Phosphoinositide 3-kinase allosteric inhibitors for treatment of diseases associated with PI3K modulation

Abstract

The invention discloses a phosphoinositide 3-kinase allosteric inhibitor for treating diseases related to PI3K (phosphoinositide 3-kinase) regulation, and particularly provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The phosphoinositide 3-kinase allosteric inhibitor can effectively inhibit PI3K alpha mutation, especially PI3K alpha H1047R mutation in an allosteric targeting mode, has good selectivity and is expected to treat and / or prevent related diseases or obstacles.

Description

Allosteric inhibitors of phosphoinositide 3-kinase for the treatment of diseases associated with PI3K regulation

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2023110780761 filed on August 24, 2023, the benefit of priority to Chinese Patent Application No. 2024103545418 filed on March 26, 2024, and the benefit of priority to Chinese Patent Application No. 2024106506504 filed on May 23, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a phosphoinositide 3-kinase allosteric inhibitor for treating diseases related to PI3K regulation. Background Art

[0003] Phosphoinositide 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase that regulates key cellular processes, including cell growth, proliferation, differentiation, and intracellular trafficking. PI3Ks can be divided into three classes (I, II, and III), with class I being the most widely studied. Class I PI3Ks can be further divided into class IA and class IB based on signaling pathways and regulatory proteins. Class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) are located downstream of receptor tyrosine kinases (RTKs) and are heterodimeric complexes composed of the catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and the regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α). Class IB PI3Ks (PI3Kγ) are located downstream of G protein-coupled receptors (GPCRs) and are heterodimeric complexes composed of the catalytic subunit p110γ and the regulatory subunits p101 or p84. Class I PI3Ks are activated by receptor tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases. Regulatory subunits contain domains that allow for anchoring to cell surface receptors and other regulatory proteins; catalytic subunits (p110α, p110β, p110γ, and p110δ) contain ATP-binding domains. The catalytic subunits, particularly their ATP-binding sites, have been the focus of research on small-molecule PI3K inhibitors.

[0004] PI3Kα and PI3Kβ are ubiquitously expressed in the body, while PI3Kγ and PI3Kδ are primarily found in leukocytes. Dysregulation of PI3Kα and PI3Kβ is associated with the development and progression of solid tumors, while dysregulation of PI3Kγ and PI3Kδ is associated with inflammatory and immune system diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma, and hematologic malignancies.

[0005] Mutations in the gene encoding PI3Kα or mutations that lead to PI3Kα upregulation occur in many human cancers, such as lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene encoding PI3Kα are point mutations clustered within several hotspots within the helical and kinase domains, such as E542K, E545K, and H1047R. The majority of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate of PI3Kα, targeting this pathway may offer valuable therapeutic opportunities.

[0006] Due to the central role of PI3Kα in regulating glucose homeostasis, PI3Kα inhibition in patients often leads to hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin may have mitogenic and / or anti-apoptotic effects on cancer cells, thereby counteracting the antiproliferative effects of PI3K inhibitors. In the case of cancers with mutant PI3Kα, one approach to overcoming the compensatory production of insulin and / or glucose following systemic PI3Kα inhibition is to develop inhibitors that are more selective for mutant PI3Kα than wild-type PI3Kα, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

[0007] Many PI3K inhibitors currently under development (e.g., Taselisib, Buparlisib, etc.) are small molecule compounds that competitively bind to the ATP binding site to block the phosphorylation of PIP2 and the formation of PIP3. These inhibitors inhibit multiple class IA PI3K isoforms and are referred to as "pan-PI3K" inhibitors. Pan-PI3K inhibitors have certain target-related toxicities, including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their isoform selectivity. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, myelosuppression, and transaminase activity (Hanker et al., Cancer Discovery (2019) PMID: 30837161). Currently developed PI3Kα inhibitors (e.g., Alpelisib) are small molecule compounds that also bind to the ATP binding site of PI3K and are nearly equally effective against wild-type and mutant PI3Kα, with toxic side effects such as hyperglycemia. Therefore, there is still a need to continue to develop small molecule PI3Kα selective inhibitors that abandon binding to the ATP binding site of PI3K and allosterically target the inhibition of PI3Kα mutants (such as PI3KαH1047R mutation) to treat related diseases (such as cancer) while avoiding dose-limiting toxicity.

[0008] Summary of the Invention

[0009] The present invention addresses the technical problem of the single structure of existing PI3K inhibitors by providing an allosteric phosphoinositide 3-kinase inhibitor for the treatment and / or prevention of diseases or disorders associated with PI3K regulation. The allosteric phosphoinositide 3-kinase inhibitor of the present invention effectively allosterically inhibits PI3Kα mutations, particularly the PI3Kα H1047R mutation, with good selectivity and potential for the treatment and / or prevention of related diseases or disorders.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0012] in:

[0013] R 1 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 1a replace;

[0014] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0015] R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6- 10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 2a replace;

[0016] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0017] Cy 1 for

[0018] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0019] R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 7a replace;

[0020] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0021] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 8a replace;

[0022] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0023] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0024] R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4a replace;

[0025] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-a replace;

[0026] Each R 4-a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6Alkyl or -OC 1-6 alkyl;

[0027] R 4B is hydrogen, hydroxyl, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3- 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4b replace;

[0028] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11)C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-b replace;

[0029] Each R 4-b are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0030] Each R 10 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a replace;

[0031] Each R 10a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0032] Each R 11 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a replace;

[0033] Each R 11a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0034] Each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0035] Each R 5a 、R 5b 、R 5c 、R 5d 、R5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2、-S(O)R 12 、-S(O)N(R 13 )2、-S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 )2、C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0036] Each R 5-a 、R 5-b 、R 5-c 、R 5-d 、R 5-e 、R 5-f 、R 5-g 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0037] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0038] Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace;

[0039] Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0040] Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace;

[0041] Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0042] Cy 2 for

[0043] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 6a replace;

[0044] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0045] In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0046] In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0047] In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0048] And the compound shown in formula I is not the following compound:

[0049] In a certain embodiment, in the compound of Formula I or a pharmaceutically acceptable salt thereof, certain groups have the following definitions. Definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment"),

[0050] R 1 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 1a replace;

[0051] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0052] R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6- 10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 2a replace;

[0053] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0054] Cy 1 for

[0055] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0056] R 7is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 7a replace;

[0057] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0058] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 8a replace;

[0059] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6Alkyl or -OC 1-6 alkyl;

[0060] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0061] R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4a replace;

[0062] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、 -OC(O)N(R11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-a replace;

[0063] Each R 4-a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0064] R 4B is hydrogen, hydroxyl, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3- 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4b replace;

[0065] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-b replace;

[0066] Each R 4-b are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0067] Each R 10 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a replace;

[0068] Each R 10a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6Alkyl or -OC 1-6 alkyl;

[0069] Each R 11 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a replace;

[0070] Each R 11a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0071] Each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0072] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2、-S(O)R 12 、-S(O)N(R 13)2、-S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、 -N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 )2、C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5-g Substituted C 3-12Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0073] Each R 5-a 、R 5-b 、R 5-c 、R 5-d 、R 5-e 、R 5-f 、R 5-g 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0074] Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace;

[0075] Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0076] Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace;

[0077] Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0078] Cy 2 for

[0079] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 6a replace;

[0080] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0081] In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0082] In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0083] In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0084] And the compound shown in formula I is not the following compound:

[0085] In one scenario, R 1 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 1a replace;

[0086] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0087] R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6- 10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 2a replace;

[0088] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0089] Cy 1 for

[0090] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0091] R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 7a replace;

[0092] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6Alkyl or -OC 1-6 alkyl;

[0093] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 8a replace;

[0094] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0095] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0096] R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4a replace;

[0097] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-a replace;

[0098] Each R 4-a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0099] R 4B is hydrogen, hydroxyl, -N(R 9 )2、-C(O)N(R 9 )2、-C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3- 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4b replace;

[0100] Each R4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2、-S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 4-b replace;

[0101] Each R 4-b are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0102] Each R 10 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a replace;

[0103] Each R 10a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0104] Each R 11 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a replace;

[0105] Each R 11a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0106] Each R 5Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0107] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2、-S(O)R 12 、-S(O)N(R 13 )2、-S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13)2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 )2、C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0108] Each R 5-a 、R 5-b 、R 5-c 、R 5-d 、R 5-e 、R 5-f 、R 5-g 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0109] Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace;

[0110] Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0111] Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace;

[0112] Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0113] Cy 2 for

[0114] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 6a replace;

[0115] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0116] In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0117] In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0118] In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

[0119] In one scenario, R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace;

[0120] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0121] R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace;

[0122] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0123] Cy 1 for

[0124] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0125] R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace;

[0126] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0127] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0128] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0129] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0130] R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace;

[0131] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0132] R 4B is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace;

[0133] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0134] Each R 11 are independently hydrogen or C 1-6 alkyl;

[0135] Each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5csubstituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0136] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl;

[0137] Each R 5-a 、R 5-b 、R 5-c 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0138] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0139] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0140] Cy 2 for

[0141] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace;

[0142] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0143] In one scenario, R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace;

[0144] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0145] R 2 and R 3are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace;

[0146] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0147] Cy 1 for

[0148] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0149] R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace;

[0150] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0151] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0152] Each R8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0153] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0154] R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace;

[0155] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0156] R 4B is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace;

[0157] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0158] Each R 11 are independently hydrogen or C 1-6 alkyl;

[0159] Each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0160] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl;

[0161] Each R 5-a 、R 5-b 、R 5-c 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0162] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0163] Cy 2 for

[0164] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace;

[0165] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0166] In one scenario, R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace;

[0167] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0168] R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6The alkyl groups are each independently optionally substituted with one or more R 2a replace;

[0169] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0170] Cy 1 for

[0171] X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , the other is NR 7 , N, O or S;

[0172] R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace;

[0173] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0174] R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0175] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0176] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0177] R4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace;

[0178] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0179] R 4B is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace;

[0180] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0181] Each R 11 are independently hydrogen or C 1-6 alkyl;

[0182] Each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0183] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0184] Each R 5-a 、R 5-b 、R 5-c 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0185] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0186] Cy 2 for

[0187] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace;

[0188] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0189] In one scenario, R 1 is hydrogen or C 1-6 alkyl;

[0190] R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 alkyl;

[0191] Cy 1 for

[0192] X is NR 7 , N, O or S, Y is CR 8 ;

[0193] R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace;

[0194] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0195] R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0196] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC1-6 alkyl;

[0197] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0198] R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl;

[0199] R 4B For hydrogen, C 1-6 Alkyl or -N(R 9 )2, wherein said C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0200] Each R 4b are independently deuterium, halogen, cyano, -NH2 or hydroxyl;

[0201] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0202] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0203] Each R 5-a 、R 5-b 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0204] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0205] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0206] Cy 2 for

[0207] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl.

[0208] In one scenario, R 1 is hydrogen or C1-6 alkyl;

[0209] R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 alkyl;

[0210] Cy 1 for

[0211] X is NR 7 , N, O or S, Y is CR 8 ;

[0212] R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace;

[0213] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0214] R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0215] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0216] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0217] R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl;

[0218] R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0219] Each R 4b are independently deuterium, halogen, -NH2 or hydroxyl;

[0220] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0221] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0222] Each R 5-a 、R5-b 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0223] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0224] Cy 2 for

[0225] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl.

[0226] In one scenario, R 1 is hydrogen or C 1-6 alkyl;

[0227] R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 alkyl;

[0228] Cy 1 for

[0229] X is NR 7 , N, O or S, Y is CR 8 ;

[0230] R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace;

[0231] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0232] R 8For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0233] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0234] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0235] R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl;

[0236] R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0237] Each R 4b are independently deuterium, halogen, -NH2 or hydroxyl;

[0238] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0239] Each R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0240] Each R 5-a 、R 5-b 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0241] Each R 13 are independently hydrogen or C 1-6 alkyl;

[0242] Cy 2 for

[0243] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl.

[0244] In one scenario, R 1 is hydrogen or C 1-6 alkyl;

[0245] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0246] Cy 1 for

[0247] X is NR 7 , N, O or S, Y is CR 8 ;

[0248] R 7is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen;

[0249] R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0250] R 4A is hydrogen or C 1-6 alkyl;

[0251] R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0252] Each R 4b is deuterium or cyano;

[0253] Each R 5 Each independently is C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0254] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0255] Each R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0256] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0257] Cy 2 for

[0258] Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxy.

[0259] In one scenario, R 1 is hydrogen or C 1-6 alkyl;

[0260] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0261] Cy 1 for

[0262] X is NR 7 , N, O or S, Y is CR 8 ;

[0263] R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7aare independently halogen;

[0264] R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0265] R 4A is hydrogen or C 1-6 alkyl;

[0266] R 4B is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0267] Each R 4b for deuterium;

[0268] Each R 5 Each independently is C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0269] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0270] Each R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0271] Cy 2 for

[0272] Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxy.

[0273] In one scenario, R 1 is hydrogen or C 1-6 alkyl;

[0274] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0275] Cy 1 for

[0276] X is NR 7 , N, O or S, Y is CR 8 ;

[0277] R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen;

[0278] R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0279] R 4A and R 4B are independently hydrogen or C 1-6 alkyl;

[0280] Each R 5 are independently 3-12 membered heterocycloalkyl, 5csubstituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0281] Each R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0282] Each R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl;

[0283] Cy 2 for

[0284] Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxy.

[0285] In one scenario, R 1 is hydrogen;

[0286] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0287] Cy 1 for

[0288] X is S, Y is CR 8 ;

[0289] R 8 C1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0290] R 4A is hydrogen or C 1-6 alkyl;

[0291] R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0292] Each R 4b is deuterium or cyano;

[0293] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0294] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0295] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0296] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0297] Cy 2 for

[0298] Each R 6 are independently hydrogen or halogen.

[0299] In one scenario, R 1 is hydrogen;

[0300] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0301] Cy 1 for

[0302] X is S, Y is CR 8 ;

[0303] R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0304] R 4A is hydrogen or C 1-6 alkyl;

[0305] R 4B is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0306] Each R 4b for deuterium;

[0307] Each R 5 are independently one or more R 5a Substituted C 3-12Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0308] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0309] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0310] Cy 2 for

[0311] Each R 6 are independently hydrogen or halogen.

[0312] In one scenario, R 1 is hydrogen;

[0313] R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

[0314] Cy 1 for

[0315] X is S, Y is CR 8 ;

[0316] R8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen;

[0317] R 4A and R 4B are independently hydrogen or C 1-6 alkyl;

[0318] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0319] Each R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0320] Each R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl;

[0321] Cy 2 for

[0322] Each R 6 are independently hydrogen or halogen.

[0323] In one scenario, R 1 is hydrogen;

[0324] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0325] Cy 1 for

[0326] X is S, Y is CR 8 ;

[0327] R 8 C 1-6 alkyl;

[0328] R 4A is hydrogen or C 1-6 alkyl;

[0329] R 4B -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b is deuterium or cyano;

[0330] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0331] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0332] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6Alkyl, -C(O)NH2, one or more R 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0333] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0334] Cy 2 for

[0335] Each R 6 are independently hydrogen or halogen.

[0336] In one scenario, R 1 is hydrogen;

[0337] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0338] Cy 1 for

[0339] X is S, Y is CR 8 ;

[0340] R 8 C 1-6 alkyl;

[0341] R 4A is hydrogen or C 1-6 alkyl;

[0342] R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium;

[0343] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R5f substituted 5-10 membered heteroaryl;

[0344] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0345] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0346] Cy 2 for

[0347] Each R 6 are independently hydrogen or halogen.

[0348] In one scenario, R 1 is hydrogen;

[0349] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0350] Cy 1 for

[0351] X is S, Y is CR 8 ;

[0352] R 8 C 1-6 alkyl;

[0353] R 4A is hydrogen or C 1-6 alkyl;

[0354] R 4BC 1-6 alkyl;

[0355] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0356] Each R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0357] Each R 5-k Independently C 1-6 alkyl;

[0358] Cy 2 for

[0359] Each R 6 are independently hydrogen or halogen.

[0360] In one scenario, R 1 is hydrogen;

[0361] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0362] Cy 1 for

[0363] X is S, Y is CR 8 ;

[0364] R 8 C 1-6 alkyl;

[0365] R 4A is hydrogen or C 1-6 alkyl;

[0366] R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R4b Replace; each R 4b for deuterium;

[0367] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0368] Each R 5a 、R 5c 、R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0369] Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0370] Each R 5b’ Independently -OC 1-6 alkyl;

[0371] Cy 2 for

[0372] Each R 6 are independently hydrogen or halogen.

[0373] In one scenario, R 1 is hydrogen;

[0374] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0375] Cy 1for

[0376] X is S, Y is CR 8 ;

[0377] R 8 C 1-6 alkyl;

[0378] R 4A is hydrogen or C 1-6 alkyl;

[0379] R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium;

[0380] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0381] Each R 5a 、R 5c 、R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0382] Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl or -OC 1-6 alkyl;

[0383] Cy 2 for

[0384] Each R 6 are independently hydrogen or halogen.

[0385] In one scenario, R 1 is hydrogen;

[0386] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0387] Cy 1 for

[0388] X is S, Y is CR 8 ;

[0389] R 8 C 1-6 alkyl;

[0390] R 4A is hydrogen or C 1-6 alkyl;

[0391] R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium;

[0392] Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0393] Each R 5a 、R 5c 、R 5e and R 5f are each independently halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0394] Each R 5-k and R 5-j Each independently is C1-6 Alkyl or -OC 1-6 alkyl;

[0395] Cy 2 for

[0396] Each R 6 are independently hydrogen or halogen.

[0397] In one scenario, R 1 is hydrogen;

[0398] R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl;

[0399] Cy 1 for

[0400] X is S, Y is CR 8 ;

[0401] R 8 C 1-6 alkyl;

[0402] R 4A is hydrogen or C 1-6 alkyl;

[0403] R 4B C 1-6 alkyl;

[0404] Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0405] Each R 5c 、R 5e and R 5f are each independently halogen, C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0406] Each R 5-k Independently C 1-6 alkyl;

[0407] Cy2 for

[0408] Each R 6 are independently hydrogen or halogen.

[0409] In one scenario, R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace;

[0410] Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0411] In one scenario, R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace;

[0412] Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0413] In one scenario, R 7 is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace;

[0414] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0415] In one scenario, R 8is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1- 6 alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0416] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0417] In one scenario, R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace;

[0418] Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; each R 11 are independently hydrogen or C 1-6 alkyl.

[0419] In one scenario, R 4B is hydrogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace;

[0420] Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC1-6 alkyl;

[0421] Each R 11 are independently hydrogen or C 1-6 alkyl.

[0422] In one scheme, each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0423] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2、-S(O)R 12 、-S(O)N(R 13 )2、-S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13)C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 )2、C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0424] Each R 5-a 、R 5-b 、R 5-c 、R 5-d 、R 5-e 、R 5-f 、R 5-g 、R 5-h、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0425] Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace;

[0426] Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0427] Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace;

[0428] Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0429] In one scheme, each R 5 Independently C 3-12Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0430] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl;

[0431] Each R 5-a 、R 5-b 、R 5-c 、R 5-e 、R 5-h 、R 5-i 、R5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0432] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0433] Each R 13 are independently hydrogen or C 1-6 alkyl.

[0434] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0435] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, C 2-6 Alkynyl, one or more R5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0436] Each R 5-a 、R 5-b 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0437] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2;

[0438] Each R 13 are independently hydrogen or C 1-6 alkyl.

[0439] In one scenario, R 4B For hydrogen, C 1-6 Alkyl or -N(R 9 )2, wherein said C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0440] Each R 4b are independently deuterium, halogen, cyano, -NH2 or hydroxyl;

[0441] Each R 9 are independently hydrogen or C1-6 alkyl.

[0442] In one scheme, each R 5 Each independently is C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0443] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0444] Each R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0445] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2.

[0446] In one scenario, R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0447] Each R 4b It is deuterium or cyano.

[0448] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0449] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0450] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0451] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2.

[0452] In one scenario, R 4B -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b It is deuterium or cyano.

[0453] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0454] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0455] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, one or more R 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0456] Each R 5a’ and R 5b’ Each independently represents -NH2, -OC 1-6 Alkyl or -C(O)NH2.

[0457] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0458] Each R 5a 、R 5c 、R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0459] Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5b’ Replaced -OC 1-6 alkyl;

[0460] Each R 5b’ Independently -OC 1-6 alkyl.

[0461] In one scheme, each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0462] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0463] Each R 5-a 、R 5-b 、R 5-c 、R 5-h 、R 5-i 、R 5-j and R 5-kare independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0464] Each R 13 are independently hydrogen or C 1-6 alkyl.

[0465] In one scenario, Cy 2 for

[0466] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace;

[0467] Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0468] In one scenario, R 1 is hydrogen or C 1-6 alkyl.

[0469] In one scenario, R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 )2、C 1-6 Alkyl or -OC 1-6 alkyl.

