BET inhibitors for cancer treatment

Abstract

This specification provides a method for using a BET inhibitor to treat cancer involving loss of function or deletion of the EP300 gene or a part thereof.

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Application No. 63 / 581,241 filed on 7 September 2023 and U.S. Provisional Application No. 63 / 625,852 filed on 26 January 2024, the contents of which are incorporated herein by reference. [Background technology]

[0002] BET inhibitors are a class of drugs that target a family of proteins called bromodomains and extraterminal (BET) proteins. These proteins can play a major role in regulating gene expression and chromatin structure, cell cycle progression, and other important cell biological functions. By being involved in cell growth and differentiation, they are potentially important to the pathophysiology of cancer. Among many different mechanisms of action, BET inhibitors have the ability to disrupt the interaction between BET proteins and chromatin, leading to alterations in gene expression that can inhibit the growth and survival of cancer cells. Although they have shown promise in some studies, the lack of clinical efficacy, dose-limiting toxicity, and the prevalence of resistance to BET inhibitors remain significant challenges. Therefore, the development of novel BET inhibitor treatments for cancer targeted therapy is needed. [Overview of the project]

[0003] This disclosure is based in part on the finding that cancer may be associated with loss of function or deletion of the EP300 gene, and once identified, such cancer may be treated by administering (for example, in a therapeutically effective dose) a pharmaceutical composition comprising a bromodomain and an extraterminal (BET) inhibitor.

[0004] In some embodiments, this specification provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, and the cancer has been determined to involve loss of function or deletion of the EP300 gene, and the patient is

[0005] [ka] or

[0006] [ka] If the patient is not receiving treatment for the above cancers simultaneously, and the cancer is triple-negative breast cancer, the above BET inhibitor is not JQ1.

[0007] In some embodiments, this specification provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, and the cancer has been determined to involve a decrease in the amount or activity of p300 compared to wild-type p300, and the patient is

[0008] [ka] or

[0009] [ka] If the patient has not received both treatments simultaneously and the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1. In some embodiments, the loss of function is caused by a gene mutation. In some embodiments, the subject has not previously received compound 1 or compound 2. In some embodiments, the above BET inhibitors include ABBV-075, ABBV-744, Apabetalon, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1, LY-294002, NEO2734, ODM-207, OM This includes T-001, OMT-002, OTX-015, perabreciv, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, ZEN-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, allobreciv, GSK778, GSK046, mibebleciv, trotabreciv, molybreciv, perabreciv, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof.

[0010] In some embodiments, the BET inhibitor is defined by formula (I):

[0011] [ka] The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 is a (C1-C3) alkyl group optionally substituted with cyano, halo, or 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy, where X is halo, if present. In some embodiments, R 1 is (C1-C2)alkyl, cyano, or fluoro. In some embodiments, R 1 is methyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 It is cyano.

[0012] In some embodiments, the BET inhibitor is defined by formula (II):

[0013] [ka] The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 R is a (C1-C3) alkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy. In some embodiments, R 1 It is methyl.

[0014] In some embodiments, the BET inhibitor is expressed by formula (III):

[0015] [ka] The compound comprises a compound or a pharmaceutically acceptable salt thereof, where X is a halo, if present.

[0016] In some embodiments, the BET inhibitor is Compound 3:

[0017]

化

[0018]

化

[0019]

Chemical Structure

[0020] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0021] In some embodiments, the BET inhibitor is compound 9:

[0022] [ka] or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof. In some embodiments, the cancers include bladder cancer, lung cancer, gynecological cancer, adrenocortical cancer, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, nerve sheath tumor, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or a combination thereof. In some embodiments, the cancers include lung cancer. In some embodiments, the lung cancers include non-small cell lung cancer. In some embodiments, the non-small cell lung cancers include squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the non-small cell lung cancers include squamous cell carcinoma. In some embodiments, the non-small cell lung cancers include large cell carcinoma. In some embodiments, the non-small cell lung cancers include adenocarcinoma. In some embodiments, the lung cancers include small cell lung cancer. In some embodiments, the BET inhibitors include AZD-5153, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the cancer includes bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the BET inhibitors include AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the BET inhibitors include BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumor. In some embodiments, the lymphoma includes non-Hodgkin lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma.In some embodiments, the lymphoma includes mature B-cell tumors. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors, esophageal and gastric cancer, gastrointestinal neuroendocrine tumors, small intestine cancer, anal cancer, colon cancer, or a combination thereof. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors. In some embodiments, the gastrointestinal cancer includes esophageal and gastric cancer. In some embodiments, the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small intestine cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer. In some embodiments, the colon cancer includes colorectal cancer. In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the endometrial cancer includes endometrial cancer of the uterine body. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the uterine sarcoma includes carcinosarcoma. In some embodiments, the BET inhibitor inhibits one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor inhibits BRD4 and BRD2. In some embodiments, the BET inhibitor inhibits BRD3 and BRD4. In some embodiments, the BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the BET inhibitor includes a selective BET inhibitor. In some embodiments, the selective BET inhibitor inhibits one or more of the following bromodomains: BRD2, BRD3, and BRD4.In some embodiments, the selective BET inhibitor is selective for BRD4 and BRD2. In some embodiments, the selective BET inhibitor is selective for BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the selective BET inhibitor comprises GSK778. In some embodiments, the selective BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the selective BET inhibitor comprises GSK046, ABBV-744, compound 9, or any combination thereof. In some embodiments, the loss of function or deletion is for the EP300 gene.

[0023] In some embodiments, this specification provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, and the cancer has been determined to involve loss of function or deletion of the EP300 gene. The above BET inhibitor is expressed by formula IV:

[0024] [ka] The compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the formula includes, R1 is hydrogen, deuterium, -C 1-6 Alkyl, or -C 3-8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6Alkyl)2, or -C 3-8 Selected from carbocyclic structures, R2 can be hydrogen, deuterium, halogen, or -OR 21 , -NR 21 R 22 -CN, -SR 21 -SOR 21 , -SO2R 21 , -SO2NR 21 R 22 , -C 1-8 Alkyl,

[0025] [ka] carboxyl, -COOR 21 ,-CONR 21 R 22 , -NR 21 COR 22 , -NR 21 SO2R 22 , or -C 3_8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently and optionally substituted with deuterium, halogen, -OH, -CN, -NH2, or -C 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Selected from a carbocyclic structure or a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N and O, R 21 and R 22 Each of these elements appears independently as follows: hydrogen, deuterium, -OH, NH2, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 1-8 Alkylene-C 3-8 Carbocyclic, or -C 3-8 Selected from carbocyclic formulas, R 23 and R 24 Each of these independently, each instance of it, is either hydrogen, deuterium, or -C. 1-8 Selected from alkyl groups, A is

[0026] [ka] Selected from, Y1 is N or CR Y1 Selected from, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from, R Y1 and R Y2 Each of these elements appears independently as follows: hydrogen, deuterium, halogen, -OH, NH2, -CN, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys, R3 and R4 are each independently, each instance being hydrogen, deuterium, or -C 1-6 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -NH2, -CN, or -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys, n is selected from 0, 1, 2, 3, 4, 5, or 6, and W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3A 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, N, or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 4-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 5-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered carbocyclic structure; a 4-membered carbocyclic structure; a 5-membered carbocyclic structure; or a 6-membered carbocyclic structure, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent being deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, or -C 1-3 Alkyl, or -C 1-3 Selected from alkoxys, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C 1-3A 5-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S; a 6-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 7-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; an 8-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 9-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 10-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered heterocyclic compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; or N, O, or S. A four-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a five-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a three-membered carbocyclic structure; a four-membered carbocyclic structure; a five-membered carbocyclic structure; or a six-membered carbocyclic structure, each independently and optionally substituted with one, two, three, four, or five substituents, each substituent selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, where Z is hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxy.

