, methoxy,

147. The compound of any one of claims 127-145 wherein W₁Is H, F, Cl, methyl, methoxy, CH₂CH₂CF₃、

148. The compound as set forth in any one of claims 127-147, wherein W₂Is H, F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each W₂Independently by F, Cl, Br, I, NH₂OH, carboxyl, C_1-3Alkyl or C_1-3Alkoxy substituted or unsubstituted; and wherein each of said heteroaryl groupsOr heterocyclyl contains 1,2 or 3 heteroatoms selected from N, O or S.

149. The compound of any one of claims 127-148, wherein W₂Is H, F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each W₂Independently by F, Cl, NH₂OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted or unsubstituted; and wherein each said heteroaryl or heterocyclyl group contains 1,2 or 3 heteroatoms selected from N or O.

150. The compound as defined in any one of claims 127-149, wherein W₂Is H, F, Cl, NH₂OH, methyl, methoxy,

151. The compound according to claims 1-150, wherein said compound is

152. A compound, or a pharmaceutically acceptable salt thereof, said compound being:

153. a pharmaceutical composition comprising at least one compound as defined in any one of claims 1-152 and at least one pharmaceutically acceptable excipient.

154. The pharmaceutical composition of claim 153, wherein the weight ratio of said compound to said excipient ranges from about 0.0001 to about 10.

155. A combination pharmaceutical product comprising a compound according to any one of claims 1 to 152, and one or more additional therapeutically active agents.

156. Use of a pharmaceutical composition as defined in claim 153 or 154 for the manufacture of a medicament.

157. Use according to claim 156 in the manufacture of a medicament for a disease or condition characterized by a bromodomain inhibitor.

158. The use according to claim 157, wherein said disease or condition is cancer.

159. The use of claim 158, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematological cancers.

160. The use according to claim 158 or 159, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myeloid Leukemia (AML).

161. The use according to claim 158, wherein said cancer is selected from the group consisting of acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers.

162. The use of claim 157, wherein the disease or condition is acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute nephropathy or condition, chronic nephropathy or condition, male infertility.

163. Use of at least one compound of any one of claims 1-152 for the manufacture of a medicament.

164. The use of claim 163 for the preparation of a medicament for the treatment of a disease or condition characterized by a bromodomain inhibitor.

165. The use according to claim 164, wherein the disease or condition is cancer.

166. The use of claim 165, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematological cancers.

167. The use according to claim 165 or 166, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myeloid Leukemia (AML).

168. The use according to claim 165, wherein the cancer is selected from the group consisting of acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers.

169. The use according to claim 164, wherein said disease or condition is selected from the group consisting of acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute nephropathy or condition, chronic nephropathy or condition, male infertility.

170. At least one compound as defined in any one of claims 1-152 for use in the treatment of a disease or disorder characterized by a bromodomain inhibitor.

171. Use of at least one compound as defined in any one of claims 1 to 152 in the manufacture of a medicament for use as a bromodomain inhibitor.

172. A method of treating a patient having a disease or disorder characterized by a bromodomain inhibitor, the method comprising administering to the patient a therapeutically effective amount of at least one compound as defined in any one of claims 1-152, or a pharmaceutically acceptable salt thereof.

173. The method of claim 172, wherein the disease or condition is cancer.

174. The method of claim 173, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers.

175. The method of claim 173 or 174, wherein said cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML).

176. The method of claim 173, wherein the cancer is selected from the group consisting of acoustic neuroma; acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic); acute T cell leukemia; basal cell carcinoma; bile duct cancer; bladder cancer; brain cancer; breast cancer; bronchial cancer; cervical cancer; chondrosarcoma; chordoma; choriocarcinoma; chronic leukemia; chronic lymphocytic leukemia; chronic myelogenous (granulocytic) leukemia; chronic myelogenous leukemia; colon cancer; colorectal cancer; craniopharyngioma; bladder adenocarcinoma; diffuse large B cell T cell or lymphoid malignancies of B cell origin; dysplastic changes (dysplasia and tissue deformation); an embryonic carcinoma; endometrial cancer; an endothelial sarcoma; ependymoma; epithelial cancer; erythroleukemia; esophageal cancer; estrogen receptor positive breast cancer; triple negative breast cancer; essential thrombocythemia; ewing's tumor (Ewing's tumor); fibrosarcoma; lymphoid malignancies of follicular T cell or B cell origin; germ cell testicular cancer; glioma; glioblastoma; gliosarcoma; heavy chain disease; hemangioblastoma; liver cancer; hepatocellular carcinoma; hormone insensitive prostate cancer; leiomyosarcoma; leukemia; liposarcoma; lung cancer; lymphatic endothelial cell sarcoma; lymphangioleiomyosarcoma; lymphocytic leukemia; lymphoid malignancies of T-cell or B-cell origin (lymphoid malignancies of hodgkin T-cell or B-cell origin and lymphoid malignancies of non-hodgkin T-cell or B-cell origin); malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoid malignancies of T-cell or B-cell origin; leukemia; lymphoma; medullary tumor; medulloblastoma; melanoma; meningioma; mesothelioma; multiple myeloma; myeloid leukemia; a myeloma cell; myxosarcoma; neuroblastoma; NUT Midline Carcinoma (NMC); non-small cell lung cancer; oligodendroglioma; osteogenic sarcoma; ovarian cancer; pancreatic cancer; papillary adenocarcinoma; papillary carcinoma; pineal tumor; polycythemia vera; prostate cancer; rectal cancer; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; a sarcoma; sebaceous gland cancer; seminoma; skin cancer; small cell lung cancer; solid tumors (carcinomas and sarcomas); small cell lung cancer; gastric cancer; squamous cell carcinoma; a synovial tumor; sweat gland cancer; thyroid cancer; macroglobulinemia; testicular tumors; uterine cancer; and Wilms 'tumor (Wilms' tumor); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); liver cancer; other solid tumors or other hematologic cancers.

177. The method of claim 172, wherein said disease or disorder is acquired immunodeficiency syndrome (AIDS), hypertrophy, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, hepatic lipidosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, acute kidney disease or disorder, chronic kidney disease or disorder, male infertility.

178. At least one compound as defined in any one of claims 1 to 152, or a pharmaceutically acceptable salt thereof, for use as a medicament.

179. At least one compound of any one of claims 1-152, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

180. A method of treating cancer selected from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors, or other hematologic cancers in a mammal, comprising administering to a mammal in need of such treatment an effective amount of at least one compound as defined in any one of claims 1-152, or a pharmaceutically acceptable salt thereof.