[0470] In one embodiment, X is NR 7 , N, O or S, Y is CR 8 .

[0471] In one scenario, R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace;

[0472] Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6Alkyl or -OC 1-6 alkyl.

[0473] In one scenario, R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace;

[0474] Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl.

[0475] In one scenario, R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1- 6 alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxy.

[0476] In one scenario, R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b are independently deuterium, halogen, -NH2 or hydroxy.

[0477] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0478] Each R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0479] Each R 5-a 、R 5-b 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0480] Each R 13 are independently hydrogen or C 1-6 alkyl.

[0481] In one scenario, Cy 2 for

[0482] Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl.

[0483] In one scenario, R 2 and R 3 are each independently hydrogen or C 1-6 alkyl.

[0484] In one scenario, R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen.

[0485] In one scenario, R 8 is hydrogen or C1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen.

[0486] In one scenario, R 4A is hydrogen or C 1-6 alkyl.

[0487] In one scenario, R 4B is hydrogen or C 1-6 alkyl.

[0488] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0489] Each R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0490] Each R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl.

[0491] In one scenario, Cy 2 for

[0492] Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxy.

[0493] In one scenario, R 1 For hydrogen.

[0494] In a certain scheme, X is S and Y is CR 8 .

[0495] In one scenario, R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen.

[0496] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0497] Each R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0498] Each R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl.

[0499] In one scenario, Cy 2 for

[0500] Each R 6 are independently hydrogen or halogen.

[0501] In one scenario, R 2 and R 3 One is H and the other is C1-6 alkyl.

[0502] In one scenario, R 8 C 1-6 alkyl.

[0503] In one scenario, R 4B C 1-6 alkyl.

[0504] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0505] Each R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0506] Each R 5-k Independently C 1-6 alkyl.

[0507] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0508] Each R 5c 、R 5e and R 5f are each independently halogen, C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0509] Each R 5-k Independently C 1-6alkyl.

[0510] In one scheme, each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0511] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2、-S(O)R 12 、-S(O)N(R 13 )2、-S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 )2、C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0512] Each R 5-a 、R 5-b 、R 5-c 、R 5-d 、R 5-e 、R 5-f 、R 5-g 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C1-6 Alkyl or -OC 1-6 alkyl.

[0513] In one scheme, each R 5 Independently C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0514] Each R 5a 、R 5b 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl;

[0515] Each R 5-a 、R 5-b 、R 5-c 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0516] In one scheme, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0517] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 5-b Replaced -OC 1-6 Alkyl, C 2-6 Alkynyl, one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0518] Each R 5-a 、R 5-b 、R 5-e 、R 5-h 、R 5-i 、R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0519] In one scheme, each R 5 Each independently is C 3-12 Cycloalkyl, one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0520] Each R 5a 、R 5c 、R 5d 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl;

[0521] Each R5-h 、R 5-i 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0522] In one scenario, R 4B is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace;

[0523] Each R 4b For deuterium.

[0524] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0525] Each R 5a 、R 5c 、R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h substituted 3-12 membered heterocycloalkyl;

[0526] Each R 5-h 、R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0527] In one scenario, R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b For deuterium.

[0528] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0529] Each R 5a 、R 5c 、R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0530] Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl or -OC 1-6 alkyl.

[0531] In one scheme, each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl;

[0532] Each R 5a 、R 5c 、R 5e and R 5f are each independently halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 aryl;

[0533] Each R 5-k and R 5-j Each independently is C 1-6 Alkyl or -OC 1-6 alkyl.

[0534] In one embodiment, the compound represented by formula I is a compound represented by any one of the following formulas (IA) to (ID):

[0535] In one embodiment, the compound represented by formula I is a compound represented by any one of the following formulas (IE) to (IH):

[0536] In one embodiment, each of the “C 1-6 "alkyl" are each independently C 1-4 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0537] In one embodiment, each of the “C 2-6 "Alkynyl" are each independently C 2-4 Alkynyl, such as ethynyl, propynyl or propargyl, is preferably ethynyl.

[0538] In one embodiment, each of the “C 2-6 The "alkenyl" groups are each independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl.

[0539] In one embodiment, each of the “C 3-12 "Cycloalkyl" are each independently C 3-6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0540] In one embodiment, each of the “C 3-12"Cycloalkyl" are each independently C 3-6 Monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or C 4-10 Bridged cycloalkyl (e.g. ).

[0541] In one embodiment, each of the “C 3-12 "Cycloalkyl" are each independently C 3-6 Monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or C 4-10 Bridged cycloalkyl (e.g. For example ).

[0542] In one embodiment, each of the “C 3-12 "Cycloalkenyl" are each independently C 3-6 Cycloalkenyl, for example cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

[0543] In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidine, for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).

[0544] In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidine, for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).

[0545] In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidine, for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example ) or 7-10 membered bridged heterocycloalkyl (e.g. 8-azabicyclo[3.2.1]octanyl or 2-oxabicyclo[2.2.2]octanyl, for example ).

[0546] In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidine, for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example ) or 7-10 membered bridged heterocycloalkyl (e.g. 8-azabicyclo[3.2.1]octanyl, e.g. ).

[0547] In a certain embodiment, each of the "3-12 membered heterocycloalkenyl" is independently a 3-12 membered heterocycloalkenyl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heterocycloalkenyl group, for example (1,2,3,6-tetrahydropyridinyl), for example

[0548] In one embodiment, each of the “C 6-10 "Aryl" are each independently phenyl or naphthyl, preferably phenyl.

[0549] In a certain embodiment, each of the "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl or pyrrolyl, for example ) or 9-10 membered heteroaryl (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, for example For example ).

[0550] In a certain embodiment, each of the "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, for example For example ).

[0551] In a certain embodiment, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (for example, 1H-tetrazolyl, 2H-tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolinyl, for example ).

[0552] In a certain embodiment, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or 9-10 membered heteroaryl ring (for example, quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolinyl, for example ).

[0553] In one embodiment, each of the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0554] In one embodiment, each of the "deuterated C 1-6 "Alkyl" are each independently deuterated methane or deuterated ethane, for example -CD3.

[0555] In one embodiment, each of the "-OC 1-6 "alkyl" are each independently -OC 1-4 Alkyl groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy are preferred, and methoxy or ethoxy is more preferred.

[0556] In a certain embodiment, the compound shown in Formula I is not the following compound:

[0557] In one scenario, R 2 and R 3 In the formula (1), one is H and the other is methyl.

[0558] In one embodiment, X is S and Y is CCH3 or CCF3.

[0559] In one scenario, R 4A is hydrogen or methyl.

[0560] In one scenario, R 4B It is methyl, amino, -CH2CN or -CD3.

[0561] In one scenario, R 4B is methyl or -CD3.

[0562] In one scenario, R 4B It is a methyl group.

[0563] In one scheme, each R 5 are independently phenyl,

[0564] In one scheme, each R 5 are independently phenyl,

[0565] In one scheme, each R 5 are independently phenyl,

[0566] In one scheme, each R 5 are independently phenyl,

[0567] In one scenario, Cy 1 for

[0568] In one scenario, Cy 1 for

[0569] In one scenario, Cy 1 for

[0570] In one scenario, Cy 1 for

[0571] In one scenario, Cy 2 for

[0572] In one embodiment, the compound as shown in Formula I is any of the following compounds:

[0573] In some embodiments, the compound as shown in Formula I contains or does not contain a chiral center. When it contains a chiral center, the compound as shown in Formula I is a stereoisomer or a mixture thereof. For example, when it contains one chiral center, the compound as shown in Formula I is an R configuration, an S configuration, or an R, S configuration racemate.

[0574] In some embodiments, the compound as shown in Formula I is any of the following compounds:

[0575] In some embodiments, the compound as shown in Formula I is any of the following compounds:

[0576] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5′-[(1-amino-2-nitropropene)-1-thiophene]-1-thiophene: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / [ethanol (0.1% formic acid):acetonitrile = 1:1] = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm.

[0577] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5′-[(1-amino-2-nitropropene)-1-thiophene]-1-thiophene: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / [ethanol (0.1% formic acid):acetonitrile = 1:1] = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm.

[0578] The compound that elutes later under the following conditions is One stereoisomer in the: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol = 40 / 60; flow rate: 100 mL / min; detection wavelength: 214 nm;

[0579] The compound that elutes later under the following conditions is One stereoisomer in the: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol = 40 / 60; flow rate: 100 mL / min; detection wavelength: 214 nm;

[0580] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5′-[(1-amino-2-nitropropene)-1-thiophene]-1-thiophene: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / [ethanol (0.1% formic acid):acetonitrile = 1:1] = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm.

[0581] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5′-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-[1-1-2 ...

[0582] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5′-[(1-amino-2-nitropropene)-1-thiophene]-1-thiophene: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / [ethanol (0.1% formic acid):acetonitrile = 1:1] = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm.

[0583] The compound that elutes later under the following conditions is One stereoisomer in the: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm;

[0584] The compound that elutes later under the following conditions is One stereoisomer in the: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm;

[0585] The compound that elutes later under the following conditions is The following table describes the determination of one stereoisomer in the 5-mer of the 5-mer: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol = 50 / 50; flow rate: 100 mL / min; detection wavelength: 214 nm.

[0586] The present invention also provides a method for preparing the compound of formula I, which is any of the following routes:

[0587] Route 1:

[0588] Step 1: Under alkaline or neutral conditions, a condensation reaction is carried out in the presence of a condensation reagent. The operating conditions of the condensation reaction can be conventional operations and conditions for such reactions in the art. The condensation reagent can be 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI);

[0589] Step 2: performing a transposition reaction in the presence of a base. The operating conditions of the transposition reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydride or lithium bis(trimethylsilyl)amide (LiHMDS).

[0590] Step 3: performing a ring-closing reaction in the presence of an acid. The operating conditions of the ring-closing reaction may be conventional operations and conditions for such reactions in the art. The acid may be sulfuric acid or hydrobromic acid.

[0591] Step 4: a coupling reaction in the presence of a palladium catalyst, wherein the operating conditions of the coupling reaction may be conventional operations and conditions for such reactions in the art, and the palladium catalyst may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

[0592] Step 5: performing a carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride.

[0593] Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions for such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

[0594] Step 7: performing nucleophilic substitution in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be diisopropylethylamine (DIPEA) or sodium carbonate.

[0595] Step 8: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the ester hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

[0596] Route 2:

[0597] Step 1: performing an aldol reaction in the presence of a base. The operating conditions of the aldol reaction may be conventional operations and conditions for such reactions in the art. The base may be potassium hydroxide or lithium diisopropylamide (LDA).

[0598] Step 2: performing a hydroxyl group oxidation reaction in the presence of an oxidant. The operating conditions of the oxidation reaction may be conventional operations and conditions for such reactions in the art. The oxidant may be a Dess-Martin oxidant or manganese dioxide.

[0599] Step 3: performing demethylation and ring-closure reactions in the presence of an acid. The reaction conditions may be conventional operations and conditions for such reactions in the art. The acid may be a hydrobromic acid-acetic acid solution or a hydrobromic acid aqueous solution.

[0600] Step 4: performing a coupling reaction in the presence of a palladium reagent. The operating conditions of the coupling reaction may be conventional operations and conditions for such reactions in the art. The palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride.

[0601] Step 5: performing a carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride.

[0602] Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions for such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

[0603] Step 7: performing nucleophilic substitution in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be DIPEA or sodium carbonate.

[0604] Step 8: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

[0605] Route 3:

[0606] wherein P1 is a hydroxyl protecting group, such as Boc, PMB, Bn or Cbz;

[0607] Step 1: performing a nucleophilic substitution reaction in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be potassium carbonate or sodium carbonate.

[0608] Step 2: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

[0609] Step 3: carrying out an acid-amine condensation reaction in the presence of a condensing agent. The operating conditions of the condensation reaction may be conventional operations and conditions for such reactions in the art. The condensing agent may be HATU or EDCI.

[0610] Step 4: performing a nucleophilic substitution reaction in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be LDA or LiHMDS.

[0611] Step 5: performing a deprotection reaction in the presence of a deprotection reagent. The operating conditions of the deprotection reaction may be conventional operations and conditions for such reactions in the art. The deprotection reagent may be trifluoroacetic acid or hydrogen chloride.

[0612] Step 6: performing a cyclization reaction in the presence of a cyclization reagent. The operating conditions of the cyclization reaction may be conventional operations and conditions for such reactions in the art. The cyclization reagent may be trifluoromethanesulfonic anhydride or methanesulfonic anhydride.

[0613] Step 7: performing a coupling reaction in the presence of a palladium reagent. The operating conditions of the coupling reaction may be conventional operations and conditions for such reactions in the art. The palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride.

[0614] Step 8: performing a carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride.

[0615] Step 9: performing a chlorination reaction in the presence of a chlorination agent. The operating conditions of the chlorination reaction may be conventional operations and conditions for such reactions in the art. The chlorination agent may be phosphorus oxychloride or thionyl chloride.

[0616] Step 10: performing a nucleophilic substitution reaction in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be DIPEA or sodium carbonate.

[0617] Step 11: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

[0618] Route 4:

[0619] Step 1: performing a halogenation reaction in the presence of a halogenating agent. The operating conditions of the halogenation reaction may be conventional operations and conditions for such reactions in the art. The halogenating agent may be liquid bromine or N-bromosuccinimide (NBS);

[0620] Step 2: performing a urea synthesis reaction in the presence of a base. The operating conditions of the urea synthesis reaction may be conventional operations and conditions for such reactions in the art. The base may be DIPEA or potassium carbonate.

[0621] Step 3: performing a ring-closing reaction in the presence of a base. The operating conditions of the ring-closing reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium methoxide or potassium tert-butoxide.

[0622] Step 4: carrying out a nucleophilic substitution reaction in the presence of a condensing agent. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The condensing agent may be tripyrrolidinylphosphonium bromide hexafluorophosphate (Pybrop) or 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (Pybop);

[0623] Step 5: performing a coupling reaction in the presence of a palladium reagent. The operating conditions of the coupling reaction may be conventional operations and conditions for such reactions in the art. The palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride.

[0624] Step 6: performing a carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride.

[0625] Step 7: performing a chlorination reaction in the presence of a chlorination agent. The operating conditions of the chlorination reaction may be conventional operations and conditions for such reactions in the art. The chlorination agent may be phosphorus oxychloride or thionyl chloride.

[0626] Step 8: performing a nucleophilic substitution reaction in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be DIPEA or potassium carbonate.

[0627] Step 9: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

[0628] Route 5:

[0629] Step 1: performing an ester hydrolysis reaction in the presence of a hydrolysis reagent. The operating conditions of the ester hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The hydrolysis reagent may be sodium hydroxide or lithium hydroxide.

[0630] Step 2: carrying out an acid-amine condensation reaction in the presence of a condensing agent. The operating conditions of the acid-amine condensation reaction may be conventional operations and conditions for such reactions in the art. The condensing agent may be HATU or EDCI.

[0631] Step 3: performing a cyclization reaction in the presence of an oxidant. The operating conditions of the cyclization reaction may be conventional operations and conditions for such reactions in the art. The oxidant is iodine or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).

[0632] Step 4: performing a coupling reaction in the presence of a palladium reagent. The operating conditions of the coupling reaction may be conventional operations and conditions for such reactions in the art. The palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride.

[0633] Step 5: performing a carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride.

[0634] Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions for such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

[0635] Step 7: performing nucleophilic substitution in the presence of a base. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The base may be DIPEA or potassium carbonate.

[0636] Step 8: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for this type of reaction in the art. The base may be sodium hydroxide or lithium hydroxide.

[0637] The present invention also provides a compound represented by any one of the following formulas (I-1) to (I-4):

[0638] Among them, R 4A 、R 4B , X, Y are as defined above;

[0639] Preferably, each R 4A R 4B Can be methyl; X can be S; Y can be CR 8 (e.g. CCH3);

[0640] More preferably, the compound shown in formula I-1 is The compound shown in formula I-2 is The compound shown in formula I-3 is The compound shown in formula I-4 is

[0641] The present invention also provides a method for preparing the compound shown in formula I-2.

[0642] Where X is S and Y is CR 8 ;

[0643] Specifically, the steps include:

[0644] Wherein, X is a halogen atom (such as Cl, Br or I),

[0645] Step 1: performing an addition reaction in the presence of an addition reagent. The operating conditions of the addition reaction may be conventional operations and conditions for such reactions in the art. The addition reagent may be liquid bromine or chlorine gas.

[0646] Step 2: performing a cyclization reaction in the presence of a base. The operating conditions of the cyclization reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium methoxide or sodium ethoxide.

[0647] Step 3: conducting an electrophilic halogenation reaction in the presence of a halogenating agent. The operating conditions of the electrophilic halogenation reaction may be conventional operations and conditions for such reactions in the art. The halogenating agent may be liquid bromine or NBS.

[0648] Step 4: performing a methylation reaction in the presence of a methylating agent. The operating conditions of the methylation reaction may be conventional operations and conditions for such reactions in the art. The methylating agent may be methyl iodide or dimethyl sulfate.

[0649] Step 5: performing an ester reduction reaction in the presence of a reducing agent. The operating conditions of the ester reduction reaction may be conventional operations and conditions for such reactions in the art. The reducing agent may be lithium aluminum tetrahydride or borane.

[0650] Step 6: performing a hydroxyl group oxidation reaction in the presence of an oxidant. The operating conditions of the oxidation reaction may be conventional operations and conditions for such reactions in the art. The oxidant may be a Dess-Martin oxidant or manganese dioxide.

[0651] Step 7: performing a nucleophilic substitution reaction in the presence of a nucleophilic reagent. The operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art. The nucleophilic reagent may be a Grignard reagent, a lithium reagent, or a zinc reagent.

[0652] Step 8: performing a hydroxyl group oxidation reaction in the presence of an oxidant. The operating conditions of the oxidation reaction may be conventional operations and conditions for such reactions in the art. The oxidant may be a Dess-Martin oxidant or manganese dioxide.

[0653] Step 9: performing a demethylation reaction in the presence of a demethylation agent. The operating conditions of the demethylation reaction may be conventional operations and conditions for such reactions in the art. The demethylation agent may be an aqueous solution of hydrobromic acid, a hydrobromic acid-acetic acid solution, or boron tribromide.

[0654] The present invention also provides a pharmaceutical composition comprising a substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); the substance A is the compound represented by Formula I or a pharmaceutically acceptable salt thereof. The substance A may be in a therapeutically effective amount.

[0655] The present invention also provides the use of substance A or the aforementioned pharmaceutical composition in the preparation of a PI3Kα inhibitor, wherein substance A is the aforementioned compound represented by Formula I or a pharmaceutically acceptable salt thereof. In such use, the PI3Kα inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, for example, as a standard or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PI3Kα.

[0656] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or disorders related to PI3Kα regulation; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0657] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or disorders related to PI3Kα regulation; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS).

[0658] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to treat and / or prevent cancer; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

[0659] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS); the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

[0660] The present invention also provides a method for inhibiting PI3Kα, which comprises administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0661] The present invention also provides a method for treating and / or preventing a disease or disorder associated with PI3Kα regulation, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the disease or disorder associated with PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0662] The present invention also provides a method for treating and / or preventing diseases or disorders associated with PI3Kα regulation, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the disease or disorder associated with PI3Kα regulation is preferably CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS).

[0663] The present invention also provides a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0664] The present invention also provides a method for treating and / or preventing CLOVES syndrome (e.g., manifested as congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis, skeletal or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS), which comprises administering to a patient a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition; the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0665] The PI3Kα as described above is a PI3Kα mutation, preferably a PI3Kα H1047R mutation or a PI3Kα E545K mutation, more preferably a PI3Kα H1047R mutation.

[0666] In addition to the foregoing, when used in this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0667] The term "plurality" refers to 2, 3, 4 or 5.

[0668] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site. When the group R does not specify its connection site, the group R can be connected to other parts in the compound through any of its allowed connection sites; for example, 6-azaspiro[2.5]octanol It means that it can be connected to other parts of the compound through any permissible ring atom on any ring, for example, the connection point can be on a ring containing a heteroatom (such as ), or on a ring containing no heteroatoms (e.g. ).

[0669] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0670] As used herein, a "pharmaceutical composition" refers to a formulation comprising a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). This medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0671] In the present invention, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0672] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to the excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations in addition to the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0673] The term "stereoisomer" refers to cis-trans isomers or optical isomers. Cis-trans isomers are isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely, and optical isomers are stereoisomers with different optical properties caused by the lack of anti-axis symmetry in the molecule. They can be defined as (R)- / (S)- or (D)- / (L)- or (R,R)- / (R,S)- / (S,S)- based on the absolute stereochemistry of amino acids. Optically active (+) and (-), (R)- and (S)- and (R,R)- / (R,S)- / (S,S)- or (D)- and (L)- isomers can be synthesized using chiral raw materials, prepared by chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using a chiral column. In the chemical structure, the bond The configuration is not specified, i.e. if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations.