[0027] In some embodiments, this specification provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, wherein the cancer has been determined to involve a decrease in the amount or activity of p300 compared to wild-type p300, and the BET inhibitor comprises formula IV:

[0028] [ka] The formula includes a compound of the same, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R1 is hydrogen, deuterium, -C 1-6 Alkyl, or -C 3-8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, or -C 3-8 Selected from carbocyclic structures, R2 can be hydrogen, deuterium, halogen, or -OR 21 , -NR 21 R 22 -CN, -SR 21 -SOR 21 , -SO2R 21 , -SO2NR 21 R 22 , -C 1-8 Alkyl,

[0029] [ka] carboxyl, -COOR 21 ,-CONR 21 R 22 , -NR 21 COR 22 , -NR 21 SO2R 22 , or -C 3_8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently and optionally substituted with deuterium, halogen, -OH, -CN, -NH2, or -C 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8Selected from a carbocyclic structure or a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N and O, R 21 and R 22 Each of these elements appears independently as follows: hydrogen, deuterium, -OH, NH2, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 1-8 Alkylene-C 3-8 Carbocyclic, or -C 3-8 Selected from carbocyclic formulas, R 23 and R 24 Each of these independently, each instance of it, is either hydrogen, deuterium, or -C. 1-8 Selected from alkyl groups, A is

[0030] [ka] Selected from, Y1 is N or CR Y1 Selected from, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from, R Y1 and R Y2 Each of these elements appears independently as follows: hydrogen, deuterium, halogen, -OH, NH2, -CN, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys, R3 and R4 are each independently, each instance being hydrogen, deuterium, or -C 1-6 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -NH2, -CN, or -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys, n is selected from 0, 1, 2, 3, 4, 5, or 6, and W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3A 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, N, or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 4-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 5-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered carbocyclic structure; a 4-membered carbocyclic structure; a 5-membered carbocyclic structure; or a 6-membered carbocyclic structure, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent being deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, or -C 1-3 Alkyl, or -C 1-3 Selected from alkoxys, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C 1-3A 5-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S; a 6-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 7-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; an 8-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 9-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 10-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered heterocyclic compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; or N, O, or S. A four-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a five-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N, O, or S; a three-membered carbocyclic structure; a four-membered carbocyclic structure; a five-membered carbocyclic structure; or a six-membered carbocyclic structure, each independently and optionally substituted with one, two, three, four, or five substituents, each substituent selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, where Z is hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys. In some embodiments, the loss of function is caused by a gene mutation. In some embodiments, the BET inhibitor is compound 5:

[0031] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0032] In some embodiments, the BET inhibitor is compound 6:

[0033] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0034] In some embodiments, the BET inhibitor is compound 7:

[0035] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0036] In some embodiments, the BET inhibitor is compound 8:

[0037] [ka] or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof. In some embodiments, the cancers include bladder cancer, lung cancer, gynecological cancer, adrenocortical cancer, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, nerve sheath tumor, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or a combination thereof. In some embodiments, the cancers include lung cancer. In some embodiments, the lung cancers include non-small cell lung cancer. In some embodiments, the non-small cell lung cancers include squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the non-small cell lung cancers include squamous cell carcinoma. In some embodiments, the non-small cell lung cancers include large cell carcinoma. In some embodiments, the non-small cell lung cancers include adenocarcinoma. In some embodiments, the lung cancers include small cell lung cancer. In some embodiments, the cancers include bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumor. In some embodiments, the lymphoma includes non-Hodgkin lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma. In some embodiments, the lymphoma includes mature B-cell tumor. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumor, esophageal and gastric cancer, gastrointestinal neuroendocrine tumor, small intestine cancer, anal cancer, colon cancer, or a combination thereof. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumor. In some embodiments, the gastrointestinal cancer includes esophageal and gastric cancer. In some embodiments, the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small intestine cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer. In some embodiments, the colon cancer includes colorectal cancer.In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the endometrial cancer includes endometrial cancer of the uterine body. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the uterine sarcoma includes carcinosarcoma of the uterine body. In some embodiments, the subject has NUT midline cancer. In some embodiments, the subject has castration-resistant prostate cancer. In some embodiments, the subject has solid cancer or humoral cancer. In some embodiments, the subject has humoral cancer selected from myelofibrosis. In some embodiments, the subject has humoral cancer selected from myeloma and leukemia. In some embodiments, the subject has humoral cancer selected from leukemia. In some embodiments, the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In some embodiments, the loss of function or deletion is for the EP300 gene. In some embodiments, R1 is hydrogen, deuterium, or -C. 1-6 Alkyl, or -C 3-8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C 1-8 Alkyl, or -C 1-8 Selected from alkoxy, R2 is hydrogen, deuterium, halogen, -C 1-8 Alkyl,

[0038] [ka] carboxyl, -COOR 21 , or -CONR 21 R22 These are selected from, and each is independently substituted with 1, 2, 3, 4, 5, or 6 substituents as it appears, and each substituent is independently substituted with deuterium, halogen, -OH, -CN, -NH2, -C as it appears 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Selected from a carbocyclic structure or a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N and O, R 21 and R 22 Each of these elements appears independently as follows: hydrogen, deuterium, -OH, NH2, -CN, -C 1-8 Alkyl, or -C 3-8 Selected from carbocyclic formulas, R 23 and R 24 Each of these independently, each instance of it, is either hydrogen, deuterium, or -C. 1-8 Selected from alkyl groups, A is

[0039] [ka] Selected from, Y1 is N or CR Y1 Selected from, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from, R Y1 and R Y2 Each of these elements appears independently as follows: hydrogen, deuterium, halogen, -OH, NH2, -CN, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxys, R3 and R4 are each independently, each instance being hydrogen, deuterium, or -C 1-6 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -NH2, -CN, or -C 1-6 Alkyl, or -C 1-6Selected from alkoxy, n is selected from 0, 1, or 2, and W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 A six-membered heterocyclic formula is selected, containing one, two, or three heteroatoms selected from alkoxy, N, and O, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent being deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, or -C 1-3 Alkyl, or -C 1-3 Selected from alkoxys, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C 1-3 Selected from a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S, or a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S, each independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each substituent selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, where Z is hydrogen, deuterium, halogen, -NH2, -CN, -OH, or -C 1-6Selected from alkoxys. In some embodiments, the above compound of formula IV is (S)-2-(6-(3,5-dimethylisoxazole-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(3,5-dimethylisoxazole-4-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo [3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetra Hydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5- (S)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(3,5-dimethylisoxazole-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-Dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 6-(1,4-Dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine -3-carboxamide, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-amine, 2-(4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazole-5-yl)-1, 4-Dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3- Selected from methoxypyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol and 4-((6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)methyl)morpholine.