[0674] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0675] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0676] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0677] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0678] In the present invention, the term "substituted" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the position of substitution is not specified, substitution can be at any position, but only if a stable or chemically feasible chemical is formed is allowed. Examples are as follows: The structure indicates that the hydrogen atoms on ring A are replaced by p R4. When the attachment site is not specified, the substituent can be attached to the rest of the molecule through any permissible attachment site; for example, 6-azaspiro[2.5]octanyl indicates that it can be attached to the rest of the molecule through any permissible ring atom on any ring, for example, the attachment site can be on a ring containing a heteroatom (e.g. ), or on a ring containing no heteroatoms (e.g. ).

[0679] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with one or more R, then the group may be optionally substituted with at least one R, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0680] In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. 1-4 The alkyl group is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0681] In the present invention, the term "-OC 1-6 "Alkyl" refers to an alkoxy group, wherein "C 1-6 "Alkyl" is as defined above. Preferably it is an alkoxy group having 1 to 4 carbon atoms, such as methoxy or ethoxy.

[0682] In the present invention, the term "deuterated C 1-6 "Alkyl" refers to a C 1-6 On the alkyl group, one or more hydrogen atoms are replaced by deuterium atoms, such as -CD3.

[0683] In the present invention, the term "-C(O)-C 1-6 "C" in "alkyl" 1-6 "Alkyl" is as defined above, for example -C(O)-CH3, -C(O)-CH2CH3.

[0684] In the present invention, the term "C 2-6 "Alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having C2 to C6 carbon atoms, which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 Triple bond, preferably C 2-4 Alkynyl. Alkynyl includes but is not limited to: ethynyl, wait.

[0685] In the present invention, the term "C 2-6 "Alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having C2 to C6 carbon atoms, which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond, preferably C 2-4 Alkenyl. Alkenyl includes but is not limited to: vinyl, wait.

[0686] In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, and it can be connected to the rest of the molecule by a single bond via any suitable carbon atom. Such as 3-12 membered cycloalkyls having 3 to 12 carbon atoms, more preferably 3-7 membered monocyclic cycloalkyls having 3 to 7 carbon atoms (most preferably 3-6 membered monocyclic cycloalkyls having 3 to 6 carbon atoms) or 4-10 membered bridged ring cycloalkyls having 4 to 10 carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc., for example In the present invention, any ring carbon atom in the cycloalkyl group may be oxidized.

[0687] In the present invention, the term "cycloalkenyl" means a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) non-aromatic carbocyclic substituent having at least one double bond (e.g., carbon-carbon double bond), and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom; such as a 3-12 membered cycloalkenyl having 3 to 12 carbon atoms, more preferably a 3-7 membered cycloalkenyl having 3 to 7 carbon atoms, and most preferably a 3-6 membered cycloalkenyl having 3 to 6 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g., ), cyclopentadienyl (e.g. ), cyclohexenyl (e.g. ), cycloheptenyl, cyclohexadienyl, etc. In the present invention, any appropriate ring carbon atom in the cycloalkenyl group may be oxidized.

[0688] In the present invention, the term "heterocycloalkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-12, 4-6, 7-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified heteroatom species (one or more of N, O, and S), a monocyclic or polycyclic (e.g., a bicyclic, tricyclic, or more cyclic bridged, fused, or spirocyclic system), which is attached to the rest of the molecule via any suitable carbon atom or heteroatom. It can be a 4-6 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl, or a 7-10 membered bridged heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, tetrahydropyranyl, oxetanyl, azetidinyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[3.3]heptyl, 2-oxabicyclo[2.2.2]octanyl or 8-azabicyclo[3.2.1]octanyl, e.g. In the present invention, any appropriate ring atom in the heterocycloalkyl group may be substituted with oxo.

[0689] In the present invention, the term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-12, 4-6, 7-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified type of heteroatom (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 The heterocycloalkenyl group is connected to the rest of the molecule via any suitable carbon atom or heteroatom. Examples of heterocycloalkenyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridyl, for example In the present invention, any appropriate ring atom in the heterocycloalkenyl group may be oxidized.

[0690] In the present invention, the term "aryl" refers to a group having a specified number of carbon atoms (e.g., C 6-10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl, or 1,2,3,4-tetrahydronaphthyl, for example In the present invention, when a non-aromatic ring exists in the aryl group, any suitable ring carbon atom on the non-aromatic ring may be oxidized.

[0691] As used herein, the term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10, 5-6, or 9-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). The group may be monocyclic or polycyclic; in the case of polycyclic groups, two atoms and one bond are shared between each pair of monocyclic rings, and at least one ring is aromatic. The heteroaryl group is attached to the rest of the molecule via any suitable carbon atom or heteroatom; the heteroaryl group is attached to the rest of the molecule via a ring containing heteroatoms or a ring without heteroatoms; or the heteroaryl group is attached to the rest of the molecule via a ring that is aromatic or non-aromatic. It may be a 5-6-membered monocyclic heteroaryl group or a 9-10-membered polycyclic heteroaryl group. Heteroaryl includes, but is not limited to, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl, or 1,2,3,4-tetrahydroisoquinolinyl, for example. In the present invention, when a non-aromatic ring exists in the heteroaryl group, any suitable ring atom on the non-aromatic ring may be substituted with oxo.

[0692] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, especially F or Cl.

[0693] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0694] The reagents and raw materials used in the present invention are commercially available.

[0695] The positive progress of the present invention is that the phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively allosterically target and inhibit PI3Kα mutations, especially PI3Kα H1047R mutations, with good selectivity, and is expected to treat and / or prevent related diseases or disorders. DETAILED DESCRIPTION

[0696] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0697] Intermediate 1: 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester

[0698] Step: 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester

[0699] Methyl 3-hydroxy-5-methylthiophene-2-carboxylate (53 g) was synthesized using reference to patent JP05078348A. Methyl 3-hydroxy-5-methylthiophene-2-carboxylate (16 g, 93 mmol, 1.0 eq) was dissolved in acetic acid (20 mL) at room temperature, inertized, and stirred. Liquid bromine (44.6 g, 278.8 mmol, 3.0 eq) was added and allowed to react for 3 hours. The mixture was then poured into ice water (150 mL), filtered, and the filter cake washed with water, 0.5 mol / L aqueous sodium bicarbonate solution, and aqueous sodium thiosulfite solution, and dried. Recrystallization from 2-propanol afforded the pure product, methyl 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylate (19 g, 81% yield), as a pale yellow solid.

[0700] MS m / z:251.2 / 253.2[M+H] +

[0701] 1 H NMR (400 MHz, deuterated chloroform) δ 3.86 (s, 3H), 2.45 (s, 3H).

[0702] Intermediate 2: 4-bromo-3-methoxythiophene-2-carbaldehyde

[0703] Step 1: Methyl 4-bromo-3-methoxy-5-methylthiophene-2-carboxylate

[0704] Methyl 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylate (2 g, 8.0 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (DMF) (200 mL), and dimethyl sulfate (1.51 g, 12.1 mmol, 1.5 eq) and potassium carbonate (2.2 g, 16 mmol, 2.0 eq) were added. The mixture was reacted at room temperature for 1 hour. Water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to give methyl 4-bromo-3-methoxy-5-methylthiophene-2-carboxylate (1.7 g, yield 80.5%).

[0705] MS m / z:265.1 / 267.1[M+H] +

[0706] 1H NMR (400 MHz, deuterated chloroform) δ 4.03 (s, 3H), 3.88 (s, 3H), 2.43 (s, 3H).

[0707] Step 2: (4-Bromo-3-methoxy-5-methylthiophen-2-yl)methanol

[0708] To a solution of methyl 4-bromo-3-methoxy-5-methylthiophene-2-carboxylate (3 g, 11.3 mmol, 1.0 eq) in anhydrous tetrahydrofuran (15 mL) was slowly added lithium aluminum hydride (0.43 g, 11.3 mmol, 1.0 eq) at 0°C. The mixture was reacted at 0°C for 1 hour. Water (3 mL), 15% sodium hydroxide (3 mL), and water (9 mL) were slowly added. The solid was removed by filtration and the mixture was concentrated. The crude product was separated by column chromatography to give the product 4-bromo-3-methoxy-5-methylthiophene-2-methanol (2.4 g, yield 89.5%).

[0709] MS m / z:237 / 239[M+H] +

[0710] 1 H NMR (400MHz, DMSO-d6) δ5.43 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.77 (s, 3H), 2.31 (s, 3H).

[0711] Step 3: 4-Bromo-3-methoxy-5-methylthiophene-2-carbaldehyde

[0712] 4-Bromo-3-methoxy-5-methylthiophene-2-methanol (18 g, 75.9 mmol, 1.0 eq) was dissolved in dichloromethane (65 mL), and Dess-Martin oxidant (35.4 g, 83.5 mol, 1.1 eq) was added in three batches. The mixture was stirred for 2 hours and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL), extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography to give 4-bromo-3-methoxy-5-methylthiophene-2-carbaldehyde (15.1 g, yield 84.5%).

[0713] MS m / z:235 / 237[M+H] +

[0714] 1 H NMR (400 MHz, deuterated chloroform) δ 10.05 (s, 1H), 4.18 (s, 3H), 2.47 (s, 3H).

[0715] Intermediates 3-1 and 3-2: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one

[0716] Step 1: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-ol and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol

[0717] To a 100 mL three-necked flask, 4-bromo-3-methoxy-5-methylthiophene-2-carbaldehyde (1.0 g, 4.25 mmol, 1.0 eq) and THF (10 mL) were added dropwise under argon. Methylmagnesium bromide (4.25 mL, 4.3 mmol, 1.0 eq) was added dropwise at -78°C. The mixture was reacted for 0.5 h at -78°C. Water (50 mL) was added for dilution and extraction with ethyl acetate (50 mL) was performed three times. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-ol (0.95 g, 89% yield) as a yellow oil.

[0718] MS m / z:251 / 253[M+H] +

[0719] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol (0.66 g, yield 78%) was prepared using the above method as a white solid.

[0720] MS m / z:265 / 267[M+H] +

[0721] Step 2: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one (Intermediate 3-1) and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (Intermediate 3-2)

[0722] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol (19.5 g, 74 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL), and Dess-Martin oxidant (34.4 g, 81 mmol, 1.0 eq) was added in three batches. The mixture was stirred for 2 hours and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL) and extracted three times with dichloromethane (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to give the product 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (16.3 g, yield 83%).

[0723] MS m / z:263 / 265[M+H] +

[0724] 1 H NMR (400 MHz, deuterated chloroform) δ 4.02 (s, 3H), 2.96 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H).

[0725] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one (3.6 g, yield 76%) was prepared using the above method as a yellow solid.

[0726] MS m / z:249 / 251[M+H] +

[0727] Intermediates 4-1 and 4-2: 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one

[0728] step:

[0729] At room temperature, 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (13 g, 49.5 mmol, 1.0 eq) was added to HBr acetic acid solution (15 mL), heated at 120 ° C for 1 hour, concentrated to dryness under reduced pressure, and separated by column chromatography to give 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (intermediate 4-2) (11 g, yield 89.4%) as a white solid.

[0730] MS:m / z:249 / 251[M+H] +

[0731] The above method was used to prepare 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one (Intermediate 4-1) (6.3 g, yield 85%) as a white solid.

[0732] MS m / z:235 / 237[M+H] +

[0733] Example 1: 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid

[0734] Step 1: 4-Bromo-5-methyl-2-propionylthiophen-3-yl benzoate

[0735] Triethylamine (2.44 g, 24 mmol, 2.0 eq) and 4-dimethylaminopyridine (0.03 g, 0.24 mmol, 0.02 eq) were added to a solution of 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (3.0 g, 12 mmol, 1.0 eq) and benzoyl chloride (1.68 g, 12 mmol, 1.0 eq) in dichloromethane (50 mL) at 0°C. The mixture was stirred at room temperature for 4 hours. Water was added, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 4-bromo-5-methyl-2-propionylthiophen-3-yl benzoate (1.3 g, yield 91.5%) as a white solid.

[0736] MS m / z:353 / 355[M+H] +

[0737] Step 2: 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-2-methyl-3-phenylpropane-1,3-dione

[0738] Benzoic acid 4-bromo-5-methyl-2-propionylthiophen-3-yl ester (800 mg, 2.26 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (10 mL), cooled to 0°C, and 60% sodium hydrogen sulfide (210 mg, 6.80 mmol, 3.0 eq) was added. The reaction was allowed to react for 1 hour, and 1 mol / L hydrochloric acid (30 mL) was added to quench the reaction. Ethyl acetate (50 mL) was added, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was used directly in the next reaction.

[0739] MS m / z:353 / 355[M+H] +

[0740] Step 3: 3-Bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

[0741] 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-2-methyl-3-phenylpropane-1,3-dione (1.18 g, 3.4 mmol, 1.0 eq) was dissolved in anhydrous acetic acid (20 mL), and one drop of concentrated sulfuric acid was added. The mixture was reacted at 120°C for 2 hours. The reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 3-bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (884 mg, yield 79%) as a white solid.

[0742] MS m / z:335 / 336[M+H]+

[0743] Step 4: 3-Acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

[0744] 3-Bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (880 mg, 2.6 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and tributyl(1-ethoxyethylene)tin (1144 mg, 3.2 mmol, 1.2 eq), bistriphenylphosphine palladium dichloride (185 mg, 0.26 mmol, 0.1 eq) and tetrakis(triphenylphosphine)palladium (300 mg, 0.26 mmol, 0.1 eq), reacted at 100 ° C in argon system for 16 hours, 6 mol / L hydrochloric acid solution (5 mL) was added to the reaction solution, and stirring was continued for 30 minutes. The reaction solution was poured into water (50 mL), extracted twice with ethyl acetate (30 mL), and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 3-acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (597 mg, yield 76%) as a white solid.

[0745] MS m / z:299.1[M+H] +

[0746] 1 H NMR (400 MHz, deuterated chloroform) δ 7.67–7.61 (m, 2H), 7.59–7.52 (m, 3H), 2.86 (s, 3H), 2.66 (s, 3H), 2.21 (s, 3H).

[0747] Step 5: 3-(1-Hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

[0748] To a solution of 3-acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (300 mg, 1.0 mmol, 1.0 eq) in anhydrous methanol (20 mL) was added sodium borohydride (50 mg, 1.3 mol, 1.3 eq) at 0°C, the mixture was warmed to room temperature, reacted for 1 hour, and quenched by slowly adding 2.0 mol / L aqueous hydrochloric acid solution (2 mL). The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 3-(1-hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (279 mg, yield 93%) as a white solid.

[0749] MS m / z:301.1[M+H] +

[0750] 1 H NMR (400 MHz, deuterated chloroform) δ 7.65–7.59 (m, 2H), 7.54 (dt, J = 4.6, 2.9 Hz, 3H), 5.16 (q, J = 6.6 Hz, 1H), 2.60 (s, 3H), 2.32 (d, J = 13.9 Hz, 1H), 2.18 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H).

[0751] Step 6: 3-(1-chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

[0752] To a solution of 3-(1-hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (200 mg, 0.66 mmol, 1.0 eq) in dichloromethane (20 mL) was added thionyl chloride (0.5 mL) at 0°C. The mixture was warmed to room temperature and reacted for 5 hours. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to give 3-(1-chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (159 mg, yield 75%) as a white solid.

[0753] MS m / z:319 / 321[M+H] +

[0754] Step 7: Methyl 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate

[0755] 3-(1-Chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (120 mg, 0.51 mmol, 1.0 eq), potassium iodide (78.5 mg, 0.50 mmol, 1.0 eq), 18-crown-6 (124.6 mg, 0.50 mmol, 1.0 eq), methyl 2-aminobenzoate (211 mg, 1.41 mmol, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide. To the amine (10 mL), potassium carbonate (195 mg, 1.41 mmol, 3.0 eq) was added, and the reaction was carried out at 80 ° C for 16 hours. The reaction solution was diluted with water and extracted three times with ethyl acetate (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to give methyl 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate (75 mg, yield 49%) as a white solid.

[0756] MS m / z:434[M+H] +

[0757] Step 8: 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid

[0758] Methyl 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate (82.1 mg, 0.2 mmol, 1.0 eq), lithium hydroxide monohydrate (47 mg, 1.1 mmol, 5.9 eq), and water (0.5 mL) were dissolved in a mixed solution of methanol and tetrahydrofuran (4 mL, V / V=1:1), stirred at 50°C for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to preparative liquid separation to give 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid (36 mg, yield 46%) as a white solid.

[0759] MS m / z:420[M+H] +

[0760] Example 2: 2-({1-[2,6-dimethyl-5-(2-methylphenyl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0761] 2-({1-[2,6-dimethyl-5-(2-methylphenyl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (1.8 mg) was prepared as a white solid using o-methylbenzoyl chloride as starting material according to the method of Example 1.

[0762] MS m / z:434[M+H] +

[0763] Example 3: 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0764] Step 1: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one

[0765] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (150 mg, 0.5 mmol, 1.0 eq) was dissolved in a tetrahydrofuran / water = 3:2 mixed solvent (5 mL), and 2-fluorobenzaldehyde (212 mg, 1.7 mmol, 3.0 eq) and potassium hydroxide (192 mg, 3.4 mmol, 6.0 eq) were added. The mixture was heated at 30 ° C for 6 hours, cooled to room temperature, and dichloromethane (5 mL) was added. The mixture was filtered and concentrated. The residue was separated by column chromatography to give 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one (110 mg, yield 52%) as an off-white solid.

[0766] MS m / z:387 / 389[M+H] +

[0767] Step 2: 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione

[0768] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one (1.0 g, 2.6 mmol, 1.0 eq) was dissolved in ethyl acetate, and Dess-Martin oxidant (3.29 g, 7.7 mmol, 3.0 eq) was added portionwise. The mixture was stirred for 2 hours. The reaction solution was filtered and the filtrate was washed with saturated sodium bicarbonate solution (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to give 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione (710 mg, yield 71.5%).

[0769] MS m / z:385 / 387[M+H] +

[0770] Step 3: 3-Bromo-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[0771] 1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione (500 mg, 1.3 mmol, 1.0 eq) was dissolved in 40% hydrobromic acid and acetic acid solution (10 mL) and reacted at 120°C for 2 hours. The reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to give 3-bromo-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (260 mg, yield 57%) as a white solid.

[0772] MS m / z:353 / 355[M+H] +

[0773] Step 4: 3-Acetyl-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[0774] 3-Acetyl-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (162 mg, yield 79%) was prepared according to the method of step 4 of Example 1.

[0775] MS m / z:317[M+H] +

[0776] Step 5: 5-(2-Fluorophenyl)-3-(1-hydroxyethyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[0777] 5-(2-Fluorophenyl)-3-(1-hydroxyethyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (153 mg, yield 95%) was prepared according to the method of Step 5 of Example 1 as a white solid.

[0778] MS m / z:319[M+H] +

[0779] Step 6: 3-(1-chloroethyl)-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[0780] According to the method of step 6 of Example 1, 3-(1-chloroethyl)-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (134 mg, yield 78%) was prepared as a white solid.

[0781] MS m / z:337 / 339[M+H] +

[0782] Step 7: Methyl 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate

[0783] According to the method of step 7 of Example 1, methyl 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate (115 mg, yield 65%) was prepared as a white solid.

[0784] MS m / z:451[M+H] +

[0785] Step 8: 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0786] According to the method of step 8 of Example 1, 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (38 mg, yield 34%) was prepared as a white solid.

[0787] MS m / z:438[M+H] +

[0788] 1H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.31(d,J=7.2Hz,1H),7.78(dd,J=7.9,1.7Hz,1H),7.72-7.59(m,2H),7.50-7.37(m,2H),7.2 8(ddd,J=8.7,7.1,1.7Hz,1H),6.61-6.45(m,2H),4.92(q,J=6.9Hz,1H),2.64(s,3H),1.84(d,J=1.6Hz,3H),1.57(d,J=6.8Hz,3H).

[0789] Example 4: 2-({1-[5-(2,3-difluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0790] 2-({1-[5-(2,3-difluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (70 mg) was prepared using 2,3-difluorobenzaldehyde as a white solid according to the method of Example 3.

[0791] MS m / z:456[M+H] +

[0792] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.31(d,J=7.3Hz,1H),7.83–7.63(m,2H),7.44(dt,J=8.0,4.8Hz,2H),7.27(ddd,J=8.6,7.2,1.7H z,1H),6.53(ddd,J=10.3,7.9,2.0Hz,2H),4.94(t,J=7.0Hz,1H),3.35(s,1H),2.65(s,3H),1.85(d,J=1.6Hz,3H),1.57(d,J=6.8Hz,3H).

[0793] Example 5: 2-({1-[5-(2-methoxyphenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0794] 2-({1-[5-(2-methoxyphenyl)-2,6-dimethyl-7-oxyidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (44.8 mg) was prepared as a white solid using o-anisylbenzoyl chloride as the starting material according to the method of Example 1.