[0040] Reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. This specification is intended to supersede and / or take precedence over any publications and patents or patent applications incorporated by reference to the extent that they conflict with any disclosures contained herein. [Brief explanation of the drawing]

[0041] Novel features of the present invention are specifically described in the appended claims. For a better understanding of the features and advantages of the present invention, please refer to the following detailed description and the appended drawings, which describe exemplary embodiments in which the principles of the present invention are used. [Figure 1A] Figure 1A shows the inhibitory activity of AZD-5153 in H2009 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 1B] Figure 1B shows the inhibitory activity of AZD-5153 in SW780 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 2A] Figure 2A shows the inhibitory activity of BI-2536 in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 2B] Figure 2B shows the inhibitory activity of BI-2536 in KP4 cells containing wild-type EP300 or in which EP300 is knocked out. [Figure 3] Figure 3 shows the inhibitory activity of BI-894999 in KP4 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 4A] Figure 4A shows the inhibitory activity of BMS-986158 in SW780 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 4B]Figure 4B shows the inhibitory activity of BMS-986158 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 5A] Figure 5A shows the inhibitory activity of GSK525762 in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 5B] Figure 5B shows the inhibitory activity of GSK525762 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 6] Figure 6 shows the inhibitory activity of INCB054329 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 7A] Figure 7A shows the inhibitory activity of OTX-015 in RT11284 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 7B] Figure 7B shows the inhibitory activity of OTX-015 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 7C] Figure 7C shows the inhibitory activity of OTX-015 in SW780 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 7D] Figure 7D shows the inhibitory activity of OTX-015 in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 8A] Figure 8A shows the inhibitory activity of PLX-51107 in RT11284 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 8B] Figure 8B shows the inhibitory activity of PLX-51107 in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 8C] Figure 8C shows the inhibitory activity of PLX-51107 in KP4 cells containing wild-type EP300 or in which EP300 is knocked out. [Figure 9]Figure 9 shows the inhibitory activity of TEN-010 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 10] Figure 10 shows the inhibitory activity of C177(JQ1) in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 11] Figure 11 shows the in vivo activity of PLX-51107 and OTX-015 in a bladder cancer PDX model with a loss-of-function mutation in EP300. [Figure 12] Figure 12 shows the changes in body weight of mice in a bladder cancer PDX model with a loss-of-function mutation in EP300 after administration of PLX-51107 or OTX-015. [Figure 13] Figure 13 shows the inhibitory activity of AZD-5153 in H2009 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 14] Figure 14 shows the inhibitory activity of TEN-010 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 15] Figure 15 shows the inhibitory activity of INCB057643 in KP4 cells with wild-type EP300 or in which EP300 has been knocked out. [Figure 16] Figure 16 shows the inhibitory activity of INCB057643 in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 17] Figure 17 shows the inhibitory activity of INCB057643 in HCC827 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 18] Figure 18 shows the inhibitory activity of CC-90010 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 19]Figure 19 shows the inhibitory activity of BI-2536 in KP4 cells with wild-type EP300 or in which EP300 is knocked out. BI-2536 is a potent Plk1 inhibitor with more than 40-fold specificity to Plk1 compared to BRD4. [Figure 20] Figure 20 shows the inhibitory activity of PLX-51107 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 21] Figure 21 shows the inhibitory activity of PLX-51107 in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 22] Figure 22 shows the inhibitory activity of PLX-51107 in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 23] Figure 23 shows the inhibitory activity of alloblesib in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 24] Figure 24 shows the inhibitory activity of alloblesib in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 25] Figure 25 shows the inhibitory activity of ODM-207 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 26] Figure 26 shows the inhibitory activity of GSK778 in KP4 cells with wild-type EP300 or in which EP300 is knocked out. [Figure 27] Figure 27 shows the inhibitory activity of GSK778 in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 28] Figure 28 shows the inhibitory activity of GSK046 in KP4 cells with wild-type EP300 or in which EP300 has been knocked out. [Figure 29] Figure 29 shows the inhibitory activity of ABBV-744 in Calu1 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 30] Figure 30 shows the inhibitory activity of ABBV-744 in KP4 cells containing wild-type EP300 or in which EP300 is knocked out. [Figure 31] Figure 31 shows the inhibitory activity of compound 5 in KP4 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 32] Figure 32 shows the inhibitory activity of mibeblesib in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 33] Figure 33 shows the inhibitory activity of ZEN-3694 in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 34] Figure 34 shows the inhibitory activity of trotaburesib in KP4 cells having wild-type EP300 or in which EP300 is knocked out. [Figure 35] Figure 35 shows the inhibitory activity of molyblesib in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 36] Figure 36 shows the inhibitory activity of molyblesib in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 37] Figure 37 shows the inhibitory activity of vilabresib in Calu1 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 38] Figure 38 shows the inhibitory activity of vilabrecib in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 39] Figure 39 shows the inhibitory activity of vilabrecib in SW780 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 40] Figure 40 shows the inhibitory activity of vilabrecib in SW1271 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 41]Figure 41 shows the inhibitory activity of INCB054329 in KP4 cells with wild-type EP300 or in which EP300 has been knocked out. [Figure 42] Figure 42 shows the inhibitory activity of BI-894999 in KP4 cells that have wild-type EP300 or in which EP300 is knocked out. [Figure 43] Figure 43 shows the inhibitory activity of perablesib in KP4 cells that have wild-type EP300 or in which EP300 has been knocked out. [Figure 44] Figure 44 shows the inhibitory activity of C177(JQ1) in KP4 cells containing wild-type EP300 or in which EP300 has been knocked out. [Figure 45A] Figure 45A shows a volcano plot illustrating the effect size and significance of driver gene changes in CRISPR knockout / virabrecib pharmacogenetic screening in KP4 cells. [Figure 45B] Figure 45B shows a volcano plot illustrating the effect size and significance of driver gene changes in CRISPR knockout / vilabrecib pharmacogenetic screening in MDAMB231 triple-negative breast cancer cells. [Figure 46A] Figure 46A shows the time course of tumor volume in the PDX model J000108112 of bladder cancer. The mouse model was treated with a vehicle, 20 mg / kg of virabrecib, or 20 mg / kg of PLX-51107. [Figure 46B] Figure 46B shows the time course of body weight in the PDX model J000108112 of bladder cancer. The mouse model was treated with a vehicle, 20 mg / kg of virabrecib, or 20 mg / kg of PLX-51107. [Figure 46C] Figure 46C shows the time course of tumor volume in the PDX model J000108112 of bladder cancer. The mouse model was treated with either a vehicle or 20 mg / kg of virabrecib. [Figure 46D]Figure 46D shows the time course of tumor volume in the PDX model J000108112 of bladder cancer. The mouse model was treated with either a vehicle or 20 mg / kg of PLX-51107. [Figure 47A] Figure 47A shows the time course of tumor volume in the PDX model TM00244, a lung cancer. The mouse model was treated with a vehicle, 20 mg / kg of virabrecib, or 20 mg / kg of PLX-51107. [Figure 47B] Figure 47B shows the time course of body weight in the PDX model TM00244, a lung cancer mouse model. The mouse model was treated with either a vehicle, 20 mg / kg of virabrecib, or 20 mg / kg of PLX-51107. [Figure 47C] Figure 47C shows the time course of tumor volume in the PDX model TM00244, a lung cancer mouse model. The mouse model was treated with either a vehicle or 20 mg / kg of virabrecib. [Figure 47D] Figure 47D shows the time course of tumor volume in the PDX model TM00244, a lung cancer mouse model. The mouse model was treated with either a vehicle or 20 mg / kg of PLX-51107. [Modes for carrying out the invention]

[0042] While various embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions can be conceived by those skilled in the art without departing from the present invention. It should be understood that various alternative forms to the embodiments of the present invention described herein may be used.