[0795] MS m / z:450[M+H] +

[0796] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.30(d,J=7.0Hz,1H),7.78(dd,J=7.9,1.7Hz, 1H),7.57(ddd,J=8.8,7.4,1.8Hz,1H),7.43(dd,J=7.5,1.8Hz,1H),7.29(ddd,J=8.7, 7.0,1.7Hz,1H),7.22(d,J=8.4Hz,1H),7.12(td,J=7.5,1.0Hz,1H),6.59-6.48(m,2H) ,4.90(p,J=6.9Hz,1H),3.81(s,3H),2.60(s,3H),1.76(s,3H),1.56(d,J=6.8Hz,3H).

[0797] Example 6: 2-[(1-{2,6-dimethyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid

[0798] 2-[(1-{2,6-dimethyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid (3.04 mg) was prepared as a white solid using 3-(1-methylpyrazol-4-yl)benzoyl chloride as the starting material according to the method of Example 1.

[0799] MS m / z:500[M+H] +

[0800] 1 H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.46(s,1H),8.24(s,1H),8.03-7.89(m,2H),7.85-7.72(m,2H),7.60-7.46(m,2H), 7.37-7.27(m,1H),6.66-6.46(m,2H),4.98(t,J=6.8Hz,1H),3.88(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J=6.8Hz,3H).

[0801] Preparation of 3-(1-methylpyrazol-4-yl)benzoyl chloride

[0802] 3-(1-methylpyrazol-4-yl)benzoic acid was prepared according to the method of patent WO2021066559. 3-(1-methylpyrazol-4-yl)benzoic acid was chlorinated to give 3-(1-methylpyrazol-4-yl)benzoyl chloride (446 mg) as a white solid.

[0803] Example 7: 2-({1-[5-(6-methoxypyridin-3-yl)-2,6-dimethyl-7-oxyidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0804] 2-({1-[5-(6-methoxypyridin-3-yl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid was prepared from 6-methoxypyridine-3-carbonyl chloride as a white solid according to the method of Example 1.

[0805] MS m / z:451.1[M+H] +

[0806] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=2.5Hz,1H),8.41(s,1H),8.02(dd,J=8.7,2.5Hz,1H),7.78(dd,J=8.0,1.7Hz,1H),7.32-7.24(m, 1H),7.03(d,J=8.6Hz,1H),6.63-6.48(m,2H),4.98(t,J=6.8Hz,1H),3.96(s,3H),2.64(s,3H),2.02(s,3H),1.60(d,J=6.8Hz,3H).

[0807] Example 8: 2-({1-[5-(2,3-difluorophenyl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0808] Using 2,3-difluorobenzaldehyde and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as raw materials, 2-({1-[5-(2,3-difluorophenyl)-2-methyl-7-oxyidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (0.64 mg) was prepared as a white solid according to the method of Example 3.

[0809] MS m / z:442[M+H] +

[0810] Example 9: 2-[(1-{2-methyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid

[0811] Using 3-(1-methylpyrazol-4-yl)benzoyl chloride and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as raw materials, 2-[(1-{2-methyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxyidenethieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid (12 mg) was prepared as a white solid according to the method of Example 1.

[0812] MS m / z:486[M+H] +

[0813] 1 HNMR (400MHz, DMSO-d6) δ12.72(s,1H),8.59(d,J=6.9Hz,1H),8.30(s,1H),8.25(d,J=2.0Hz,1H),8.04(s ,1H),7.92-7.85(m,1H),7.79(dd,J=7.9,1.7Hz,2H),7.57(t,J=7.8Hz,1H),7.33(ddd,J=8.7,7.1,1.7Hz, 1H), 7.21 (s, 1H), 6.66 (d, J = 8.5Hz, 1H), 6.56 (t, J = 7.5Hz, 1H), 5.10 (p, J = 6.7Hz, 1H), 3.88 (s, 3H), 2.68 (s, 3H), 1.71 (d, J = 6.8Hz, 3H).

[0814] Example 10: 2-({1-[2-methyl-5-(2-methylphenyl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0815] 2-({1-[2-methyl-5-(2-methylphenyl)-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (9.1 mg) was prepared as a white solid using 2-methylbenzoyl chloride and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as starting materials according to the method of Example 1.

[0816] MS m / z:420[M+H] +

[0817] 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.36(d,J=6.5Hz,1H),7.79(dd,J=7.9,1.7Hz,1H),7.57(dd,J=7.6,1.5Hz,1H),7.48(td,J=7.5,1.5Hz,1H),7.41 -7.35(m,2H),7.28(ddd,J=8.7,7.1,1.7Hz,1H),6.58-6.49(m,2H),6.49(s, 1H), 4.96 (t, J = 6.7Hz, 1H), 2.62 (s, 3H), 2.44 (s, 3H), 1.61 (d, J = 6.8Hz, 3H).

[0818] Example 11: 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0819] Step 1: Methyl 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylate

[0820] Methyl 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylate (5 g, 20 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (200 mL). 4-Methoxybenzyl chloride (PMBCl) (4 g, 24 mmol, 1.2 eq) and potassium carbonate (3.59 g, 26 mmol, 1.3 eq) were added sequentially. The mixture was reacted at 80°C for 1 hour. Water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography to afford methyl 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylate (4.9 g, 66% yield).

[0821] MS m / z:371 / 373[M+H] +

[0822] Step 2: 4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid

[0823] Methyl 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylate (4.6 g, 12.39 mmol, 1.0 eq) and sodium hydroxide (0.5 g, 12.39 mmol, 1.0 eq) were added to a mixture of tetrahydrofuran (9 mL), methanol (9 mL) and water (9 mL), and stirred at room temperature for 5 h. The pH was adjusted to 5 with 1.0 mol / L HCl solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to give 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid (4.1 g, yield 92%).

[0824] MS m / z:357 / 359[M+H] +

[0825] Step 3: 4-Bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide

[0826] 4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid (6.4 g, 17.9 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (DMF) (50 mL), and N,O-dimethylhydroxylamine (1.1 g, 17.92 mmol, 1.0 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added. (HATU) (10.2 g, 26.9 mmol, 1.5 eq), diisopropylethylamine (DIPEA) (5.4 g, 53.8 mmol, 3.0 eq), stirred at 30 ° C for 2 h, the reaction solution was concentrated and purified by column chromatography to give 4-bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide (4.7 g, yield 65.5%) as a white solid.

[0827] MS m / z:400 / 402[M+H] +

[0828] Step 4: 1-(4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione

[0829] Acetylpiperidine (31.8 mg, 0.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C, and 2.0 mol / L lithium bistrimethylsilylamide (0.48 mL, 3.8 eq) was slowly added. The mixture was reacted at -78 °C for 30 minutes, and 4-bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide (100 mg) was added. , 0.25mmol, 1.0eq), reacted at -78 ° C for 1h, diluted with citric acid aqueous solution (100mL), extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 1-(4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophen-2-yl)-3-(hexahydropyridine-1-yl)propane-1,3-dione (78mg, yield 65%).

[0830] MS m / z:466 / 468[M+H] +

[0831] Step 5: 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione

[0832] 1-(4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (580 mg, 1.24 mmol, 1.0 eq) was added to trifluoroacetic acid / dichloromethane (10 mL / 10 mL) at 0°C and stirred at 30°C for 1 h. The reaction solution was diluted with water (100 mL) and extracted three times with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (330 mg, 77% yield).

[0833] MS m / z:346 / 348[M+H] +

[0834] Step 6: 3-Bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

[0835] 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (130 mg, 0.37 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and trifluoromethanesulfonic anhydride (472 mg, 1.68 mmol, 4.5 eq) was added. The mixture was stirred at room temperature for 2 hours, and methanol (5 mL) was added and stirred for 1 hour. The mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give 3-bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (110 mg, 90% yield).

[0836] MS m / z:328 / 330[M+H] +

[0837] Step 7: 3-Acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

[0838] Using 3-bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (110 mg) as starting material, 3-acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (95 mg, yield 96%) was prepared according to the method of step 4 of Example 1.

[0839] MS m / z:292[M+H] +

[0840] Step 8: 5-(Hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

[0841] Using 3-acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (95 mg) as starting material, 5-(hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (89 mg, yield 94%) was prepared according to the method of Step 5 of Example 1.

[0842] MS m / z:276[M-H2O+H] +

[0843] Step 9: 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

[0844] Using 5-(hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (89 mg) as starting material, 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (68 mg, yield 72%) was prepared according to the method of Step 6 of Example 1 as a white solid.

[0845] MS m / z:312 / 314[M+H] +

[0846] Step 10: Methyl 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate

[0847] Using 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (68 mg) as starting material, methyl 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate (51 mg, 55% yield) was prepared as a white solid according to the method of Step 7 of Example 1.

[0848] MS m / z:427[M+H]

[0849] Step 11: 2-({1-[5-(Hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0850] Using methyl 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate (51 mg) as starting material, 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (6.1 mg, 12% yield) was prepared as a white solid according to the method of Step 8 of Example 1.

[0851] MS m / z:413[M+H] +

[0852] 1H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.40(d,J=6.3Hz,1H),7.79(dd,J=7.9,1.7Hz,1H),7.36-7.22(m,1H),6.68-6.38 (m,2H),5.36(s,1H),4.89(t,J=6.7Hz,1H),3.52-3.40(m,4H),2.60(s,3H),1.61-1.55(m,6H),1.21(d,J=26.6Hz,3H).

[0853] Example 12: 2-({1-[2-methyl-7-oxyylidene-5-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0854] 2-({1-[2-methyl-7-oxyylidene-5-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (5 mg) was prepared from 1,2,3,4-tetrahydroisoquinoline as a white solid according to the method of Example 12.

[0855] MS m / z:461[M+H] +

[0856] Example 13: 2-({1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)-5-fluorobenzoic acid

[0857] Using 4,4-difluorohexahydropyridine and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[5-(4,4-difluorohexahydropyridine-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)-5-fluorobenzoic acid (3 mg) was prepared as a white solid according to the method of Example 12.

[0858] MS m / z:467[M+H] +

[0859] 1H NMR (400MHz, DMSO-d6) δ13.05(s,1H),8.25(s,1H),7.51(dd,J=9.8,3.2Hz,1H),7.24(t,J=8.5Hz,1H),6.53(dd,J=9.3,4 .5Hz,1H),5.53(s,1H),4.94-4.83(m,1H),3.61(t,J=5.9Hz,4H),2.61(s,3H),2.14-1.98(m,4H),1.61(dd,J=6.8Hz,3H).

[0860] Example 14: 2-({1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0861] 2-({1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (4.5 mg) was prepared as a white solid using 4,4-difluorohexahydropyridine as the starting material according to the method of Example 12.

[0862] MS m / z:449[M+H] +

[0863] 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.84-7.74(m,1H),7.43-7.24(m,1H),6.61-6.45(m,2H),5.53(s,1 H), 4.90 (t, J = 6.8Hz, 1H), 3.62 (t, J = 5.9Hz, 4H), 2.62 (s, 3H), 2.13-2.01 (m, 4H), 1.60 (d, J = 6.1Hz, 3H).

[0864] Example 15: 2-({1-[2-methyl-5-(1,4-oxazepan-4-yl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0865] 2-({1-[2-methyl-5-(1,4-oxazepan-4-yl)-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (6.1 mg) was prepared as a white solid using morpholine as the starting material according to the method of Example 12.

[0866] MS m / z:415[M+H] +

[0867] 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.40(d,J=6.5Hz,1H),7.80(dd,J=8.0,1.7Hz,1H),7.30(t,J=7.5Hz,1H),6.63–6.48(m,2H),5 .38(s,1H),4.91(t,J=6.8Hz,1H),3.70(q,J=8.6,6.9Hz,4H),3.44(dq,J=10.7,5.2,4.6Hz,4H),2.61(s,3H),1.64(d,J=6.8Hz,3H).

[0868] Example 16: 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0869] Step 1: Methyl 3-amino-4-bromo-5-methylthiophene-2-carboxylate

[0870] Methyl 3-amino-5-methylthiophene-2-carboxylate (5.0 g, 29.2 mmol, 1.0 eq) was dissolved in acetic acid (50 mL). The reaction solution was stirred at 20°C, and N-bromosuccinimide (NBS) (5.98 g, 33.6 mmol, 1.1 eq) was added in four batches. The reaction was continued at 20°C for 1 hour. The reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted three times with ethyl acetate (80 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 3-amino-4-bromo-5-methylthiophene-2-carboxylate (5.94 g, yield 81.32%) as a white solid.

[0871] MS m / z:250.1 / 252.1[M+H] +

[0872] 1 H NMR (400 MHz, deuterated chloroform) δ 5.44 (s, 2H), 3.84 (s, 3H), 2.40 (s, 3H).

[0873] Step 2: Methyl 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylate

[0874] 3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid methyl ester (150 mg, 0.61 mmol, 1.0 eq), diisopropylethylamine (387.6 mg, 3.0 mmol, 5.0 eq), 4-dimethylaminopyridine (DMAP) (14.65 mg, 0.12 mmol, 0.2 eq) and dichloromethane (DCM) (5 mL) were stirred at 0 ° C under argon protection, and triphosgene (88.98 mg, 0 .30mmol, 0.5eq), stirred at room temperature for 0.5 hour, methylamine hydrochloride (81.0 mg, 1.20mmol, 2.0eq) was added, stirred at room temperature for 1 hour, water (50mL) was added, filtered, the filter cake was slurried with acetonitrile (10mL), filtered, and dried to give methyl 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylate (167.64 mg, yield 91%) as a white solid.

[0875] MS m / z:307 / 309[M+H] +

[0876] Step 3: 7-Bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione

[0877] Methyl 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylate (500 mg, 1.62 mmol, 1.0 eq) was dissolved in methanol (10 mL), and sodium methoxide (262 mg, 4.86 mmol, 3.0 eq) was added at 0°C. The mixture was stirred for 2 hours and concentrated. Water (20 mL) and ethyl acetate (20 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give 7-bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione (400 mg, 89% yield).

[0878] MS m / z:275 / 277[M+H] +

[0879] Step 4: 7-Bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[0880] At room temperature, 7-bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione (400 mg, 1.46 mmol, 1.0 eq) was dissolved in N`N-dimethylformamide (10 mL), and tripyrrolidinylphosphonium bromide hexafluorophosphate (Pybrop) (748 mg, 1.60 mmol, 1.1 eq) and diisopropylethylamine (DIPEA) (570 mg, 4.38 mmol, 3.0 eq) were added. The mixture was stirred at 80°C for 0.5 hour, and piperidine (248 mg, 2.92 mmol, 2.0 eq) was added. The mixture was stirred at 80°C for 1.0 hour. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and water was added. The organic phase was separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (387 mg, yield 77%) as a white solid.

[0881] MS m / z:342.1[M+H] +

[0882] 1 H NMR (400MHz, DMSO-d6) δ3.46 (s, 3H), 3.17 (t, J = 5.2Hz, 4H), 2.53 (s, 3H), 1.70-1.58 (m, 6H).

[0883] Step 5: 7-acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[0884] 7-Bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (387 mg, 1.13 mmol, 1.0 eq), tetrakistriphenylphosphine palladium (130 mg, 0.113 mmol, 0.1 eq), bistriphenylphosphine palladium dichloride (79 mg, 0.113 mmol, 0.1 eq) and tributyl(1-ethoxyethylene)tin (611 mg, 1.69 mmol, 1.5 eq) were dissolved in dioxane (10 mL) under argon protection at 100 °C. The mixture was stirred at 400 °C for 16 hours, cooled to room temperature, 2 mol / L hydrochloric acid (1.0 mL) was added, stirred for 0.5 hours, saturated potassium fluoride solution (1.0 mL) was added, stirred for 0.5 hours, the reactant was filtered through celite, the filter cake was washed three times with dichloromethane: methanol (10: 1), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product 7-acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (270 mg, yield 78%) as a white solid.

[0885] MS m / z:306.1[M+H] +

[0886] Step 6: 2-(Hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[0887] 2-(Hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (240 mg, 86% yield) was prepared as a white solid using 7-acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as the starting material according to the method of Step 5 of Example 1.

[0888] MS m / z:308.1[M+H] +

[0889] 1 H NMR (400 MHz, deuterated chloroform) δ 5.02 (q, J = 6.6 Hz, 1H), 3.59 (s, 3H), 3.17 (t, J = 5.3 Hz, 4H), 2.48 (s, 3H), 1.80–1.66 (m, 6H), 1.57 (d, J = 6.6 Hz, 3H).

[0890] Step 7: 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[0891] 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (286 mg, yield 100%) was prepared as a yellow solid using 2-(hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material according to the method of Step 6 of Example 1.

[0892] MS m / z:326.1 / 328.1[M+H] +

[0893] Step 8: Methyl 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoate

[0894] Using 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, methyl 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoate (51 mg, yield 32%) was prepared as a white solid according to the method of Step 7 of Example 1.

[0895] MS m / z:441.1[M+H] +

[0896] Step 9: 2-({1-[2-(Hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0897] 2-({1-[2-(Hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (5 mg, yield 10%) was prepared as a white solid according to the method of Step 8 of Example 1 using methyl 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoate as starting material.

[0898] MS m / z:427.1[M+H] +

[0899] 1H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.49(s,1H),7.75(dd,J=7.9,1.7Hz,1H),7.26(ddd,J=8.7,7.0,1.7Hz,1H),6.65(d, J=8.5Hz,1H),6.53–6.45(m,1H),5.02(d,J=6.8Hz,1H),3.44(s,3H),3.17(t,J=5.2Hz,4H),2.58(s,3H),1.76–1.58(m,9H).

[0900] Example 17: 2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0901] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared from 1,2,3,4-tetrahydroisoquinoline as a white solid according to the method of Example 16.

[0902] MS m / z:475.1[M+H] +

[0903] 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.69-8.54(m,1H),7.75(dd,J=8.0,1.7Hz,1H),7.24(dt,J=26.4,4.3Hz,5H),6.66(d,J=8.5Hz,1H),6.49(t,J =7.5Hz,1H),5.09-4.97(m,1H),4.61-4.44(m,2H),3.50(s,3H),3.01(dt, J=6.7,3.5Hz,2H),2.61(s,3H),1.77-1.70(m,2H),1.61(d,J=6.7Hz,3H).

[0904] Example 18: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0905] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (7 mg) was prepared from pyrrole and methyl 2-amino-5-fluorobenzoate as a white solid according to the method of Example 16.

[0906] MS m / z:431.2[M+H] +

[0907] 1 H NMR (400MHz, DMSO-d6) δ7.42(dd,J=9.7,3.3Hz,1H),7.16(td,J=8.6,3.4Hz,1H),6.64(dd,J=9.4,4.5Hz,1H),4.9 1(q,J=6.8Hz,1H),3.47(d,J=8.2Hz,4H),3.89(s,3H),3.37(s,3H),1.85(q,J=5.6Hz,4H),1.57(d,J=6.7Hz,3H).

[0908] Example 19: 2-({1-[5-(4,4-dimethylhexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0909] 2-({1-[5-(4,4-dimethylpiperidin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (12 mg) was prepared using 4,4-dimethylpiperidin-1-yl as a starting material according to the method of Example 11 as a white solid.

[0910] MS m / z:441.1[M+H] +

[0911] Example 20: 2-({1-[2-methyl-7-oxylidene-5-(6-azaspiro[2.5]octan-6-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

[0912] 2-({1-[5-(4,4-dimethylhexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (10.5 mg) was prepared as a white solid using 6-azaspiro[2.5]octane as the starting material according to the method of Example 11.

[0913] MS m / z:439.1[M+H] +

[0914] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.42(s,1H),7.79(s,1H),7.31(d,J=8.9Hz,1H),6.80-6.25(m,2H),5.48-5.30(m,1H),4.89(s,1H) ,3.68(d,J=131.9Hz,4H),2.61(s,3H),2.22-1.93(m,2H),1.61(d,J=7.0Hz,3H),1.38(d,J=22.1Hz,2H),1.24(s,2H),1.10-0.74(m,2H).

[0915] Example 21: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0916] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (10.1 mg) was prepared from pyrrole as a white solid according to the method of Example 16.

[0917] MS m / z:413.1[M+H] +

[0918] 1 H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.53(s,1H),7.75(dd,J=8.0,1.7Hz,1H),7.27(ddd,J=8.7,7.0,1.8Hz,1H),6.66(d,J=8.5Hz,1H),6.5 3-6.43(m,1H),5.00(s,1H),3.56(dtd,J=16.6,10.8,9.7,6.0Hz,4H), 3.41 (s, 3H), 2.57 (s, 3H), 1.89 (q, J = 5.8Hz, 4H), 1.62 (d, J = 6.7Hz, 3H).

[0919] Example 22: 2-({1-[2-(4,4-dimethylhexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0920] 2-({1-[2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared using 4,4-dimethylpiperidin as the starting material according to the method of Example 16 as a white solid.