[0043] This disclosure provides novel methods for treating or preventing cancer that result in unexpectedly superior inhibition of cancer cells or cancer treatment. The methods provided herein can overcome challenges associated with BET inhibitors by utilizing synthetic lethality.

[0044] Precision medicine can offer several modern approaches to cancer treatment. Targeted therapies can leverage disease biology and be designed to define which patients should receive specific treatments. One concept underlying this approach is that the molecular characteristics of a patient's tumor can influence the clinical response to drugs and, therefore, can be used to guide treatment (e.g., drug selection). Thus, precision medicine can result in increased efficacy (e.g., inhibition of tumor cell growth or increased death) and reduced toxicity.

[0045] Tumor genetics can be central to this approach. For example, cancer can be caused by driver mutations that provide a selective advantage and enable the proliferation of cancer cells. Driver mutations can be used to define patients and can be highly predictive of drug activity; that is, the presence of a particular driver mutation can be an indicator of the effectiveness of a given treatment. Approximately one-third of cancers can be caused by driver mutations that induce gain-of-function (GOF) oncogenes, resulting in protein products that can be therapeutically targeted. The remaining two-thirds of cancers are caused by loss-of-function (LOF) mutations in tumor suppressor genes (TSGs). In normal cells, TSGs can act to regulate cell growth and division. Loss-of-function mutations in these genes can lead to uncontrolled growth and cancer. Such cancers are typically more difficult to target than cancers caused by GOF mutations because, in cancers caused by LOF mutations, there is no functional protein that leads to tumorigenesis. Therefore, target identification is more difficult. Evidence of this disparity in treatability is that drugs exist for approximately two-thirds of oncogenes, but only about 2% of tumor suppressor genes (e.g., PARPi-targeted homologous recombination deficiencies, e.g., BRCA1 / 2, ATM, ATR mutations). One potential approach to targeting LOF cancers is to leverage the vulnerability specific to tumor cells by identifying synthetic lethal (SL) interactions. In synthetic lethal relationships between two genes, loss of function of either, rather than both, is acceptable. Since only tumor cells contain driver mutations, drugs that specifically target these mutations are expected to affect only these tumor cells, minimizing off-target effects such as toxicity. This approach can be applied to identify both the genetic dependence and small molecule sensitivity of cancer cell lines. Evidence of the importance of this approach is that a massive and ongoing effort by a large consortium is underway to comprehensively map synthetic lethal networks in hundreds of cancer cell lines, aiming to identify drug targets and the patients expected to respond best to them.

[0046] While these efforts offer valuable insights and identify potential drug candidates, significant challenges remain. For example, many patients do not benefit from targeted therapies because large-scale screenings generate new target predictions and feed them into the early stages of the drug pipeline, taking several years to act on; drugs identified in screenings (e.g., small molecule screenings) may not replicate gene perturbation profiles; and synthetic lethal relationships identified in cell lines may not translate to tumors in patients.

[0047] Several systematic approaches, such as Cancer Dependency Maps, have provided a comprehensive mapping of synthetic lethality in human cancer cells. Based on drug targets with synthetic lethality relationships between mutations widely observed in cancer patients, it is possible to predict new drug uses as genetically targeted therapies for cancer. However, this approach has limitations because pharmacological inhibition rarely replicates gene deletions of known drug targets. For further information, see Goncalves E et al., Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens. Mol.Syst.Biol.2020,16,e9405, and also Babak T et al., Abstract 4035:Driver-gene dependencies reveal clinically actionable drug repositioning opportunities, Cancer Res(2022)82(12_Supplement):4035.

[0048] The development of resistance to BET inhibitors is a growing concern because resistance can emerge early in the treatment of certain cancers. The mechanisms leading to BET inhibitor resistance are multifactorial. Interestingly, none of the reported resistance mechanisms are associated with bromodomain (i.e., BRD2 / 3 / 4 mutations) genetic abnormalities. In ovarian cancer, long-term treatment with BET inhibitors has been reported to induce receptor tyrosine kinase reprogramming and subsequent resistance to BET inhibitors. In colorectal cancer, activated interleukin 6 / 8-Janus kinase 2 signaling is known to promote Brd4 phosphorylation. For this purpose, phosphorylated Brd4 is more stable and binds to BET inhibitors with lower affinity, thus contributing to BET inhibitor resistance. In AML and pancreatic cancer cells, compensatory upregulation of MYC via the WNT pathway has been reported to reduce the responsiveness of these cancer cells to BET inhibitors. Furthermore, JQ1-resistant AML cells did not undergo apoptosis but were switched to pro-survivability autophagy. JQ-1-induced autophagy in resistant AML cells was associated with becrin 1 upregulation, increased LC3-II expression, and autophagosome accumulation, which was independent of mTOR signaling. In triple-negative breast cancer, resistance to BET inhibitors was mediated by a bromodomain-independent mechanism. In prostate cancer, loss-of-function mutations in SPOP (Brd4 E3 ubiquitin ligase) have been shown to confer resistance to BET inhibitors by impairing ubiquitination-mediated Brd4 degradation. Maintaining MYC expression has also been reported to promote de novo resistance to BET inhibitors in castration-resistant prostate cancer. Acquired resistance has been shown to emerge after long-term treatment with CRBN or VHL-based BET-targeted protacs by genomic modifications that impair the core components of the CRBN or VHL E3 ligase complex.On the other hand, hyperphosphorylation of Brd4 caused by downregulation of phosphatase PP2A and increased expression ratio of BCL2L1 / BCL-XL has also been reported to contribute to BET inhibitor resistance in triple-negative breast cancer. In pancreatic cancer, long-term treatment with JQ1 has been shown to induce a rebound increase in BET inhibitor target genes including FOSL1 and HMGA2. Exploring the synthetic lethal relationship with BET inhibitors may provide a solution to this concern.

[0049] Synthetic lethality refers to a phenomenon in which simultaneous loss of function or deletion of two genes (or a combination of both) leads to cell death, whereas loss of function of either single gene alone does not cause cell death. This concept can be used in cancer research as a therapeutic strategy for target identification, wherein the objective is to identify pairs of genes whose combined inhibition results in cell death in cancer cells but does not cause death of non-cancerous cells. The key concept underlying synthetic lethality may lie in targeting vulnerabilities in cancer cells that do not exist in normal cells. Since cancer cells already carry mutated genes, a promising approach may be to identify a synthetic lethal partner for one of the mutated genes, and then target it pharmacologically. However, the identification of synthetic lethal gene pairs and the further identification of pharmaceutical interventions for use in targeting synthetic lethal partners remain significant challenges.

[0050] In certain embodiments, the present disclosure provides methods and kits for treating cancer via synthetic lethality. Synthetic lethality can occur in cancers comprising a loss-of-function mutation of the EP300 gene or deletion of EP300 resulting from administration of a BET inhibitor. In some embodiments, the methods provided herein comprise determining the presence of a mutation or deletion of the EP300 gene (e.g., in a subject). In some embodiments, the methods comprise treating a cancer comprising a loss-of-function mutation in the EP300 gene or a deletion of the EP300 gene or a portion thereof. In some embodiments, the loss-of-function mutation is in the EP300 gene. In some embodiments, the deletion is a deletion of the EP300 gene. In some embodiments, the BET inhibitor inhibits BRD2, BRD3, BRD4, or a combination thereof. In some embodiments, the BET inhibitor inhibits BD1 or BD2. In some embodiments, the BET inhibitor inhibits BD2. In some embodiments, the BET inhibitor is a selective BD2 inhibitor. In some embodiments, the selective BD2 inhibitor comprises GSK046, ABBV-744, or Compound 9. In some embodiments, the BET inhibitor is a selective BD1 inhibitor. In some embodiments, the selective BD1 inhibitor comprises GSK778.

[0051] I. Methods of Treating Cancer In some embodiments, provided herein is a method of treating cancer in a subject in need of cancer treatment, comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and extra-terminal domain (BET) inhibitor, and the cancer has previously been determined to comprise loss of function or deletion of the EP300 gene. In some embodiments, the loss of function is caused by a genetic mutation. In some embodiments, the patient is

[0052] ## Chemical Formula## or

[0053] [ka] They are not receiving both simultaneously. In some embodiments, the method includes the condition that the BET inhibitor does not inhibit CREB-binding protein (CREBBP). In some embodiments, the method includes the condition that the BET inhibitor does not inhibit Plk1. In some embodiments, the BET inhibitor is at least 10 times more selective to BET than to Plk1. In some embodiments, the method includes the condition that the BET inhibitor is not JQ1. In some embodiments, the method includes the condition that the cancer is not triple-negative breast cancer. In some embodiments, the method includes the condition that the BET inhibitor is not JQ1 and the cancer is not triple-negative breast cancer.

[0054] In some embodiments, this specification further provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, the cancer has been determined to involve a decrease in the amount or activity of p300 compared to wild-type p300, and the patient has not received compound 1 or compound 2 simultaneously, or has not previously received compound 1 or compound 2. In some embodiments, the cancer has been determined to involve a decrease in the amount of p300 compared to wild-type p300. In some embodiments, the cancer has been determined to involve a decrease in the activity of p300 compared to wild-type p300. In some embodiments, the method includes the condition that the BET inhibitor does not inhibit CREB-binding protein (CREBBP). In some embodiments, the method includes the condition that the BET inhibitor does not inhibit Plk1. In some embodiments, the method includes the condition that the BET inhibitor is not JQ1. In some embodiments, the method includes the condition that the cancer is not triple-negative breast cancer. In some embodiments, the method includes the condition that the BET inhibitor is not JQ1 and the cancer is not triple-negative breast cancer.

[0055] In some embodiments, the subject has not received compound 1 or compound 2 and the BET inhibitor simultaneously. In some embodiments, the subject has not previously received compound 1 or compound 2. In some embodiments, the above BET inhibitors include ABBV-075, ABBV-744, Apabetalon, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, and OMT-001. This includes OMT-002, OTX-015, Perablecib, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, ZEN-3694, CPI-0610, INCB0543294, JAB-8263, INCB057643, CC-90010, Alloblecib, GSK778, GSK046, Mibeblecib, Trotablecib, Molyblecib, Perablecib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or a combination thereof. In some embodiments, the BET inhibitor includes compound 5. In some embodiments, the BET inhibitor includes compound 9. In some embodiments, the above BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof.In some embodiments, the BET inhibitor is a small molecule compound.

[0056] In some embodiments, the BET inhibitor is defined by formula (I):

[0057] [ka] The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 is a (C1-C3) alkyl group optionally substituted with cyano, halo, or 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy, where X is halo, if present. In some embodiments, R 1 is (C1-C2)alkyl, cyano, or fluoro. In some embodiments, R 1 is methyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 It is cyano.

[0058] In some embodiments, the BET inhibitor is defined by formula (II):

[0059] [ka] The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 R is a (C1-C3) alkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy. In some embodiments, R 1 It is methyl.

[0060] In some embodiments, the BET inhibitor is expressed by formula (III):

[0061] [ka] comprising the compound or a pharmaceutically acceptable salt thereof, wherein X, when present, is halo.

[0062] In some embodiments, the BET inhibitor is of Formula IV:

[0063]

Chemical structure

[0064]

Chemical structure

[0065] [ka] Selected from, Y1 is N or CR Y1 Selected from, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from, R Y1 and R Y2 Each of these elements appears independently as follows: hydrogen, deuterium, halogen, -OH, NH2, -CN, -C 1_6 Alkyl, or -C 1-6 Selected from alkoxy, R3 and R4, independently, each instance, represent hydrogen, deuterium, or -C. 1-6Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -NH2, -CN, or -C 1-6 Alkyl, or -C 1-6 Selected from alkoxy, n is selected from 0, 1, 2, 3, 4, 5, or 6. W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 A 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, N, or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 4-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 5-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, or O; a 3-membered carbocyclic structure; a 4-membered carbocyclic structure; a 5-membered carbocyclic structure; or a 6-membered carbocyclic structure, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent being deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, or -C 1-3 Alkyl, or -C 1-3 Selected from alkoxy, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C 1-3A 5-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S; a 6-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 7-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; an 8-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 9-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 10-membered heteroaryl compound containing 1, 2, or 3 heteroatoms selected from N, O, or S; and a compound containing 1, 2, or 3 heteroatoms selected from N, O, or S. A 3-membered heterocyclic structure, a 4-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, O, or S, a 5-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, O, or S, a 6-membered heterocyclic structure containing 1, 2, or 3 heteroatoms selected from N, O, or S, a 3-membered carbocyclic structure, a 4-membered carbocyclic structure, a 5-membered carbocyclic structure, or a 6-membered carbocyclic structure, each independently and optionally substituted with 1, 2, 3, 4, or 5 substituents, each substituent selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, Z represents hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, and -C. 1-6 Alkyl, or -C 1-6 Selected from alkoxy.