[0921] MS m / z:455.1[M+H] +

[0922] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.51(d,J=8.0Hz,1H),7.75(dd,J=7.9 ,1.7Hz,1H),7.26(ddd,J=8.7,7.0,1.7Hz,1H),6.66(d,J=8.5Hz,1H),6.53-6 .42(m,1H),5.03(t,J=6.9Hz,1H),3.43(s,3H),3.20(t,J=5.7Hz,4H),2.58( s, 3H), 1.63 (d, J = 6.7Hz, 3H), 1.49 (dq, J = 19.3, 7.4, 6.6Hz, 4H), 1.01 (s, 6H).

[0923] Example 23: 2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0924] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid using 1,2,3,4-tetrahydroisoquinoline and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

[0925] MS m / z:493.2[M+H] +

[0926] 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.53(s,1H),7.46(dd,J=9.8,3.2Hz,1H),7.30-7.24(m,1H ),7.23-7.16(m,4H),6.67(dd,J=9.4,4.5Hz,1H),5.00(d,J=7.1Hz,1H),4.62-4.41(m,2H),3.59- 3.45(m,5H),3.13-2.94(m,2H),2.61(s,3H),1.60(d,J=6.8Hz,3H).

[0927] Example 24: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0928] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid using 1,2,3,6-tetrahydropyridine and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

[0929] MS m / z:443.1[M+H] +

[0930] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.37(s,1H),7.46(dd,J=9.8,3.2Hz,1H),7.21(ddd,J=9.3,7.9,3.2Hz,1H),6.68(dd,J=9.4,4.5Hz,1H),5. 93-5.79(m,2H),5.01(d,J=7.2Hz,1H),3.95-3.71(m,2H),3.44(s,3H),3 .39-3.23(m,2H),2.59(s,3H),2.42-2.22(m,2H),1.62(d,J=6.7Hz,3H).

[0931] Example 25: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0932] 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (7 mg) was prepared from 1,2,3,6-tetrahydropyridine as a white solid according to the method of Example 16.

[0933] MS m / z:425.1[M+H] +

[0934] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.54(d,J=8.3Hz,1H),7.75(dd,J=8.0,1.7Hz,1H),7 .27(ddd,J=8.6,7.1,1.8Hz,1H),6.67(d,J=8.3Hz,1H),6.54–6.45(m,1H),5.95–5.78(m,2H ),5.04(q,J=6.8Hz,1H),3.91(dt,J=17.5,2.8Hz,1H),3.77(dt,J=17.4,2.6Hz,1H),3.43( s,3H),3.40–3.24(m,3H),2.60(s,3H),2.33(q,J=18.0,17.5Hz,2H),1.63(d,J=6.7Hz,3H).

[0935] Example 26: 2-({1-[3,6-dimethyl-4-oxyidene-2-(6-azaspiro[2.5]octan-6-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0936] 2-({1-[3,6-dimethyl-4-oxyidene-2-(6-azaspiro[2.5]octan-6-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (15 mg) was prepared as a white solid using 6-azaspiro[2.5]octane as the starting material according to the method of Example 16.

[0937] MS m / z:453.1[M+H] +

[0938] 1H NMR (400MHz, DMSO-d6) δ12.50 (s, 1H), 8.48 (d, J = 8.1Hz, 1H), 7.76 (dd, J = 8.0, 1.7Hz,1H),7.26(ddd,J=8.7,7.1,1.7Hz,1H),6.65(d,J=8.5Hz,1H),6.54–6.4 5(m,1H),5.04(t,J=6.7Hz,1H),3.46(s,3H),3.25(q,J=3.6,2.8Hz,4H),2.58 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.52 (dp, J = 23.5, 6.1, 5.0 Hz, 4H), 0.38 (s, 4H).

[0939] Example 27: 2-({1-[2-(2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0940] 2-({1-[2-(2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid using 2,3-dihydro-1H-isoindole and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

[0941] MS m / z:479.2[M+H] +

[0942] 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.45(s,1H),7.47(dd,J=9.8,3.2Hz,1H),7.40(dd,J=5.6,3.2Hz,2H),7.32(dd,J=5.7,3.2Hz,2 H), 7.17 (td, J = 8.6, 3.2Hz, 1H), 6.65 (dd, J = 9.4, 4.5Hz, 1H), 5.04 (q, J = 13.7Hz, 5H), 3.57 (s, 3H), 2.56 (s, 3H), 1.62 (d, J = 6.7Hz, 3H).

[0943] Example 28: 5-Fluoro-2-({1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0944] Using 5-fluoro-2,3-dihydro-1H-isoindole and methyl 2-amino-5-fluorobenzoate as starting materials, 5-fluoro-2-({1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (25 mg) was prepared as a white solid according to the method of Example 16.

[0945] MS m / z:497.1[M+H] +

[0946] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.38(s,1H),7.45(ddd,J=19.1,9.1,4.2Hz,2H),7.27(dd,J=8.9,2.5Hz,1H),7.17(dtd, J=19.7,8.8,8.4,2.9Hz,2H),6.66(dd,J=9.4,4.5Hz,1H),5.12–4.92(m,5H),3.56(s,3H),2.57(s,3H),1.61(d,J=6.7Hz,3H).

[0947] Example 29: 6-chloro-3-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[0948] 6-Chloro-3-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (9 mg) was prepared as a white solid using 1,2,3,4-tetrahydroisoquinoline and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 16.

[0949] MS m / z:510.1[M+H] +

[0950] 1H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.68(d,J=8.5Hz,1H),7.40(d,J=9.0Hz,1H),7.31-7.24(m,2H),7.20(d,J=3.8 Hz, 3H), 5.04 (q, J = 7.3Hz, 1H), 4.61-4.42 (m, 2H), 3.50 (s, 5H), 3.10-2.94 (m, 2H), 2.62 (s, 3H), 1.61 (d, J = 6.7Hz, 3H).

[0951] Example 30: 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}benzoic acid

[0952] Step 1: 3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid

[0953] To an eggplant-shaped flask, methyl 3-amino-5-methylthiophene-2-carboxylate (8.0 g, 32.0 mmol, 1.0 eq), potassium hydroxide (5.4 g, 96.0 mmol, 3.0 eq), water (20 mL), methanol (20 mL), and tetrahydrofuran (THF) (80 mL) were added and stirred at 60°C for 14 h. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added to the residue, and the pH was adjusted to 4 with concentrated hydrochloric acid. The mixture was filtered, and the filter cake was washed once with water and dried to give 3-amino-4-bromo-5-methylthiophene-2-carboxylic acid (6.80 g, yield 90%) as a white solid.

[0954] MS m / z:235.9 / 237.9[M+1] +

[0955] Step 2: 3-Amino-4-bromo-5,N-dimethylthiophene-2-carboxamide

[0956] 3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid (6.8 g, 28.8 mmol, 1.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (13.1 g, 34.6 mmol, 1.2 eq), methylamine hydrochloride (2.9 g, 43.2 mmol, 1.5 eq), diisopropylethylamine (11.2 g, 86.4 mmol, 3.0 eq) and N,N-dimethylformamide (DMF) (60 mL), stirred at room temperature for 0.5 h under argon protection, the reaction solution was diluted with water (150 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-amino-4-bromo-5,N-dimethylthiophene-2-carboxamide (6.94 g, yield 96.71%) as a yellow solid.

[0957] MS m / z: 248.9[M+1] +

[0958] 1 H NMR (400 MHz, deuterated chloroform) δ 5.32 (s, 1H), 4.62 (s, 2H), 2.94 (s, 3H), 2.39 (s, 3H).

[0959] Step 3: 7-Bromo-3,6-dimethyl-2-phenyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[0960] 3-Amino-4-bromo-5,N-dimethylthiophene-2-carboxamide (300 mg, 1.2 mmol, 1.0 eq), benzaldehyde (192 mg, 1.8 mmol, 1.5 eq), and iodine (460 mg, 1.8 mmol, 1.5 eq) were dissolved in ethanol (10 mL) and stirred at 85 ° C for 1.0 hour. The mixture was concentrated and the residue was purified by column chromatography to give 7-bromo-3,6-dimethyl-2-phenyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (298 mg, yield 74%) as a white solid.

[0961] MS m / z:335.2 / 337.2[M+H] +

[0962] 1 H NMR (400 MHz, deuterated chloroform) δ 7.60 (dd, J = 6.7, 3.0 Hz, 2H), 7.57–7.52 (m, 3H), 3.55 (s, 3H), 2.62 (s, 3H).

[0963] Steps 4, 5, 6, 7, and 8 were prepared by referring to the method of Example 1 to obtain 2-{[1-(3,6-dimethyl-4-oxyidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}benzoic acid (4.6 mg) as a white solid.

[0964] MS m / z:420.1[M+H] +

[0965] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.47(d,J=7.7Hz,1H),7.77(td,J=7.2,2.7Hz,3H),7.58(dd,J=5.0,1.9Hz,3H),7.26(ddd,J=8 .7,7.1,1.8Hz,1H),6.61(d,J=8.5Hz,1H),6.54–6.48(m,1H),5.11(t,J=7.0Hz,1H),3.40(s,3H),2.61(s,3H),1.59(d,J=6.8Hz,3H).

[0966] Example 31: 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-5-fluorobenzoic acid

[0967] 2-{[1-(3,6-dimethyl-4-oxyidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-5-fluorobenzoic acid (15 mg) was prepared as a white solid using 2-amino-5-fluorobenzoic acid methyl ester as starting material according to the method of Example 30.

[0968] MS m / z:438.1[M+H] +

[0969] 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.30(s,1H),7.76(dd,J=6.5,3.0Hz,2H),7.58(dd,J=5.0,1.9Hz,3H),7.49(dd,J=9.8,3.2Hz,1H) ,7.20(ddd,J=9.3,8.1,3.3Hz,1H),6.61(dd,J=9.4,4.5Hz,1H),5.09(d,J=7.2Hz,1H),3.40(s,3H),2.60(s,3H),1.58(d,J=6.8Hz,3H).

[0970] Example 32: 2-({1-[2-(2-cyanophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0971] 2-({1-[2-(2-cyanophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (2 mg) was prepared as a white solid using 2-cyanobenzaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[0972] MS m / z:463.2[M+H] +

[0973] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.11(d,J=7.7Hz,1H),8.02–7.88(m,2H),7.80(td,J=7.6,1.4Hz,1H),7.48(dd, J=9.8,3.2Hz,1H),7.03(s,1H),6.52(d,J=7.6Hz,1H),5.11(s,1H),3.35(s,3H),2.59(s,3H),1.58(d,J=6.8Hz,3H).

[0974] Example 33: 2-({1-[3,6-dimethyl-4-oxyidene-2-(3-phenylazetidin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0975] 2-({1-[3,6-dimethyl-4-oxyidene-2-(3-phenylazetidin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (9 mg) was prepared as a white solid using 3-phenylazetidine hydrochloride and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

[0976] MS m / z:493.1[M+H] +

[0977] 1H NMR(400MHz, DMSO-d6)δ8.16(d,J=11.1Hz,1H),7.59-7.44(m,1H),7.37(d, J=7.4Hz,2H),7.27(p,J=6.7,6.1Hz,2H),7.21-7.02(m,1H),6.39(ddd,J=1 09.7,9.3,4.3Hz,1H),5.09(d,J=54.8Hz,1H),4.59-4.21(m,2H),3.73-3.5 7(m,2H),3.26(d,J=12.7Hz,3H),2.52(s,3H),1.61(dd,J=31.2,6.6Hz,3H).

[0978] Example 34: 2-({1-[2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0979] 2-({1-[2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (10 mg) was prepared as a white solid using 3-phenylazetidine hydrochloride and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

[0980] MS m / z:493.2[M+H] +

[0981] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.54(dd,J=9.6,3.2Hz,1H),7.21(d,J=3.1Hz,1H),6.44(dd,J=9.5,4.4Hz,1H),5.17(s,1H),4.39(d,J=10.6H z,1H),4.09(d,J=10.7Hz,1H),3.48(q,J=14.2Hz,4H),3.20(s,3H),2.79 –2.54(m,3H),2.45(s,3H),2.39(d,J=12.9Hz,1H),1.68(d,J=6.6Hz,3H).

[0982] Example 35: 5-Fluoro-2-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0983] 5-Fluoro-2-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (3 mg) was prepared as a white solid using 6-methoxypyridine-3-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[0984] MS m / z:469.1[M+H] +

[0985] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.64(d,J=2.4Hz,1H),8.36(s,1H),8.13(dd,J=8.6,2.5Hz,1H),7.48(dd,J=9.8,3.2Hz,1H),7.20(td,J= 8.6, 3.3Hz, 1H), 7.00 (d, J = 8.7Hz, 1H), 6.64 (dd, J = 9.4, 4.5Hz, 1H), 5.09 (s, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 2.62 (s, 3H), 1.59 (d, J = 6.8Hz, 3H).

[0986] Example 36: 6-chloro-3-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[0987] 6-Chloro-3-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (3 mg) was prepared as a white solid using 6-methoxypyridine-3-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[0988] MS m / z:469.1[M+H] +

[0989] 1H NMR (400MHz, DMSO-d6) δ9.87(s,1H),9.39(s,1H),8.69(s,1H),8.20(d,J=8.6Hz,1H),7.17(d,J=13.5Hz,1 H),6.99(d,J=8.7Hz,2H),5.10–4.98(m,1H),3.96(s,3H),3.47(s,3H),2.58(s,3H),1.57(d,J=6.8Hz,3H).

[0990] Example 37: 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[0991] 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (16 mg) was prepared as a white solid using 1-methylpyrazole-4-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[0992] MS m / z:459.1[M+H] +

[0993] 1 H NMR (400MHz, DMSO-d6) δ 8.61 (s, 1H), 8.20 (s, 1H), 7.15 (d, J = 74.5Hz, 3H), 5.06 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 2.60 (s, 3H), 1.59 (d, J = 6.7Hz, 3H).

[0994] Example 38: 5-Fluoro-2-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[0995] 5-Fluoro-2-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared as a white solid using 2-fluorobenzaldehyde and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 30.

[0996] MS m / z:456.1[M+H] +

[0997] Example 39: 2-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[0998] 2-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (15 mg) was prepared as a white solid using 1-methylpyrazole-4-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[0999] MS m / z:445.2[M+H] +

[1000] 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 8.49 (s, 2H), 8.19 (s, 1H), 7.48 (dd, J = 9.8, 3.2Hz, 1H), 7.21(td,J=8.7,3.3Hz,1H),6.65(dd,J=9.3,4.5Hz,1H),5.09(d,J=7.4Hz,1H),3.96(s,3H),3.69(s,3H),2.62(s,3H),1.61(d,J=6.7Hz,3H).

[1001] Example 40: 6-chloro-3-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1002] 6-Chloro-3-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (4 mg) was prepared as a white solid using 2-fluorobenzaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[1003] MS m / z:473.2[M+H] +

[1004] 1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.37(s,1H),7.81(s,1H),7.73–7.64(m,1H),7.52–7.41(m,2H ),7.13(s,1H),6.96(s,1H),5.04(t,J=7.1Hz,1H),3.35(s,3H),2.58(s,3H),1.56(d,J=6.7Hz,3H).

[1005] Example 41: 6-chloro-3-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1006] 6-Chloro-3-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (16 mg) was prepared as a white solid using 5-fluoropyridine-3-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[1007] MS m / z:474.2[M+H] +

[1008] 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.81(d,J=2.8Hz,1H),8.63(d,J=8.2Hz,1H),8.21(d,J=9. 5Hz,1H),7.40(d,J=8.9Hz,1H),7.24(d,J=9.0Hz,1H),5.13(t,J=7.3Hz,1H),3.42(s,3H),2.65 (s,3H),1.60(d,J=6.7Hz,3H).

[1009] Example 42: 5-Fluoro-2-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[1010] 5-Fluoro-2-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (21 mg) was prepared as a white solid using 5-fluoropyridine-3-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials according to the method of Example 30.

[1011] MS m / z:457.2[M+H] +

[1012] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.87(d,J=2.0Hz,1H),8.81(d,J=2.8Hz,1H),8.46(s,1H),8.22(dt,J=9.6,2.4Hz,1H),7.48(dd,J=9 .8, 3.2Hz, 1H), 7.16 (d, J = 3.2Hz, 1H), 6.60 (dd, J = 9.4, 4.5Hz, 1H), 5.08 (d, J = 7.0Hz, 1H), 3.43 (s, 3H), 2.63 (s, 3H), 1.58 (d, J = 6.7Hz, 3H).

[1013] Example 43: 2-({1-[3,6-dimethyl-2-(1-methylindazol-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[1014] 2-({1-[3,6-dimethyl-2-(1-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (7 mg) was prepared as a white solid using 1-methylindazole-5-carbaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[1015] MS m / z:492.2[M+H] +

[1016] 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),8.38(s,1H),8.29–8.18(m,2H),7.84–7.73(m,2H),7.51(dd,J=9.8,3.2Hz,1H),7.20(ddd,J=11 .2,8.1,3.2Hz,1H),6.62(dd,J=9.4,4.5Hz,1H),5.09(d,J=7.0Hz,1H),4.13(s,3H),3.45(s,3H),2.61(s,3H),1.58(d,J=6.9Hz,3H).

[1017] Example 44: 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylindazol-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1018] 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (6 mg) was prepared as a white solid using 1-methylindazole-5-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[1019] MS m / z:509.2[M+H] +

[1020] 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.09(s,1H),8.23(d,J=13.0Hz,2H),7.81(d,J=2.0Hz,2H),7.18(d,J=3 0.0Hz,1H),7.03(s,1H),5.08(d,J=6.6Hz,1H),4.12(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J=6.5Hz,3H).

[1021] Example 45: 2-({1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[1022] 2-({1-[3,6-dimethyl-2-(2-methylindazole-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid using 2-methylindazole-5-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[1023] MS m / z:492.2[M+H] +

[1024] 1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.54(s,1H),8.39(s,1H),8.21–8.12( m,1H),7.74(d,J=9.0Hz,1H),7.58(dd,J=9.0,1.7Hz,1H),7.51(dd,J=9.8,3 .2Hz,1H),7.19(td,J=8.6,3.2Hz,1H),6.61(dd,J=9.4,4.5Hz,1H),5.09(d, J=7.2Hz,1H),4.23(s,3H),3.45(s,3H),2.60(s,3H),1.58(d,J=6.7Hz,3H).

[1025] Example 46: 5-Fluoro-2-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid

[1026] Using 1-(2-methoxyphenyl)pyrazole-4-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials, 5-fluoro-2-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid (30 mg) was prepared as a white solid according to the method of Example 30.

[1027] MS m / z:534.2[M+H] +

[1028] 1 H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.88(s,1H),8.54(s,1H),8.47(s,1H) ,7.71(dd,J=7.9,1.6Hz,1H),7.55–7.40(m,2H),7.31(d,J=8.3Hz,1H),7.23( td,J=8.7,3.2Hz,1H),7.19–7.10(m,1H),6.70(dd,J=9.4,4.5Hz,1H),5.11(d ,J=7.2Hz,1H),3.89(s,3H),3.74(s,3H),2.64(s,3H),1.65(d,J=6.7Hz,3H).

[1029] Example 47: 6-Chloro-3-({1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1030] 6-Chloro-3-({1-[3,6-dimethyl-2-(2-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (11 mg) was prepared as a white solid using 2-methylindazole-5-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[1031] MS m / z:509.2[M+H] +

[1032] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.53(s,1H),8.19(s,1H),7.73(d,J=9.0Hz,1H),7.59(d,J=9.0Hz,1H),7 .19(d,J=34.3Hz,1H),7.01(s,1H),5.07(s,1H),4.23(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J=6.7Hz,3H).

[1033] Example 48: 6-Chloro-3-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1034] 6-Chloro-3-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (6 mg) was prepared as a white solid using 1-(2-methoxyphenyl)pyrazole-4-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[1035] MS m / z:551.2[M+H] +

[1036] 1H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.50(s,1H),8.18(s,1H),7.70(d,J=7.8Hz,1H),7.46(t,J=7.9Hz,1H),7.3 9–7.27(m,2H),7.14(t,J=7.8Hz,2H),5.10(s,1H),3.90(s,3H),3.74(s,3H),2.62(s,3H),1.63(d,J=6.7Hz,3H).

[1037] Example 49: 3-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid

[1038] Using benzo[d][1,3]dioxolan-5-carbaldehyde and methyl 3-amino-6-chloropyridine-2-carboxylate as starting materials, 3-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid (6 mg) was prepared as a white solid according to the method of Example 30.

[1039] MS m / z:499.2[M+H] +

[1040] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),7.42(s,1H),7.30(d,J=8.0Hz,1H),7.17(d,J=11.3Hz,1H),7.08(d,J=8.1Hz ,1H),6.97(d,J=8.5Hz,1H),6.14(s,2H),5.05(t,J=7.1Hz,1H),3.43(s,3H),2.55(s,3H),1.56(d,J=6.4Hz,3H).