[0066] In some embodiments, R1 is hydrogen, deuterium, -C 1-6 Alkyl, or -C 3-8 Selected from carbocyclic formulas, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C 1-8Alkyl, or -C 1-8 Selected from alkoxy, R2 is hydrogen, deuterium, halogen, -C 1-8 Alkyl,

[0067] [ka] carboxyl, -COOR 21 , or -CONR 21 R 22 These are selected from, and each is independently substituted with 1, 2, 3, 4, 5, or 6 substituents as it appears, and each substituent is independently substituted with deuterium, halogen, -OH, -CN, -NH2, -C as it appears 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O, R 21 and R 22 Each of these elements appears independently as follows: hydrogen, deuterium, -OH, NH2, -CN, -C 1-8 Alkyl, or -C 3-8 Selected from carbocyclic structures, R 23 and R 24 Each of these independently, each instance of it, is either hydrogen, deuterium, or -C. 1-8 Selected from alkyl groups, A is

[0068] [ka] Selected from, Y1 is N or CR Y1 Selected from, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from, R Y1 and R Y2Each of these elements appears independently as follows: hydrogen, deuterium, halogen, -OH, NH2, -CN, -C 1-6 Alkyl, or -C 1-6 Selected from alkoxy, R3 and R4, independently, each instance, represent hydrogen, deuterium, or -C. 1-6 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -NH2, -CN, or -C 1-6 Alkyl, or -C 1-6 Selected from alkoxy, n is selected from 0, 1, or 2. W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 A six-membered heterocyclic formula is selected, containing one, two, or three heteroatoms selected from alkoxy, N, and O, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent being deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, or -C 1-3 Alkyl, or -C 1-3 Selected from alkoxy, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C 1-3 Selected from a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S, and a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S, each independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each substituent selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, Z is hydrogen, deuterium, halogen, -NH2, -CN, -OH, or -C 1-6 Selected from alkoxy.

[0069] In some embodiments, R 1 is hydrogen, deuterium, or -C 1-6 Selected from alkyl groups. In some embodiments, R 1 R is selected from hydrogen. In some embodiments, R 1 R is selected from deuterium. In some embodiments, R 1 is -C 1-6 Selected from alkyl groups.

[0070] In some embodiments, R2 is hydrogen, deuterium, halogen, -C 1-8 Alkyl,

[0071] [ka] , or -CONR 21 R 22 These are selected from, and each is independently substituted with 1, 2, 3, 4, 5, or 6 substituents as it appears, and each substituent is independently substituted with deuterium, halogen, -OH, -CN, -NH2, -C as it appears 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The structure is selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O. In some embodiments, R2 is hydrogen, deuterium, halogen, -C 1-8 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -CN, -NH2, or -C 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8The structure is selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O. In some embodiments, R2 is hydrogen, -C 1-8 Selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, -OH, -CN, -NH2, or -C 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The structure is selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O. In some embodiments, R2 is -C 1-8 Selected from alkyl groups, which are independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time they appear, and each substituent is independently and optionally substituted with deuterium, halogen, -OH, -CN, -NH2, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The carbon atom is selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O. In some embodiments, R 21 and R 22 Each of these independently, upon appearance, is either hydrogen, deuterium, -OH, NH2, or -C. 3-8 Selected from carbocyclic formulas. In some embodiments, R 21 and R 22 Each of these is independently selected from hydrogen or deuterium each time it appears. In some embodiments, R 21 and R 22 It is selected from hydrogen.

[0072] In some embodiments, R 23 and R 24 Each of these independently, each time it appears, contains either hydrogen or -C. 1-8 Selected from alkyl groups. In some embodiments, R 23 and R 24 Each of these is independent, and each time it appears, -C 1-2Selected from alkyl groups.

[0073] In some embodiments, A is

[0074] [ka] Selected from. In some embodiments, A is

[0075] [ka] Selected from. In some embodiments, A is

[0076] [ka] Selected from. In some embodiments, Y1 is N or CR Y1 Selected from. In some embodiments, Y1 is selected from N. In some embodiments, Y1 is CR Y1 Selected from. In some embodiments, Y2 is O, S, CR Y1 R Y2 , or NR Y2 Selected from. In some embodiments, Y2 is selected from O. In some embodiments, Y2 is selected from S. In some embodiments, R Y1 and R Y2 Each of these independently, each instance of it, is either hydrogen, deuterium, or -C. 1-6 Selected from alkyl groups.

[0077] In some embodiments, R3 and R4 are, independently, hydrogen, deuterium, or -C each time they appear. 1-6 Selected from alkyl groups, each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent independently substituted with deuterium, halogen, or -C 1-6Selected from alkoxy. In some embodiments, R3 and R4 are each independently, -C each time they appear. 1-6 They are selected from alkyl groups, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent independently and optionally selected from deuterium.

[0078] In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 1. In some embodiments, n is selected from 2.

[0079] In some embodiments, W1 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-6 Alkyl, -C 1-6 A six-membered heterocyclic formula is selected from alkoxy, N, and O, containing one, two, or three heteroatoms, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent selected from deuterium, halogen, -NH2, -CN, or -OH. In some embodiments, W1 is -C 1-6 Selected from a six-membered heterocyclic formula containing one or two heteroatoms selected from alkyl and O, each independently optionally substituted with one, two, three, four, five, or six substituents, each substituent selected from deuterium, halogen, or -OH. In some embodiments, W1 is -C 1-6 A six-membered heterocyclic formula is selected, containing one heteroatom selected from alkyl and oxygen, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent selected from halogens.

[0080] In some embodiments, W2 is hydrogen, deuterium, -F, -Cl, -NH2, -CN, -OH, carboxyl, -C 1-3 Alkyl, -C1-3 W2 is selected from a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from alkoxy, phenyl, N, O, or S, each independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each substituent selected with deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy. In some embodiments, W2 is selected from a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from phenyl, N, each independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each substituent selected with deuterium, halogen, methyl, or methoxy. In some embodiments, W2 is selected from phenyl, which is independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from N, which is independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from N, which is selected from N, which is independently optionally substituted with 1, 2, 3, 4, or 5 substituents, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from N, which is selected from N, which is independently substituted with 1, 2, 3, 4, or 5 substituents, each of which substituents is selected from deuterium, halogen, methyl, or methoxy, each of which substituents is selected from N, which is independently substituted with 1, 2, 3

[0081] In some embodiments, Z is selected from hydrogen, deuterium, or halogens. In some embodiments, Z is selected from hydrogen or halogens. In some embodiments, Z is selected from hydrogen.

[0082] In some embodiments, the BET inhibitor is compound 5:

[0083] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0084] In some embodiments, the BET inhibitor is compound 6:

[0085] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0086] In some embodiments, the BET inhibitor is compound 7:

[0087] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0088] In some embodiments, the BET inhibitor is compound 8:

[0089] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0090] In some embodiments, the BET inhibitor is (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridine-2-yl)butyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxamide, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-amine, 2-(4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazole-5-yl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridine-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, and Selected from 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)methyl)morpholine.

[0091] In some embodiments, the BET inhibitor comprises (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol.

[0092] In some embodiments, the BET inhibitor is defined by formula (Va):

[0093] [ka] A compound having, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof, R 2 H is R 4 H is R 6 H is R 7 H, -OH, C 1-6 Alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, R 1 This is 1 to 3 R j A heteroaryl compound that has been optionally substituted with the base compound. R j These are, independently, halogen, -CN, -OH, -NH2, -NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -CH=C(R k )(R k ), -OR k , -SR k ,-OC(O)Rk 、-OC(S)R k 、-P(=O)HR k 、-P(=O)R k R k 、-PH(=O)OR k 、-P(=O)(OR k )2、-OP(=O)(OR k )2、-C(O)H、-O(CO)OR k 、-C(O)R k 、-C(S)R k 、-C(O)OR k 、-C(S)OR k 、-S(O)R k 、-S(O)2R k 、-C(O)NHR k 、-C(S)NHR k 、-C(O)NR k R k 、-C(S)NR k R k 、-S(O)2NHR k 、-S(O)2NR k R k 、-C(NH)N HR k 、-C(NH)NR k R k 、-NHC(O)R k 、-NHC(S)R k 、-NR k C(O)R k 、-NR k C(S)R k 、-NHS(O)2R k 、-NR k S(O)2R k 、-NHC(O)NHR k 、-NHC(S)NHR k 、-NR k C(O)NH2、-NR k C(S)NH2、-NR k C(O)NHR k 、-NR k C(S)NHR k 、-NHC(O)NR k R k 、-NHC(S)NR k R k 、-NR k C(O)NR kR k , -NR k C(S)NR k R k , -NHS(O)2NHR k , -NR k S(O)2NH2, -NR k S(O)2NHR k , -NHS(O)2NR k R k , -NR k S(O)2NR k R k , -NHR k , or -NR k R k Selected from, R k These are H and C, respectively, independently. 1-6 Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl, Two R's k When the groups are bonded to the same carbon or nitrogen atom, they unite to form a 3-6 membered carbocyclic ring or a 3-8 membered heterocyclic ring having 1-2 heteroatoms as ring members selected from O, N, or S, and the nitrogen or sulfur ring atom is optionally oxidized. R 3 H, halogen, -CN, and C substituted by any choice 1-6 Alkyl, optionally substituted deuterated C 1-6 Alkyl, optionally substituted aryl, optionally substituted aryl-C 1-4 Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C 1-4 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkyl-C 1-4 Alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkyl-C 1-4 It is alkyl, R 5 D, halogen, C1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, or 1-2 R selected independently of -CN 11 Replaced by arbitrary selection in the base

[0094] [ka] And, In the formula, the wavy line indicates the bond point to the rest of the molecule.

[0095] In some embodiments, the BET inhibitor is expressed by formula (VI):

[0096] [ka] The compound comprises a compound having, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 is a (C1-C3) alkyl group optionally substituted with cyano, halo, or 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy, where X is halo if present, and R 2 This is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from H, (C1-C3) alkyl, aryl, heteroaryl, N, and O, or a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is (C1-C2)alkyl, cyano, or fluoro. In some embodiments, R 1 is methyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is cyano. In some embodiments, R 2 is H. In some embodiments, R 2 This is a six-membered heteroaryl compound containing one, two, or three heteroatoms selected from N and O. In some embodiments, the BET inhibitor is compound 3:

[0097] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0098] In some embodiments, the BET inhibitor is compound 4:

[0099] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0100] In some embodiments, the BET inhibitor is defined by formula (VII):

[0101] [ka] This includes compounds having, or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs thereof, where R is N, O, or S.

[0102] In some embodiments, the BET inhibitor is compound 9:

[0103] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0104] In some embodiments, the above BET inhibitor is ABBV-744:

[0105] [ka] or comprising pharmaceutically acceptable salts, tautomers, solvates, or deuterated analogs thereof.

[0106] In some embodiments, the cancers described above include bladder cancer, lung cancer, gynecological cancer, adrenocortical cancer, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, nerve sheath tumor, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof.

[0107] In some embodiments, the cancer includes lung cancer. In some embodiments, the lung cancer includes non-small cell lung cancer. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma. In some embodiments, the non-small cell lung cancer includes large cell carcinoma. In some embodiments, the non-small cell lung cancer includes adenocarcinoma. In some embodiments, the lung cancer includes small cell lung cancer. In some embodiments, the cancer includes breast cancer. In some embodiments, the breast cancer includes triple-negative breast cancer. In some embodiments, the BET inhibitor includes AZD-5153, INCB57643, OTX-015, PLX-51107, or a combination thereof. In some embodiments, the above BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof.

[0108] In some embodiments, the cancer includes squamous cell carcinoma. In some embodiments, the cancer includes bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the cancer includes squamous cell carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the BET inhibitor includes AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or a combination thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, alloblecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the BET inhibitors include BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof.

[0109] In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumor. In some embodiments, the lymphoma includes non-Hodgkin lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma. In some embodiments, the lymphoma includes mature B-cell tumor. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumor, esophageal and gastric cancer, gastrointestinal neuroendocrine tumor, small intestine cancer, anal cancer, colon cancer, or a combination thereof.

[0110] In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors. In some embodiments, the gastrointestinal cancer includes esophageal and gastric cancers. In some embodiments, the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small intestine cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer. In some embodiments, the colon cancer includes colorectal cancer.

[0111] In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the endometrial cancer includes endometrial cancer of the uterine body. In some embodiments, the uterine sarcoma includes carcinosarcoma. In some embodiments, the BET inhibitor inhibits one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor inhibits BRD3 and BRD4. In some embodiments, the BET inhibitor inhibits BRD4 and BRD2. In some embodiments, the BET inhibitor inhibits the BD1 bromodomain or BD2 bromodomain of BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor includes a selective BET inhibitor. In some embodiments, the selective BET inhibitor inhibits one or more of the following bromodomains, namely BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor is selective for BRD4 and BRD2. In some embodiments, the selective BET inhibitor is selective for BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor selectively inhibits BD1. In some embodiments, the selective BET inhibitor selectively inhibits BD2. In some embodiments, the selective BD2 inhibitor includes GSK046, ABBV-744, or compound 9. In some embodiments, the selective BD1 inhibitor includes GSK778. In some embodiments, the selective BET inhibitor inhibits the BD1 bromodomain or BD2 bromodomain of BRD2, BRD3, and BRD4. In some embodiments, the loss of function or deletion is directed at the EP300 gene.

[0112] In some embodiments, the BET inhibitor includes JAB-8263. In some embodiments, the BET inhibitor includes a compound of formula IV. In some embodiments, the BET inhibitor includes compound 5. In some embodiments, the BET inhibitor includes compound 9.

[0113] In some embodiments, the cancer includes midline NUT cancer. In some embodiments, the cancer includes castration-resistant prostate cancer. In some embodiments, the cancer includes solid tumors or humoral tumors. In some embodiments, the humoral tumor is selected from myelofibrosis. In some embodiments, the humoral tumor is selected from myeloma and leukemia. In some embodiments, the humoral tumor is selected from myeloma. In some embodiments, the humoral tumor is selected from leukemia. In some embodiments, the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is selected from acute myeloid leukemia (AML). In some embodiments, the leukemia is selected from acute lymphoblastic leukemia (ALL).

[0114] a. BET inhibitors BET proteins may possess two N-terminal bromodomains (e.g., BD1 and BD2), a structural feature common to other BRD proteins, which allows them to interact with acetylated lysine residues on histones. BET proteins may structurally differ from other bromodomain-containing proteins by containing a C-terminal extraterminal (ET) domain. This ET domain can interact with various cellular proteins, such as histone-lysine N-methyltransferase (NSD3) and Jumonji domain-containing 6 (JMJD6), whose interactions are involved in acute myeloid leukemia (AML) and various solid tumors, respectively. The combination of dual BRDs and protein-interacting ET domains may enable BET proteins to effectively mediate two-way anchoring of these cancer-related factors to specific regions of chromatin.