[1041] Example 50: 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylindazol-6-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1042] 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (31 mg) was prepared as a white solid using 1-methylindazole-6-carbaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[1043] MS m / z:509.2[M+H] +

[1044] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.16(d,J=11.6Hz,2H),7.92(d,J=8.5Hz,1H),7.49(d,J=8 .4Hz,1H),7.27(d,J=67.5Hz,2H),5.09(s,1H),4.17(s,3H),2.64(s,3H),1.57(d,J=6.6Hz,3H).

[1045] Example 51: 2-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[1046] 2-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (6 mg) was prepared as a white solid using benzo[d][1,3]dioxolan-5-carbaldehyde and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 30.

[1047] MS m / z:482.2[M+H] +

[1048] 1H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.33(s,1H),7.49(dd,J=9.8,3.2Hz,1H),7.37(d,J=1.7Hz,1H),7.26(dd,J=8.1,1.8Hz,1H),7.19(ddd,J=9.2,8 .1,3.2Hz,1H),7.09(d,J=8.1Hz,1H),6.61(dd,J=9.3,4.5Hz,1H),6.15(s, 2H), 5.08 (d, J = 7.1Hz, 1H), 3.43 (s, 3H), 2.59 (s, 3H), 1.58 (d, J = 6.8Hz, 3H).

[1049] Example 52: 2-({1-[3,6-dimethyl-2-(2-methylindazol-6-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[1050] 2-({1-[3,6-dimethyl-2-(2-methylindazole-6-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (8 mg) was prepared as a white solid using 2-methylindazole-6-carbaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[1051] MS m / z:492.2[M+H] +

[1052] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.43–8.22(m,1H),8.04(s,1H),7.88(d,J=8.6Hz,1H),7.50(dd,J=9.8,3.2Hz,1H),7.36(dd,J=8.6,1.4H z,1H),7.19(d,J=2.4Hz,1H),6.62(dd,J=9.4,4.5Hz,1H),5.11(d,J=7.2Hz,1H),4.24(s,3H),3.45(s,3H),2.59(s,3H),1.59(d,J=6.7Hz,3H).

[1053] Example 53: 6-Chloro-3-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1054] 6-Chloro-3-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (11 mg) was prepared as a white solid using 3-fluoropyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[1055] MS m / z:474.2[M+H] +

[1056] 1 H NMR (400MHz, DMSO-d6) δ9.35(s,1H),8.65(d,J=4.6Hz,1H),8.07(t,J=9.1Hz,1H),7.78(dt,J=8.7,4.4Hz,1H),7. 08(d,J=8.6Hz,1H),6.89(d,J=8.7Hz,1H),5.05(p,J=6.8Hz,1H),3.40(s,3H),2.57(s,3H),1.56(d,J=6.8Hz,3H).

[1057] Example 54: 5-Fluoro-2-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[1058] 5-Fluoro-2-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (19 mg) was prepared as a white solid using 3-fluoropyridine-2-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[1059] MS m / z:457.2[M+H] +

[1060] 1H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.63(dt,J=4.7,1.4Hz,1H),8.33(s,1H),8.05(ddd,J=9.8,8.6,1.3Hz,1H),7.77(dt,J=8.6,4.4Hz,1H),7. 48(dd,J=9.8,3.2Hz,1H),7.10(td,J=8.6,3.2Hz,1H),6.53(dd,J=9.4,4 .5Hz,1H),5.07(s,1H),3.38(s,3H),2.61(s,3H),1.57(d,J=6.8Hz,3H).

[1061] Example 55: 6-chloro-3-({1-[3,6-dimethyl-2-(2-methylindazol-6-yl)-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1062] 6-Chloro-3-({1-[3,6-dimethyl-2-(2-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (2 mg) was prepared as a white solid using 2-methylindazole-6-carbaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[1063] MS m / z:509.2[M+H] +

[1064] Example 56: 2-({1-[3,6-dimethyl-2-(1-methylindazol-6-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

[1065] 2-({1-[3,6-dimethyl-2-(1-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (11 mg) was prepared as a white solid using 1-methylindazole-6-carbaldehyde and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 30.

[1066] MS m / z:492.2[M+H] +

[1067] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.19(s,1H),8.12–8.03(m,1H),7.93(d,J=8.3Hz,1H),7.58–7.44(m,2H),7.23–7.13 (m,1H),6.63(dd,J=9.3,4.5Hz,1H),5.09(d,J=7.0Hz,1H),4.14(s,3H),3.43(s,3H),2.62(s,3H),1.58(d,J=6.7Hz,3H).

[1068] Example 57: 6-chloro-3-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1069] 6-Chloro-3-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (7 mg) was prepared as a white solid using 1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 30.

[1070] MS m / z:494.2[M+H] +

[1071] 1 H NMR (400MHz, DMSO-d6) δ8.43(dd,J=4.7,1.7Hz,1H),8.15(dd,J=8.0,1.6Hz,1H),7.50(dd,J=9.9,3.3Hz,1H),7.29(d,J= 2.1Hz,1H),7.25–7.02(m,2H),6.70(dd,J=9.4,4.5Hz,1H),5.38(s,1H),3.81(s,3H),2.58(s,3H),1.60(d,J=6.8Hz,3H).

[1072] Example 58: 5-Fluoro-2-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

[1073] 5-Fluoro-2-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (3 mg) was prepared as a white solid using 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials according to the method of Example 30.

[1074] MS m / z:478.2[M+H] +

[1075] Example 59: 6-chloro-3-[(1-{2-[1-(3-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1076] Using 3-(4-formylpyrazol-1-yl)benzene-1-carbonitrile and methyl 3-amino-6-chloropyridine-2-carboxylate as starting materials, 6-chloro-3-[(1-{2-[1-(3-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid according to the method of Example 30.

[1077] MS m / z:546.2[M+H] +

[1078] 1 H NMR(400MHz, DMSO-d6)δ9.32(s,1H),8.81(s,1H),8.58(d,J=9.8Hz,1H),8.53(d,J=10.6Hz,1H),8.37(d,J=8.0Hz,1H),7.97–7.86(m,1H),7.80 (t,J=8.0Hz,1H),7.42(d,J=8.8Hz,1H),7.29(d,J=9.0Hz,1H),5.16(t,J=7.4Hz,1H),3.78(d,J=2.9Hz,3H),2.66(s,3H),1.64(d,J=6.7Hz,3H).

[1079] Example 60: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1-methylpyrazol-4-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1080] 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (8 mg) was prepared as a white solid using 4-(1-methylpyrazol-4-yl)benzoyl chloride and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 1.

[1081] MS m / z:535.2[M+H] +

[1082] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.99(s,1H),7.78–7.64(m,4H),7.38(d,J=8.9Hz,1H),7.12(d ,J=9.0Hz,1H),5.00(t,J=6.8Hz,1H),3.90(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J=6.7Hz,3H).

[1083] Example 61: 6-Chloro-3-[(1-{2,6-dimethyl-5-[6-(1-methylpyrazol-4-yl)pyridin-3-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1084] 6-Chloro-3-[(1-{2,6-dimethyl-5-[6-(1-methylpyrazol-4-yl)pyridin-3-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared as a white solid using 6-(1-methylpyrazol-4-yl)pyridine-3-carbonyl chloride and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 1.

[1085] MS m / z:536.2[M+H] +

[1086] Example 62: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(3-methyl-1,2,4-oxadiazacyclopentyl)phenyl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1087] 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)phenyl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (4 mg) was prepared as a white solid using 4-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)benzene-1-carbaldehyde and methyl 3-amino-6-chloropyridine-2-carboxylate as starting materials according to the method of Example 30.

[1088] MS m / z:537.2[M+H] +

[1089] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.26(d,J=7.8Hz,2H),8.06(d,J=8.0Hz,2H),7.42–7.34(m,1H),7.27 –7.19(m,1H),6.90(s,1H),5.08–5.01(m,1H),3.43(s,3H),2.59(s,3H),2.47(s,3H),1.57(d,J=6.7Hz,3H).

[1090] Example 63: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1091] Step 1: 7-Acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[1092] Using 5-methyl-2-(piperazin-1-yl)pyrimidine as starting material, 7-acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (449 mg) was prepared as a yellow solid according to the method of Example 16.

[1093] MS m / z:399.3[M+H] +

[1094] 1H NMR (400MHz, DMSO-d6) δ8.22(s,2H),4.04–3.96(m,4H),3.67(s,3H),3.37–3.29(m,4H),2.80(s,6H),2.17(s,3H).

[1095] Step 2: 7-(1-aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[1096] 7-Acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (260 mg, 0.65 mmol, 1.0 eq) was dissolved in isopropanol (10 mL), and ammonium acetate (503 mg, 6.5 mmol, 10.0 eq) and sodium cyanoborohydride (82 mg, 1.3 mmol, 2.0 eq) were added. The mixture was protected by argon and reacted at 85 ° C for 5 hours, and then cooled to room temperature. The reaction mixture was heated to 40 ℃ and diluted with water (50 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-(1-aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (115 mg, yield 44.1%) as a white solid.

[1097] MS m / z:400.3[M+H] +

[1098] Step 3: Methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate

[1099] 7-(1-Aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (500 mg, 1.25 mmol, 1.0 eq) was dissolved in DMSO (10 mL), and methyl 6-chloro-3-fluoropyridine-2-carboxylate (285 mg, 1.5 mmol, 1.0 eq) and diisopropylethylamine (DIPEA) (323 mg, 2.5 mmol, 2.0 eq) were added. The mixture was reacted at 120 °C for 5 hours under argon protection. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate (567 mg, yield 79.61%) as a yellow solid.

[1100] MS m / z:569.3[M+H] +

[1101] Step 4: 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1102] Methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate (567 mg, 1.00 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide monohydrate (83 mg, 1.99 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 3 hours, and the pH was adjusted to 1 mol / L hydrochloric acid. 7, the reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (345 mg, yield 62.3%) as a white solid.

[1103] MS m / z:555.2[M+H] +

[1104] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.19–6.98(m,2H),4.92(s,1H),3.90(s,7H),3.46(s,3H),3.28(s,4H),2.06(s,3H),1.56(d,J=8.3Hz,3H).

[1105] Example 64: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1106] 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (11 mg) was prepared as a yellow solid using 2-methyl-5-(piperazin-1-yl)pyrazine as the starting material and referring to the method of Example 63.

[1107] MS m / z:555.2[M+H] +

[1108] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.44(s,1H),8.29(s,1H),8.04(s,1H),7.22(s,1H),7.08(d,J=8.3Hz,1H),5.00(t,J=7.5Hz ,1H),4.16(s,1H),3.70(d,J=9.3Hz,4H),3.51(s,3H),3.39(q,J=6.9,6.3Hz,4H),2.57(s,3H),2.34(s,3H),1.61(d,J=6.7Hz,3H).

[1109] Example 65: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1110] 6-Chloro-3-[(1-{3,6-dimethyl-4-oxyylidene-2-[4-(pyrimidin-2-yl)piperazin-1-yl]thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (25 mg) was prepared as a white solid using 2-(piperazin-1-yl)pyrimidine as the starting material and referring to the method of Example 63.

[1111] MS m / z:541.2[M+H] +

[1112] 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.55(d,J=214.4Hz,1H),8.41(d,J=4.7Hz,2H),7.17(s,1H),7.02(d,J=8.7Hz,1H),6.68(t ,J=4.7Hz,1H),4.99(s,1H),3.94(dt,J=13.3,7.7Hz,4H),3.51(s,3H),3.35(t,J=5.2Hz,4H),2.55(s,3H),1.59(d,J=6.7Hz,3H).

[1113] Example 66: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1114] 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (81 mg) was prepared as a yellow solid using 6-methyl-2-(piperazin-1-yl)pyrazine as the starting material and referring to the method of Example 63.

[1115] MS m / z:555.2[M+H] +

[1116] 1H NMR (400MHz, DMSO-d6) δ12.94(s,1H),9.19(s,1H),8.18(s,1H),7.79(s,1H),7.28(s,1H),7.15(d,J=8.8Hz,1H),5.02( t,J=7.4Hz,1H),3.74(q,J=6.1Hz,4H),3.51(s,3H),3.42–3.34(m,4H),2.58(s,3H),2.33(s,3H),1.62(d,J=6.7Hz,3H).

[1117] Example 67: 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1118] Step 1: Methyl 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylate

[1119] 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (220 mg) was prepared as a yellow solid using 1-(oxyylidenemethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester as the starting material and referring to the method of Example 30.

[1120] MS m / z:347.2[M+H] +

[1121] Step 2: 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid

[1122] Methyl 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylate (220 mg, 0.64 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL) and water (4 mL), and lithium hydroxide monohydrate (53 mg, 1.27 mmol, 2.0 eq) was added. The mixture was reacted at 50 ° C for 3 hours, and the pH was adjusted with 1 mol / L hydrochloric acid. The reaction solution was diluted with water (50 mL), extracted three times with dichloromethane (20 mL), and the organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-(7-acetyl-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (209 mg, yield 99%) as a white solid.

[1123] MS m / z:333.2[M+H] +

[1124] Step 3: O-{[1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}-N-(1-azinylideneethyl)hydroxylamine

[1125] 1-(7-Acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (200 mg, 0.6 mmol, 1.0 eq) was dissolved in dioxane (10 mL), and N-(1-nitroylideneethyl)hydroxylamine (53 mg, 0.72 mmol, 1.2 eq), diisopropylethylamine (DIPEA) (233 mg, 1.8 mmol, 3.0 eq) and tripyrrolidinium phosphonium bromide hexafluorophosphate (336 mg, 0.72 mmol, 1.2 eq) were added. The mixture was reacted at 50°C for 5 hours under argon protection, cooled to room temperature, and diluted with saturated aqueous sodium bicarbonate (50 mL). The reaction solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction.

[1126] MS m / z:389.2[M+H] +

[1127] Step 4: 7-acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[1128] O-{[1-(7-acetyl-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}-N-(1-nitrogenylideneethyl)hydroxylamine (230 mg, 0.6 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (0.6 mL, 0.6 mmol, 1.0 eq) was added. The mixture was reacted at room temperature for 5 hours. The reaction solution was diluted with water (50 mL) and ethyl acetate was added. The mixture was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (219 mg, yield 99%) as a white solid.

[1129] 1 H NMR (400MHz, DMSO-d6) δ3.78(s,3H),2.87(s,6H),2.84(s,3H),2.82(s,3H),2.44(s,3H).

[1130] Step 5: 7-(1-aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

[1131] 7-Acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (110 mg, 0.3 mmol, 1.0 eq) was dissolved in isopropanol (10 mL), and ammonium acetate (229 mg, 2.97 mmol, 10.0 eq) and sodium cyanoborohydride (37 mg, 0.59 mmol, 2.0 eq) were added. The mixture was protected by argon and reacted at 85 ° C for 5 hours. Then, the mixture was cooled. The mixture was cooled to room temperature, and water (50 mL) was added to dilute the reaction solution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-(1-aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (53 mg, yield 48.1%) as a yellow solid.

[1132] MS m / z:372.3[M+H] +

[1133] Step 6: 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxoylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester

[1134] 7-(1-Aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (53 mg, 0.14 mmol, 1.0 eq) was dissolved in DMSO (6 mL), and methyl 6-chloro-3-fluoropyridine-2-carboxylate (33 mg, 0.17 mmol, 1.1 eq) and diisopropylethylamine (DIPEA) (55 mg, 0.43 mmol, 3.0 eq) were added. The mixture was reacted at 120 °C for 5 h under argon protection. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate (65 mg, yield 84.2%) as a yellow solid.

[1135] MS m / z:541.3[M+H] +

[1136] Step 7: 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1137] Methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate (65 mg, 0.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 3 hours, and the pH was adjusted with 1 mol / L hydrochloric acid. The reaction mixture was diluted with water (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (36 mg, yield 55.7%) as a white solid.

[1138] MS m / z:527.2[M+H] +

[1139] 1 H NMR (400MHz, DMSO-d6) δ12.87 (s, 1H), 9.28 (d, J = 449.7Hz, 1H), 7.44–7.03 (m, 2H), 5.08 (s, 1H), 3. 61(s,3H),2.93–2.85(m,3H),2.81–2.72(m,3H),2.65(s,3H),2.36(s,3H),1.65(d,J=6.6Hz,3H).

[1140] Example 68: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazacyclopentyl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1141] Step 1: Methyl 4-(3-acetyl-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)benzoate

[1142] Methyl 4-(3-acetyl-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)benzoate (456 mg) was prepared using methyl 4-(chlorocarbonyl)benzoate as the starting material according to the method of Example 1.

[1143] MS m / z:357.2[M+H] +

[1144] Step 2: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1145] 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazacyclopentyl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid using methyl 4-(3-acetyl-2,6-dimethyl-7-oxothieno[3,2-b]pyran-5-yl)benzoate as a starting material according to the method of Example 67.

[1146] MS m / z:537.2[M+H] +

[1147] 1 H NMR(400MHz, DMSO-d6)δ9.82(s,1H),8.27(d,J=8.1Hz,2H),8.05(d,J=8.0Hz,2H),7.29–7.18(m,1H),6 .99(t,J=12.7Hz,1H),4.98–4.83(m,1H),3.08(s,3H),2.63(s,3H),2.07(s,3H),1.56(d,J=6.7Hz,3H).

[1148] Example 69: 6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1149] Step 1: 3-Acetyl-5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1150] 3-Acetyl-5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (78 mg) was prepared as a yellow solid using 1-(2-methoxyphenyl)pyrazole-4-carbonyl chloride as starting material according to the method of Example 1.

[1151] MS m / z:395.2[M+H] +

[1152] Step 2: 6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1153] 6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one)ethyl)amino]pyridine-2-carboxylic acid (5 mg) was prepared as a white solid according to the method of Example 67 using 3-acetyl-5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one as the starting material.

[1154] MS m / z:551.1[M+H] +

[1155] 1 H NMR(400MHz,DMSO-d6)δ9.91(d,J=68.9Hz,1H),8.90(s,1H),8.45(s,1H),7.71(dd,J=7.9,1.7H z,1H),7.46(t,J=7.5Hz,1H),7.30(d,J=8.3Hz,1H),7.20–6.96(m,3H),5.05–4.94(m,1H),3.88 (s,3H),2.61(s,3H),2.19(s,3H),1.63(d,J=6.7Hz,3H).

[1156] Example 70: 6-Chloro-3-[(1-{5-[1-(3-cyanophenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1157] 6-Chloro-3-[(1-{5-[1-(3-cyanophenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared from 1-(3-cyanophenyl)pyrazole-4-carbonyl chloride as a white solid according to the method of Example 69.

[1158] MS m / z:546.1[M+H] +

[1159] 1H NMR (400MHz, DMSO-d6) δ13.12(s,1H),9.18(s,1H),8.66(s,1H),8.56(d,J=2.2Hz,1H),8.44(s,1H),8.39(d,J=8.3Hz,1H),7.89(d,J=7.6Hz,1 H), 7.80 (t, J = 8.0Hz, 1H), 7.43 (d, J = 8.9Hz, 1H), 7.18 (d, J = 9.0Hz, 1H), 5.12 (t, J = 7.0Hz, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 1.68 (d, J = 6.7Hz, 3H).

[1160] Example 71: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1,4-oxazepan-4-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1161] 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1,4-oxazepan-4-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (1.9 mg) was prepared as a light yellow solid using 4-(1,4-oxazepan-4-yl)benzoyl chloride as the starting material according to the method of Example 69.

[1162] MS m / z:540.1[M+H] +

[1163] Example 72: 6-chloro-3-({1-[5-(4-cyanophenyl)-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid

[1164] 6-Chloro-3-({1-[5-(4-cyanophenyl)-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid (10 mg) was prepared as a white solid using 4-cyanobenzoyl chloride as the starting material according to the method of Example 69.

[1165] MS m / z:480.1[M+H] +

[1166] 1H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.34(d,J=7.2Hz,1H),8.04(d,J=8.5Hz,2H),7.87(d,J=6.5Hz,2H),7.41 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 5.02 (p, J = 6.7 Hz, 1H), 2.66 (s, 3H), 1.99 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

[1167] Example 73: 6-Chloro-3-[(1-{3,6-dimethyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1168] Using 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as starting material, 6-chloro-3-[(1-{3,6-dimethyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxothieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (9 mg) was prepared as a white solid by referring to the method of Example 63.

[1169] MS m / z:569.2[M+H] +

[1170] 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.59(s,1H),8.30(s,2H),7.49–7.1 6(m,2H),4.98(d,J=58.5Hz,2H),4.48(t,J=11.5Hz,1H),3.85–3.60(m,5H ),3.35(p,J=12.5Hz,1H),3.15(t,J=15.9Hz,1H),3.07–2.84(m,1H),2.62 (s,3H),2.11(s,3H),1.63(d,J=6.6Hz,3H),1.26(dd,J=25.0,6.5Hz,3H).

[1171] Example 74: 6-Chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (74)

[1172] Using deuterated methylamine hydrochloride as starting material, 6-chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (74, 13 mg) was prepared as a white solid by referring to the method of Example 63.

[1173] MS m / z:558.2[M+H] +

[1174] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.59(d,J=8.5Hz,1H),8.29(s,2H),7.41(d,J=9.0Hz,1H),7.28(d,J=9.1Hz,1H),5. 12–4.98(m,1H),3.86(ddt,J=17.9,12.9,6.4Hz,4H),3.31–3.16(m,4H),2.61(s,3H),2.11(s,3H),1.63(d,J=6.7Hz,3H).

[1175] 6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (74-P1 and 74-P2)

[1176] The compound of Example 74 was separated and prepared by supercritical fluid chromatography (SFC) to give 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (310 mg, white solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (275 mg, white solid), 74-P1 eluted before 74-P2.

[1177] Chiral separation method:

[1178] Instrument: SFC-150 (Waters)

[1179] Chiral column: AD 25*250mm, 10μm (Daicel)

[1180] Column temperature: 35°C

[1181] Mobile phase: CO2 / [ethanol (0.1% formic acid): acetonitrile = 1:1] = 50 / 50

[1182] Flow rate: 100mL / min

[1183] Detection wavelength: 214nm.

[1184] Example 75: 6-Chloro-3-[(1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (75)

[1185] Using deuterated methylamine hydrochloride and 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as starting materials, 6-chloro-3-[(1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (75, 12 mg) was prepared as a white solid by referring to the method of Example 63.

[1186] MS m / z:572.2[M+H] +

[1187] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.59(t,J=8.3Hz,1H),8.29(d,J=3.0Hz,2H),7.41(dd,J=8 .9,2.6Hz,1H),7.26(dd,J=9.1,7.0Hz,1H),5.05(dt,J=10.9,3.7Hz,1H),4.89(d,J=7.5Hz,1H), 4.48(dd,J=13.0,10.1Hz,1H),3.71–3.47(m,2H),3.28(dd,J=12.8,3.1Hz,1H),3.17–2.85(m,2H ), 2.62 (d, J = 2.3Hz, 3H), 2.11 (s, 3H), 1.64 (dd, J = 6.7, 2.0Hz, 3H), 1.25 (dd, J = 25.9, 6.7Hz, 3H).

[1188] 6-Chloro-3-{[(1S)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (75-P1 and 75-P2)

[1189] The compound of Example 75 was prepared by SFC separation to give 6-chloro-3-{[(1S)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (301 mg, white solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (317 mg, white solid), 75-P1 eluted before 75-P2.

[1190] The chiral separation method is the same as Example 74.

[1191] Example 76: 2-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid

[1192] Using deuterated methylamine hydrochloride and methyl 2-fluorobenzoate as starting materials, 2-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid (5 mg) was prepared as a yellow solid according to the method of Example 63.

[1193] MS m / z:523.2[M+H] +

[1194] 1H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.53(s,1H),8.29(s,2H),7.74(dd,J=7.9,1.7Hz,1H),7.27(ddd,J=8.7,7.1,1.8Hz,1H),6.66(d,J=8.5Hz,1 H),6.49(t,J=7.8Hz,1H),5.02(s,1H),3.88(dtd,J=18.2,12.9,4.8Hz,4H ), 3.33 (t, J = 5.1Hz, 4H), 2.61 (s, 3H), 2.11 (s, 3H), 1.63 (d, J = 6.7Hz, 3H).

[1195] Example 77: 6-chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

[1196] Step 1: 3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1197] 3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (4.2 g) was prepared from 4-methoxybenzoyl chloride as a yellow solid according to the method of Example 69.

[1198] MS m / z:365.1 / 367.1[M+H]+

[1199] Step 2: 3-Bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1200] 3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (1.5 g, 4.1 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and boron tribromide (5.2 g, 20.5 mmol, 5.0 eq) was slowly added at -78°C under argon protection. The reaction was allowed to proceed at -78°C for 1 hour, and methanol was added to quench the reaction. The temperature was raised to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (750 mg, yield 52%) as a khaki solid.

[1201] MS m / z:351.3 / 353.3[M+H]+

[1202] Step 3: 4-(3-bromo-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)phenyl trifluoromethanesulfonate

[1203] 3-Bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (800 mg, 2.3 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (20 mL). Triethylamine (230 mg, 2.3 mmol, 1.0 eq) and trifluoromethanesulfonic anhydride (976 mg, 2.73 mmol, 1.2 eq) were added at room temperature. The mixture was protected by argon and reacted at room temperature for 2 hours. Water (50 mL) was added for dilution and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-(3-bromo-2,6-dimethyl-7-oxyidenethieno[3,2-b]pyran-5-yl)phenyl trifluoromethanesulfonate (950 mg, yield 86.36%).

[1204] MS m / z:483.3[M+H] +

[1205] Step 4: 3-Bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1206] 4-(3-bromo-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)phenyl trifluoromethanesulfonate (191 mg, 0.4 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and cesium carbonate (386 mg, 1.19 mmol, 3.0 eq), 3-(dimethylamino)azetidine hydrochloride (88 mg, 0.51 mmol, 1.3 eq), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (36 mg, 0.06 mmol, 0.1 eq) and ester were added. Palladium chloride (8.9 mg, 0.04 mmol, 0.1 eq) was added under argon protection and reacted at 100 ° C for 16 hours. The mixture was cooled to room temperature, diluted with water (40 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (81 mg, yield 47.6%).

[1207] MS m / z:433.3 / 435.3[M+H] +

[1208] Step 5: 6-Chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

[1209] 6-Chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one was prepared using 3-bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one as starting material according to the method of Example 63 to prepare 6-chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxoylidenethieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid (2 mg) as a white solid.

[1210] MS m / z:553.2[M+H] +

[1211] 1 H NMR(400MHz,DMSO-d6)δ9.80(d,J=34.9Hz,1H),7.66(d,J=8.2Hz,2H),7.13( d,J=8.6Hz,1H),6.98(s,1H),6.54(d,J=8.3Hz,2H),4.86(s,1H),3.99(q,J= 6.9Hz,2H),3.68(dq,J=8.2,4.4,3.9Hz,2H),3.23(d,J=6.2Hz,1H),2.73(d, J=7.0Hz,1H),2.58(s,3H),2.13(s,6H),2.06(s,3H),1.56(d,J=6.7Hz,3H).

[1212] Example 78: 6-Chloro-3-{[1-(5-{4-[4-(dimethylamino)hexahydropyridin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

[1213] 6-Chloro-3-{[1-(5-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid (1.6 mg) was prepared as a white solid using 4-(dimethylamino)piperidine as the starting material and referring to the method of Example 77.

[1214] MS m / z:581.2[M+H] +

[1215] Example 79: 6-Chloro-3-({1-[2-(5-fluoropyridin-2-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1216] 6-Chloro-3-({1-[2-(5-fluoropyridin-2-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (23 mg) was prepared as a white solid using 5-fluoropyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as starting materials according to the method of Example 30.

[1217] MS m / z:477.2[M+H] +

[1218] 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),8.73(d,J=2.7Hz,1H),8.60(d,J=7.5Hz,1H),8.14(dd,J=8.8,4.5Hz,1H),7. 98(td,J=8.7,2.9Hz,1H),7.31(dd,J=58.0,9.0Hz,2H),5.13(t,J=7.1Hz,1H),2.65(s,3H),1.60(d,J=6.7Hz,3H).

[1219] Example 80: 6-Chloro-3-({1-[5-(5-fluoropyridin-2-yl)-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid

[1220] 6-Chloro-3-({1-[5-(5-fluoropyridin-2-yl)-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid (5 mg) was prepared as a white solid using 5-fluoropyridine-2-carbonyl chloride as the starting material according to the method of Example 69.

[1221] MS m / z:474.1[M+H] +

[1222] 1H NMR(400MHz, DMSO-d6)δ8.79(d,J=2.8Hz,1H),8.43(d,J=7.1Hz,1H),8.10–7.90(m,2H),7.40(d,J=8.9 Hz, 1H), 7.14 (d, J = 9.0Hz, 1H), 5.05 (p, J = 7.0Hz, 1H), 2.66 (s, 3H), 2.14 (s, 3H), 1.63 (d, J = 6.8Hz, 3H).

[1223] Example 81: 3-[(1-{5-[4-(4-acetylpiperazin-1-yl)phenyl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

[1224] Using 1-(piperazin-1-yl)ethan-1-one as starting material, 3-[(1-{5-[4-(4-acetylpiperazin-1-yl)phenyl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (16 mg) was prepared as a light yellow solid by referring to the method of Example 77.

[1225] MS m / z:581.2[M+H] +

[1226] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),7.59(d,J=8.4Hz,2H),7.39(d,J=8.9Hz,1H),7.09(t,J=11.3Hz,3H),4.99 (s, 1H), 3.59 (q, J = 5.8Hz, 4H), 3.29 (d, J = 5.4Hz, 3H), 2.62 (s, 3H), 2.05 (d, J = 3.6Hz, 6H), 1.59 (d, J = 6.7Hz, 3H).

[1227] Example 82: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1228] Step 1: 3-Bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one

[1229] 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (2.0 g, 8.03 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL) under argon protection, 2 mol / L sodium bis(trimethylsilyl)amide (14 mL, 28.1 mmol, 3.5 eq) was added dropwise at -50 °C, reacted at 0 °C for 1 hour, cooled to -45 °C, carbon disulfide (0.6 g, 8.03 mmol, 1.0 eq) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was stirred overnight at room temperature, cooled to -50°C, and 15% dilute sulfuric acid was added dropwise to adjust the pH to about 7. Water (50 mL) was added to the reaction solution to dilute it, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 3-bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one (1.6 g, yield 68.4%) as a yellow solid.

[1230] MS m / z:291.2 / 293.2[M+H] +

[1231] Step 2: 3-Bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1232] 3-Bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one (1.6 g, 5.49 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (10 mL). Diethyl sulfate (0.85 g, 5.49 mmol, 1.0 eq) and potassium carbonate (0.76 g, 5.49 mmol, 1.0 eq) were added under argon protection. The reaction mixture was reacted at room temperature for 5 hours. Water (30 mL) was added to the reaction solution for dilution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 3-bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (1.0 g, yield 57.1%) as a yellow solid.

[1233] MS m / z:319.2 / 321.2[M+H] +

[1234] Step 3: 3-Bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

[1235] 3-Bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (0.5 g, 1.57 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). 3-Chloroperoxybenzoic acid (0.4 g, 2.35 mmol, 1.5 eq) was added under argon protection and reacted at room temperature for 6 hours. The reaction solution was diluted with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 3-bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (370 mg, yield 70.1%) as an off-white solid.

[1236] MS m / z:335.2 / 337.2[M+H] +

[1237] Step 4: 3-Bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one

[1238] 3-Bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DMSO (5 mL). 5-Methyl-2-(piperazin-1-yl)pyrimidine (32 mg, 0.18 mmol, 2.0 eq) was added under argon. The mixture was reacted at room temperature for 4 hours. The reaction solution was diluted with water (10 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one (10 mg, yield 25.7%) as an off-white solid.

[1239] MS m / z:435.2 / 437.2[M+H] +

[1240] Step 5: 3-Acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one

[1241] Using 3-bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one as starting material, 3-acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one (49 mg) was prepared as an off-white solid according to the method of Example 16.

[1242] MS m / z:399.2 / 401.2[M+H] +

[1243] Step 6: 6-chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1244] Starting from 3-acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one, 6-chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared as a white solid according to the method of Example 63.

[1245] MS m / z:555.2 / 557.2[M+H] +

[1246] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.83(s,1H),8.29(s,2H),7.33(d,J=11.4Hz,1H),7.05(d,J=8.8Hz,1H),4. 93(s,1H),3.93–3.77(m,4H),3.41(d,J=5.2Hz,4H),2.61(s,3H),2.12(s,3H),1.91(s,3H),1.62(d,J=6.7Hz,3H).

[1247] Example 83: 6-Chloro-3-[(1-{2-[4-(imidazo[2,3-f][1,2]diazepin-6-yl)piperazin-1-yl]-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1248] Using deuterated methylamine hydrochloride and 6-(piperazin-1-yl)imidazo[2,3-f][1,2]diazepine as starting materials, 6-chloro-3-[(1-{2-[4-(imidazo[2,3-f][1,2]diazepine-6-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (10 mg) was prepared as a white solid according to the method of Example 63.

[1249] MS m / z:583.2[M+H] +

[1250] 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),7.96(s,1H),7.89(d,J=9.9Hz,1H),7.52(s,1H),7.25(d,J=10.0Hz,1H),7.1 6–6.94(m,2H),5.00–4.90(m,1H),3.66(d,J=12.2Hz,4H),3.50–3.38(m,4H),2.56(s,3H),1.61(d,J=6.7Hz,3H).

[1251] Example 84: 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1252] 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (12 mg) was prepared as a white solid using deuterated methylamine hydrochloride and 1-(methoxycarbonyl)bicyclo[2.2.2]octane-4-carboxylic acid as starting materials according to the method of Example 67.

[1253] MS m / z:572.1[M+H] +

[1254] 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.07 (d, J = 23.5Hz, 2H), 5.04 (t, J = 7.3Hz, 1 H), 2.33 (s, 6H), 2.24–2.15 (m, 3H), 2.04 (t, J = 7.8Hz, 6H), 1.62 (d, J = 6.7Hz, 3H).

[1255] Example 85: 6-Chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-3-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (85)

[1256] Using deuterated methylamine hydrochloride and N-(1-nitropropene-2,2,2-trideuterioethyl)hydroxylamine as starting materials, 6-chloro-3-({1-[6-methyl-4-oxypropene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-3-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (85,2 mg) was prepared as a white solid according to the method of Example 67.

[1257] MS m / z:533.1[M+H] +

[1258] 1 H NMR (400MHz, DMSO-d6) δ8.77–8.66(m,1H),7.39(d,J=8.9Hz,1H),7.25(d,J=9.1Hz,1H),5.08(q,J=7. 2Hz, 1H), 2.88 (dd, J = 9.4, 1.9Hz, 3H), 2.77 (dd, J = 9.4, 1.9Hz, 3H), 2.66 (s, 3H), 1.66 (d, J = 6.7Hz, 3H).

[1259] 6-chloro-3-{[(1S)-1-[6-methyl-4-oxo-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3- {[(1R)-1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (85-P1 and 85-P2)

[1260] The compound of Example 85 was separated by SFC to obtain 6-chloro-3-{[(1S)-1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (300 mg, white solid). ) and 6-chloro-3-{[(1R)-1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (310 mg, white solid), 85-P1 eluted before 85-P2.

[1261] Chiral separation method:

[1262] Instrument: SFC-150 (Waters)

[1263] Chiral column: AD 25*250mm, 10μm (Daicel)

[1264] Column temperature: 35°C

[1265] Mobile phase: CO2 / methanol = 40 / 60

[1266] Flow rate: 100mL / min

[1267] Detection wavelength: 214nm.

[1268] Example 86: 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1269] Step 1: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

[1270] 1-(Methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (1.5 g, 8.82 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL) under argon protection. Borane dimethyl sulfide (0.97 mL, 9.7 mmol, 1.1 eq) was added dropwise at 0°C. The mixture was reacted at room temperature for 3 hours, cooled to 0°C, quenched with methanol, and concentrated under reduced pressure to give methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (1.26 g, yield 92%) as a colorless oil, which was used directly in the next reaction.

[1271] Step 2: Methyl 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylate

[1272] Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (1.26 g, 8.11 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). 4-dimethylaminopyridine (99 mg, 0.81 mmol, 0.1 eq) and imidazole (0.83 g, 12.2 mmol, 1.5 eq) were added under argon protection. The mixture was cooled to 0°C and chloro(2-methylprop-2-yl)diphenylsilane (2.67 mg, 9.73 mmol, 1.2 eq) was added. The mixture was reacted at room temperature for 5 hours. Water (50 The mixture was diluted with 4% paraformaldehyde (50 mL), extracted three times with dichloromethane (50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (2.94 g, yield 92%) as a colorless oil, which was used directly in the next reaction.

[1273] 1 H NMR (400MHz, DMSO-d6) δ7.69–7.64(m,4H),7.48–7.37(m,6H),3.70(s,3H),3.68(s,2H),1.98(s,6H),1.08(s,9H).

[1274] Step 3: 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid

[1275] Methyl 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylate (2.94 g, 7.46 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), water (4 mL) and methanol (10 mL), and lithium hydroxide monohydrate (0.94 g, 22.4 mmol, 3.0 eq) was added and reacted at 40 ° C for 2.5 hours. 1.0 mol / L L hydrochloric acid was added to adjust the pH to 4, water (50 mL) was added to dilute, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (2.83 g, yield 99.1%) as a white solid.

[1276] MS m / z:335.2 / 337.2[M+H] +

[1277] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),7.69–7.63(m,4H),7.46–7.38(m,6H),3.68(s,2H),2.00(s,6H),1.08(s,9H).

[1278] Step 4: [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol

[1279] 1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silapentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (2.83 g, 7.43 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (30 mL). Under argon protection, borane dimethyl sulfide (0.82 mL, 8.17 mmol, 1.0 eq) was added at 0°C. The reaction was allowed to react at room temperature for 1.5 hours. The mixture was cooled to 0°C and quenched by adding methanol. The reaction was concentrated under reduced pressure to give crude [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentan-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol (2.69 g, yield 98.9%) as a colorless oil.

[1280] 1H NMR(400MHz,Chloroform-d)δ7.69–7.67(m,4H),7.40(dd,J=6.5,4.5Hz,6H),3.69(s,2H),3.67(s,2H),1.63(s,6H),1.08(s,9H)

[1281] Step 5: [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanal

[1282] [1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol (2.69 g, 7.35 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), and pyridinium chlorochromate (3.17 g, 14.7 mmol, 2.0 eq) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanal (2.12 g, yield 79.4%) as a colorless oil.

[1283] 1 H NMR (400MHz, Chloroform-d) δ9.60(s,1H),7.69–7.66(m,4H),7.46–7.40(m,6H),3.70(s,2H),1.96(s,6H),1.09(s,9H).

[1284] Step 6: 1-(3-ethynylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane

[1285] [1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pent-3-yl]methanal (500 mg, 1.37 mmol, 1.0 eq) was dissolved in methanol (10 mL), and (1Z)-1-(ethazin-1-yl radical)-1-[dimethoxy(oxyylidene)-λ5-methylphosphino]prop-1-en-2-ol anion (317 mg, 1.65 mmol, 1.2 eq) and potassium carbonate (473 mg, 3.43mmol, 2.5eq), under argon protection, reacted at room temperature for 4 hours, added water (50mL) to dilute, extracted three times with dichloromethane (20mL), combined the organic phases, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 1-(3-ethynylbicyclo[1.1.1]pent-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane (287mg, yield 58.1%) as a colorless oil.

[1286] Step 7: 4,4-dimethyl-3,3-diphenyl-1-(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)-2-oxa-3-silapentane

[1287] 1-(3-Ethynylbicyclo[1.1.1]pent-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane (283 mg, 0.78 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL). Under argon protection, n-butyl lithium (0.54 mL, 0.86 mmol, 1.1 eq) was added dropwise at -78 ° C. After stirring for 20 minutes, triisopropylsilyl chloride (166 mg, 0.86 mmol, 1.1 eq) was added and the reaction was continued at room temperature overnight. 1.0 mmol / L dilute hydrochloric acid to adjust the pH to 4, add water (50 mL) to dilute, extract three times with dichloromethane (20 mL), combine the organic phases, wash with saturated brine (100 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified to give 4,4-dimethyl-3,3-diphenyl-1-(3-{[tri(propyl-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)-2-oxa-3-silapentane (351 mg, yield 86.5%) as a colorless oil.

[1288] Step 8: (3-{[tri(propan-2-yl)silyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanol

[1289] 4,4-Dimethyl-3,3-diphenyl-1-(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)-2-oxa-3-silapentane (306 mg, 0.59 mmol, 1.0 eq) was dissolved in methanol (10 mL), and acetyl chloride (0.084 mL, 1.18 mmol, 2.0 eq) was added at room temperature. The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 9 with 1.0 mmol / L sodium hydroxide. The mixture was diluted with water (50 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)methanol (146 mg, yield 89%) as a colorless oil.

[1290] Step 9: (3-{[tri(propan-2-yl)silyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanal

[1291] (3-{[Tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)methanol (146 mg, 0.52 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and pyridinium chlorochromate (169 mg, 0.79 mmol, 1.5 eq) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)methanal (110 mg, yield 75.4%) as a colorless oil.

[1292] Step 10: Methyl 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-(1-{[tri(propyl-2-yl)silyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate

[1293] Using deuterated methylamine hydrochloride and (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanal as starting materials, the method of Example 67 was used to prepare methyl 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-(1-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (49.5 mg) as a white solid.

[1294] MS m / z:642.1[M+H] +

[1295] Step 11: Methyl 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate

[1296] Methyl 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-(1-{[tri(propyl-2-yl)silyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (49.5 mg, 0.08 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride solution (0.077 mL, 0.08 mmol, 1.0 eq) was added and reacted at room temperature overnight. , diluted with water (10 mL), extracted three times with dichloromethane (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give methyl 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (24 mg, yield 64%) as a yellow oil.

[1297] MS m / z:486.2[M+H] +

[1298] Step 12: 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

[1299] Methyl 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (24 mg, 0.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), methanol (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (6.22 mg, 0.15 mmol, 3.0 eq) was added. The mixture was reacted at room temperature for 2 hours. The pH was adjusted with 1 mol / L hydrochloric acid. The H value was about 5, and the reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), and the organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (7.2 mg, yield 31%) as a white solid.

[1300] MS m / z:472.2[M+H] +

[1301] 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.12 (d, J = 59.1Hz, 2H), 5.01 (q, J = 7.3Hz, 1H), 3.21(s,1H),2.65(d,J=9.5Hz,3H),2.59(s,3H),2.55(s,3H),1.61(d,J=6.7Hz,3H).

[1302] Example 87: 6-Chloro-3-[(1-{6-methyl-2-[4-(6-methyl-1,2-diazacyclohexan-3-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

[1303] 6-Chloro-3-[(1-{6-methyl-2-[4-(6-methyl-1,2-diazacyclohexan-3-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid using deuterated methylamine hydrochloride and 6-methyl-3-(piperazin-1-yl)-1,2-diazacyclohexan-3-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid as a white solid according to the method of Example 63.

[1304] MS m / z:558.2[M+H] +

[1305] Example 88: 6-Chloro-3-[(1-{2,6-dimethyl-5-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

[1306] Using deuterated methylamine hydrochloride and 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as starting materials, 6-chloro-3-[(1-{2,6-dimethyl-5-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (1.5 mg) was prepared as a white solid by referring to the method of Example 82.

[1307] MS m / z:569.1[M+H] + .

[1308] Example 89: 6-Chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (89)

[1309] 6-chloro-3-{[(1S)-1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3- {[(1R)-1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (89-P1 and 89-P2)

[1310] Using N-(1-nitrogenylidene-2,2,2-trideuterioethyl)hydroxylamine as starting material, the method according to Example 84 was used to prepare 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (89, 714 mg) as a yellow solid.

[1311] MS m / z:575.2[M+H] +

[1312] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.93–8.63(m,1H),7.35(d,J=9.0Hz,1H),7.20(d,J=8.8Hz,1H),5.08(d, J=8.8Hz,1H),2.61(s,3H),2.38–2.26(m,3H),2.25–2.12(m,3H),2.05(t,J=7.8Hz,6H),1.64(d,J=6.7Hz,3H).

[1313] The compound of Example 89 was separated by SFC to obtain 6-chloro-3-{[(1S)-1-[6-methyl-4-o...

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, in: R 1 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 1a replace; Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6- 10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 2a replace; Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , and the other is NR 7 , N, O or S; R 7 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 )2、-C(O)N(R 9 )2. -C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 4a replace; Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2. -S(O)R 10 、-S(O)N(R 11 )2、-S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 4-a replace; Each R 4-a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 4B is hydrogen, hydroxyl, -N(R 9 )2、-C(O)N(R 9 )2. -C(O)R 9 、-C(O)OR 9 、-SO2R 9 、-SO2N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3- 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, -S(O)2R 10 、-S(O)2N(R 11 )2. -S(O)R 10 、-S(O)N(R 11 )2, -S(O)(NR 11 )OR 11 、-C(O)R 10 、-C(O)OR 11 、-C(O)N(R 11 )2、-C(O)N(R 11 )OR 11 、-OC(O)R 10 、-OC(O)N(R 11 )2、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)R 10 、-N(R 11 )C(O)N(R 11 )2、-N(R 11 )C(NR 11 )(R 10 )、-N(R 11 )C(NR 11 )N(R 11 )2、-N(R 11 )S(O)2N(R 11 )2、-N(R 11 )S(O)2R 10 、-P(O)(R 10 )2、-P(O)(R 11 )(OR 11 )、-B(OR 11 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 4-b replace; Each R 4-b are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 10 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a replace; Each R 10a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 11 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered hetero Cycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a replace; Each R 11a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2. -S(O)R 12 、-S(O)N(R 13 )2, -S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 2. C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, with one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace; Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace; Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently optionally substituted with one or more R 6a replace; Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; And the compound shown in formula I is not the following compound:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound shown in formula I satisfies any of the following schemes: Scenario 1: R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace; Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace; Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , and the other is NR 7 , N, O or S; R 7 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace; Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; R 4B is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; Each R 11 are independently hydrogen or C 1-6 alkyl; Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Each R 13 are independently hydrogen or C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace; Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Scenario 2: R 1 is hydrogen or C 1-6 alkyl; R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X is NR 7 , N, O or S, Y is CR 8 ; R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl; R 4B For hydrogen, C 1-6 Alkyl or -N(R 9 )2, wherein said C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, -NH2 or hydroxyl; Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), Multiple R 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Each R 13 are independently hydrogen or C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl; Scenario 3: R 1 is hydrogen or C 1-6 alkyl; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is NR 7 , N, O or S, Y is CR 8 ; R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen; R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A is hydrogen or C 1-6 alkyl; R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b is deuterium or cyano; Each R 5 C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxyl; Solution 4: R 1 is hydrogen; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A is hydrogen or C 1-6 alkyl; R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b is deuterium or cyano; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Cy 2 for Each R 6 are independently hydrogen or halogen; Solution 5: R 1 is hydrogen; R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 alkyl; R 4A is hydrogen or C 1-6 alkyl; R 4B -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b is deuterium or cyano; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, with one or more R 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Cy 2 for Each R 6 are independently hydrogen or halogen; Solution 6: R 1 is hydrogen; R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 alkyl; R 4A is hydrogen or C 1-6 alkyl; R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5b’ Independently for -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen; Preferably, R 1 is hydrogen; R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 alkyl; R 4A is hydrogen or C 1-6 alkyl; R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl or -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound shown in formula I satisfies any of the following schemes: Scenario 1: R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace; Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace; Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , and the other is NR 7 , N, O or S; R 7 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace; Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; R 4B is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; Each R 11 are independently hydrogen or C 1-6 alkyl; Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Replaced 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Each R 13 are independently hydrogen or C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace; Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Scenario 2: R 1 is hydrogen or C 1-6 alkyl; R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X is NR 7 , N, O or S, Y is CR 8 ; R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl; R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, -NH2 or hydroxyl; Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, One or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Each R 13 are independently hydrogen or C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 alkyl; Scenario 3: R 1 is hydrogen or C 1-6 alkyl; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is NR 7 , N, O or S, Y is CR 8 ; R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen; R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A is hydrogen or C 1-6 alkyl; R 4B is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b for deuterium; Each R 5 C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxyl; Solution 4: R 1 is hydrogen; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A is hydrogen or C 1-6 alkyl; R 4B is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b for deuterium; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen; Solution 5: R 1 is hydrogen; R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 alkyl; R 4A is hydrogen or C 1-6 alkyl; R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen; Solution 6: R 1 is hydrogen; R 2 and R 3 One is hydrogen and the other is C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 alkyl; R 4A is hydrogen or C 1-6 alkyl; R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl or -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound shown in formula I satisfies any of the following schemes: Scenario 1: R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a replace; Each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a replace; Each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Cy 1 for X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 , and the other is NR 7 , N, O or S; R 7 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a replace; Each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a replace; Each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 9 are independently hydrogen or C 1-6 alkyl; R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a replace; Each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; R 4B is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 alkyl; Each R 11 are independently hydrogen or C 1-6 alkyl; Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 13 are independently hydrogen or C 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a replace; Each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Scenario 2: R 1 is hydrogen or C 1-6 alkyl; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is NR 7 , N, O or S, Y is CR 8 ; R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently halogen; R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A and R 4B are independently hydrogen or C 1-6 alkyl; Each R 5 are independently 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxyl; Scenario 3: R 1 is hydrogen; R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Cy 1 for X is S, Y is CR 8 ; R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; R 4A and R 4B are independently hydrogen or C 1-6 alkyl; Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl; Cy 2 for Each R 6 are independently hydrogen or halogen.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1)R 1 is hydrogen, hydroxyl, -N(R 9 )2 or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 1a Replace; each R 1a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Preferably, R 1 is hydrogen or C 1-6 More preferably, R 1 is hydrogen; (2)R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 2a Replace; each R 2a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Preferably, R 2 and R 3 are independently hydrogen, halogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 alkyl; More preferably, R 2 and R 3 are independently hydrogen or C 1-6 alkyl; Also preferably, R 2 and R 3 One is H and the other is C 1-6 alkyl; (3)R 7 is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 7a Replace; each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1- 6 alkyl; Preferably, R 7 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 7a Replace; each R 7a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, each R 7a are independently halogen; (4)R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a Replace; each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Preferably, R 8 For hydrogen, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 8a Replace; each R 8a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; More preferably, R 8 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; Also preferably, R 8 C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 8a Replace; each R 8a are independently halogen; For example, R 8 C 1-6 alkyl; (5)R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; each R 11 are independently hydrogen or C 1-6 alkyl; Preferably, R 4A For hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4a Replace; each R 4a are independently deuterium, halogen, -NH2 or hydroxyl; More preferably, R 4A is hydrogen or C 1-6 alkyl; (6)R 4B is hydrogen, hydroxyl, -N(R 9 2. C 1-6 Alkyl or -OC 1-6 Alkyl, wherein the C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently optionally substituted with one or more R 4b Replace; each R 4b are independently deuterium, halogen, cyano, nitro, -N(R 11 )2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; each R 11 are independently hydrogen or C 1-6 alkyl; Preferably, R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b are independently deuterium, halogen, -NH2 or hydroxyl; More preferably, R 4B is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; For example, R 4B C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b for deuterium; Most preferably, R 4B is hydrogen or C 1-6 Alkyl; for example, R 4B C 1-6 alkyl; (7) Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f Substituted 5-10 membered heteroaryl; each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl; each R 13 are independently hydrogen or C 1-6 alkyl; Preferably, each R 5 are independently 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f Substituted 5-10 membered heteroaryl; each R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-a , R 5-b , R 5-h , R 5-i , R 5- j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 Alkyl; each R 13 are independently hydrogen or C 1-6 Alkyl; preferably, each R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl or -OC 1-6 alkyl; More preferably, each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f Substituted 5-10 membered heteroaryl; each R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-j and R 5- k Each independently is C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, each R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-k Independently for C 1-6 Alkyl; more preferably, each R 5c , R 5e and R 5f are independently halogen, C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5-k Substituted 5-10 membered heteroaryl; each R 5-k Independently for C 1-6 alkyl; (8) Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 2. C 1-6 Alkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl groups are each independently optionally substituted with one or more R 6a Replace; each R 6a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Preferably, Cy 2 for Each R 6 are independently hydrogen, deuterium, halogen, hydroxyl, -NH2, C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, each R 6 are independently hydrogen, deuterium, halogen, -NH2 or hydroxyl; More preferably, Cy 2 for Each R 6 are independently hydrogen or halogen; and (9)X is NR 7 , N, O or S, Y is CR 8 Preferably, X is S and Y is CR 8 .

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2. -S(O)R 12 、-S(O)N(R 13 )2, -S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 2. C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, with one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; (2) Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; (3) Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; (4) Each R 5 C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; (5) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; (6) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl or -OC 1-6 alkyl; (7) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl or -OC 1-6 alkyl; (8) Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, -S(O)2R 12 、-S(O)2N(R 13 )2. -S(O)R 12 、-S(O)N(R 13 )2, -S(O)(NR 13 )OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)N(R 13 )2、-C(O)N(R 13 )OR 13 、-OC(O)R 12 、-OC(O)N(R 13 )2、-N(R 13 )C(O)OR 13 、-N(R 13 )C(O)R 12 、-N(R 13 )C(O)N(R 13 )2、-N(R 13 )C(NR 13 )(R 12 )、-N(R 13 )C(NR 13 )N(R 13 )2、-N(R 13 )S(O)2N(R 13 )2、-N(R 13 )S(O)2R 12 、-P(O)(R 12 )2、-P(O)(R 13 )(OR 13 )、-B(OR 13 2. C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 5-d Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, with one or more R 5-f Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5-g Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl or deuterated C 1-6 alkyl; Each R 12 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a replace; Each R 12a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 13 are independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a replace; Each R 13a are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl; (9) Each R 5 Independently for C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 5-c Substituted-SC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5- k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Each R 13 are independently hydrogen or C 1-6 alkyl; (10) Each R 5 are independently 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkenyl, 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are each independently deuterium, halogen, cyano, nitro, -N(R 13 )2, hydroxyl, C 1-6 Alkyl, with one or more R 5-a Substituted C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 5-b Replaced-OC 1-6 Alkyl, C 2-6 Alkynyl, with one or more R 5-e Substituted C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6- 10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k Each independently is -NH2, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; Each R 13 are independently hydrogen or C 1-6 alkyl; (11) Each R 5 C 3-12 Cycloalkyl, with one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5d Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocycloalkyl, 5-h substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5-k substituted 5-10 membered heteroaryl; Each R 5-h , R 5-i , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; (12) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, -O-(3-12 membered heterocycloalkyl), 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; (13) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkynyl, C 6-10 Aryl, one or more R 5-j Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5-k substituted 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl or one or more R 5-h Substituted 3-12 membered heterocycloalkyl; Each R 5-h , R 5-j and R 5-k Each independently is C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NH2, -N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C(O)NH2, with one or more R 5a’ Substituted C 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5a’ and R 5b’ Each independently is -NH2, -OC 1-6 Alkyl or -C(O)NH2; (14) Each R 5 are independently one or more R 5a Substituted C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 5c Substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 5e Substituted C 6-10 Aryl, 5-10 membered heteroaryl or one or more R 5f substituted 5-10 membered heteroaryl; Each R 5a , R 5c , R 5e and R 5f are independently cyano, halogen, C 1-6 Alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 Alkyl, with one or more R 5-k substituted 5-10 membered heteroaryl or one or more R 5-j Substituted C 6-10 Aryl; Each R 5-k and R 5-j Each independently is C 1-6 Alkyl, cyano, deuterated C 1-6 Alkyl, -OC 1-6 Alkyl or one or more R 5b’ Replaced-OC 1-6 alkyl; Each R 5b’ Independently for -OC 1-6 alkyl; (15)R 4B For hydrogen, C 1-6 Alkyl or -N(R 9 )2, wherein said C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b are independently deuterium, halogen, cyano, -NH2 or hydroxyl; Each R 9 are independently hydrogen or C 1-6 alkyl; (16)R 4B is hydrogen, -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b replace; Each R 4b is deuterium or cyano; or (17)R 4B -NH2 or C 1-6 Alkyl; the C 1-6 The alkyl groups are independently optionally substituted with one or more R 4b Replace; each R 4b It is deuterium or cyano.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The compound shown in formula I is a compound shown in any one of the following formulas (IA) to (ID): Preferably, the compound as shown in formula I is a compound shown in any one of the following formulas (IE) to (IH):

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: It meets one or more of the following conditions: (1) Each of the above "C 1-6 "alkyl" are each independently C 1-4 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; (2) Each of the above "C 2-6 "alkynyl" are each independently C 2-4 Alkynyl; for example ethynyl, propynyl or propargyl, preferably ethynyl; (3) Each of the above "C 2-6 "alkenyl" are each independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl; (4) Each of the above "C 3-12 "Cycloalkyl" are each independently C 3-6 Monocyclic cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or C 4-10 Bridged cycloalkyl (e.g. Another example )； (5) Each of the above "C 3-12 "cycloalkenyl" are each independently C 3-6 Cycloalkenyl; for example cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (6) Each of the "3-12 membered heterocycloalkyl" is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 7-10 membered bridged heterocycloalkyl; the 4-6 membered monocyclic heterocycloalkyl is preferably morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidinyl, for example The 7-10 membered spirocyclic heterocycloalkyl is preferably 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example The 7-10 membered bridged heterocycloalkyl is preferably 8-azabicyclo[ 3.2.1]octyl or 2-oxabicyclo[2.2.2]octyl, for example Preferably, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group, a 7-10 membered spirocyclic heterocycloalkyl group or a 7-10 membered bridged heterocycloalkyl group; the 4-6 membered monocyclic heterocycloalkyl group is preferably a morpholinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydropyrrolyl group, an oxetanyl group or an azetidinyl group, for example The 7-10 membered spirocyclic heterocycloalkyl is preferably 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example The 7-10 membered bridged heterocycloalkyl is preferably 8-azabicyclo[3.2.1]octanyl, for example (7) Each of the "3-12 membered heterocycloalkenyl" is independently a 3-12 membered heterocycloalkenyl having one, two or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heterocycloalkenyl; the 5-6 membered monocyclic heterocycloalkenyl is preferably a 1,2,3,6-tetrahydropyridyl, for example (8) Each of the above "C 6-10 "Aryl" are each independently phenyl or naphthyl; preferably phenyl; (9) Each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group having one, two or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered polycyclic heteroaryl group; the 5-6 membered monocyclic heteroaryl group is preferably a 1H-tetrazolyl group, a 2H-tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, a 1,2,4-oxadiazolyl group, a pyrazinyl group, a pyridazinyl group, a 1,2,3-triazolyl group, a 1,3,4-thiadiazolyl group, a 1,3,4-oxadiazolyl group or a Pyrrolyl, e.g. The 9-10 membered heteroaryl is preferably quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolyl, for example Preferably, each of the "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered polycyclic heteroaryl group; the 5-6 membered monocyclic heteroaryl group is preferably a pyridyl, pyrimidyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example The 9-10 membered heteroaryl ring is preferably quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, Indolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolinyl, e.g. (10) Each of the "halogen" is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (11) Each of the above-mentioned "deuterated C 1-6 "Alkyl" are each independently deuterated methane or deuterated ethane, such as -CD3; and (12) each of the "-OC 1-6 "alkyl" are each independently -OC 1-4 The alkyl group is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy, more preferably methoxy.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: It meets one or more of the following conditions: (1)R 2 and R 3 In the case of , one is H and the other is methyl; (2) X is S, Y is CCH3 or CCF3; (3)R 4A is hydrogen or methyl; (4)R 4B is methyl, amino, -CH2CN or -CD3, preferably methyl or -CD3, more preferably methyl; (5) Each R 5 are independently phenyl, and (6)Cy 2 for Preferably, Cy 1 for 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound as shown in formula I is any of the following compounds: Preferably, the compound as shown in formula I contains a chiral center, and the compound as shown in formula I is each stereoisomer or a mixture thereof.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound as shown in formula I is any of the following compounds: Preferably, the compound as shown in formula I is any of the following compounds: The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / [ethanol (0.1% formic acid): acetonitrile = 1:1] = 50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / [ethanol (0.1% formic acid): acetonitrile = 1:1] = 50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / methanol=40 / 60; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / methanol=40 / 60; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / [ethanol (0.1% formic acid): acetonitrile = 1:1] = 50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / [methanol:acetonitrile=1:1]=50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / [ethanol (0.1% formic acid): acetonitrile = 1:1] = 50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / methanol=50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / methanol=50 / 50; Flow rate: 100mL / min; Detection wavelength: 214nm; The compound that eluted later under the following conditions was One stereoisomer in the: instrument: SFC-150 (Waters); chiral column: AD 25*250mm, 10μm (Daicel); column temperature: 35°C; mobile phase: CO2 / methanol=50 / 50; flow rate: 100mL / min; detection wavelength: 214nm.

12. A compound represented by any one of the following formulas (I-1) to (I-4): in, R 4A , R 4B , X, Y as defined in any one of claims 1-11; Preferably, each R 4A R 4B can be methyl; X can be S; Y can be CR 8 , such as CCH3; Further preferably, the compound as shown in formula I-1 is The compound shown in formula I-2 is The compound shown in formula I-3 is The compound shown in formula I-4 is 13. A pharmaceutical composition comprising substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); the substance A is a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A may be in a therapeutically effective amount.

14. Use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a PI3Kα inhibitor, wherein the substance A is a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; in the above-mentioned use, the PI3Kα inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PI3Kα.

15. Use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and / or prevent a disease or disorder related to PI3Kα regulation; the substance A is a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

16. Use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or disorders related to PI3Kα regulation; the substance A is a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11; the substance A is in a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably CLOVES syndrome or PI3Kα-related overgrowth syndrome.

17. Use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and / or prevent cancer; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the substance A is a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

18. Use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and / or prevent CLOVES syndrome or PI3Kα-related overgrowth syndrome; the substance A is a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

19. The use according to any one of claims 14 to 16 and 18, characterized in that: The PI3Kα is a PI3Kα mutation, preferably a PI3KαH1047R mutation or a PI3KαE545K mutation, and more preferably a PI3KαH1047R mutation.

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