[0115] BET proteins consist of four members conserved in mammals, including BRD-containing 2 (BRD2), BRD3, BRD4, and Brdt. Brdt is primarily expressed in germ cells, while BRD2, BRD3, and BRD4 are ubiquitously expressed in various tissues. All BET proteins employ a left-handed four-helix bundle structure called the "BRD fold" (αZ, αA, αB, and αC). The αZ-αA (ZA) loop and αB-αC (BC) loop between the helices constitute hydrophobic pockets that recognize acetylated lysine residues. Sequence mutations in the ZA and BC loops of different BRD folds in different BET proteins result in differences in their protein binding sites and affinities. Multiple BET proteins may be required for the rapid induction of selected target genes. Therefore, different BET proteins may have non-overlapping functions and can form protein complexes with each other to induce their biological activity.

[0116] BET proteins can act as transcription regulators. For example, BRD4 recruits PTEF-β (a positive transcription elongation factor, a multiprotein complex essential for transcriptional regulation) to the active transcription sites of cell growth-promoting genes such as MYC and NUT. During transcription elongation, BRD4 phosphorylates RNA polymerase II by directing the proper nuclear localization and activation of PTEF-β. Therefore, BRD4 can play an important role in promoting the enhancement of basal transcription to active elongation by RNA polymerase II. On the other hand, the ET domain of BRD4 is known to further promote gene transcription by recruiting other transcription activators, including NSD3, JMJD6, and CHD4. BRD3, on the other hand, specifically binds to the GATA1 transcription factor and upregulates the expression of GATA1-dependent genes. BRD2 is known to interact with E2F, histone acetyltransferase, and histone deacetylase, recruiting them to gene promoters, thereby linking histone acetylation and transcription in a PTEF-β-independent manner.

[0117] The BET family of proteins (e.g., BRD2, BRD3, and BRD4) are of clinical importance due to their roles in cell cycle regulation, epigenetic sensing, and cancers ranging from oral cancer, breast cancer, prostate cancer, lung cancer, and colon cancer to myeloid leukemia. BET proteins contain a dual bromodomain, a domain present in various cellular proteins that selectively binds to acetylated histone marks. These include the histone-lysine N-methyltransferase protein ASH1L, histone acetyltransferase p300 (EP300), P300 / CBP-related factor (PCAF), and the extended BET family. Current therapeutic approaches rely on small molecule acetylation mimes that block the bromodomain's ability to bind to its specific chromatin marks. Cancer inhibitors targeting bromodomains are clinically limited due to dose-limiting toxicity, as they target any protein containing a bromodomain. There is considerable interest in developing novel BET inhibitors for cancer treatment. Many new candidates are currently undergoing early-stage clinical trials (Targeting BET bromodomains in cancer: Patric Trojer, Annual Review of Cancer Biology, 2022, Vol. 6, pp. 313-336; Achieving clinical success with BET inhibitors as anti-cancer agents: Schorstova, British Journal of Cancer, Vol. 124, pp. 1478-1490 (2021)).

[0118] In some embodiments, the above BET inhibitors include ABBV-075, ABBV-744, Apabetalon, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, and OMT. This includes -001, OMT-002, OTX-015, perabreciv, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, ZEN-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, allobreciv, GSK778, GSK046, mibebleciv, trotabreciv, molybreciv, perabreciv, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, JAB-8263, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, alloblecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153. In some embodiments, the BET inhibitor includes BI-894999. In some embodiments, the BET inhibitor includes BMS-986158. In some embodiments, the BET inhibitor includes GSK525762.In some embodiments, the BET inhibitor includes INCB054329. In some embodiments, the BET inhibitor includes TEN-010. In some embodiments, the BET inhibitor includes PLX-51107. In some embodiments, the BET inhibitor includes PLX-2853. In some embodiments, the BET inhibitor includes OTX-015. In some embodiments, the BET inhibitor includes JAB-8263. In some embodiments, the BET inhibitor includes INCB057643. In some embodiments, the BET inhibitor includes CC-90010. In some embodiments, the BET inhibitor includes alloblecib. In some embodiments, the BET inhibitor includes ODM-207. In some embodiments, the BET inhibitor includes GSK778. In some embodiments, the BET inhibitor includes GSK046. In some embodiments, the BET inhibitor includes ABBV-744. In some embodiments, the BET inhibitor includes mibeblecib. In some embodiments, the BET inhibitor comprises trotabrecib. In some embodiments, the BET inhibitor comprises molybrecib. In some embodiments, the BET inhibitor comprises virabrecib. In some embodiments, the BET inhibitor comprises perabrecib. In some embodiments, the BET inhibitor comprises a compound of formula IV. In some embodiments, the BET inhibitor comprises compound 5. In some embodiments, the BET inhibitor comprises compound 9. A non-limiting description of some exemplary BET inhibitors is provided below.

[0119] i.JQ1 JQ1 (thieno-triazolo-1,4-diazepine) is a BET inhibitor designed to mimic acetylated lysine. It has been shown to competitively and specifically bind to the BD1 and BD2 bromodomains with high affinity and to form hydrogen bonds with conserved asparagine residues in the binding pocket. Using chromatin immunoprecipitation and fluorescence recovery after photobleaching assays, JQ1 was shown to displace BRD4 from chromatin and thus modulate bromodomain regulatory genes. JQ1 showed potent antiproliferative activity against BRD4-dependent cancer cell lines and against NMCs. However, JQ1 did not demonstrate good efficacy due to its short half-life and rapid metabolism.

[0120] [ka]

[0121] ii. Vilabreciv Virabrecib, also known as OTX-015, is a potent bromodomain inhibitor of BRD2, BRD3, and BRD4, exhibiting an IC50 in the range of 92–112 nM. Virabrecib (500 nM) showed a strong decrease in BRD2, BRD4, and c-MYC, as well as an increase in HEXIM1 protein. Virabrecib treatment at concentrations of 0.1, 1, and 5 μM induced full-length HIV-1 transcripts and viral growth in quiescent CD4+ T cells from infected individuals receiving suppressive antiretroviral therapy (ART), while having minimal impact on toxicity and T cell activation. Virabrecib-mediated HIV-1 activation is accompanied by increased CDK9 occupancy and increased phosphorylation of the C-terminal domain (CTD) of RNAP II.

[0122] [ka]

[0123] iii. PLX-51107 PLX-51107, often referred to as OPN-51107, has been shown to be a potent BET inhibitor with Kd values ​​of 1.6, 2.1, 1.7, and 5 nM for BRD2, BRD3, BRD4, and BRDT against BD1, and 5.9, 6.2, 6.1, and 120 nM for BD2, respectively. PLX-51107 also interacts with the bromodomains of CBP and EP300 (Kd in the range of 100 nM). PLX-51107 (0.156~10 μM) suppresses CpG-induced proliferation. PLX-51107 may also induce accumulation of p21 and IκBα, reduce c-MYC levels, and modulate pro-apoptotic and anti-apoptotic proteins. PLX-51107 may selectively modulate CLL driver genes and interact with BRD2, BRD3, and BRD4.

[0124] [ka]

[0125] iv.PLX-2853 PLX-2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor exhibiting low nanomolar potency and moderate preference for binding to the second of the two bromodomains of the BET protein. By modulating core genes for leukemia cell proliferation and survival (e.g., BCL2 and MYC), PLX-2853 demonstrated broad antileukemic activity in preclinical models, both as a monotherapy and in combination with other agents. The pharmacokinetic (PK) profile in patients with solid tumors revealed high peak plasma concentrations, a short terminal phase half-life (T1 / 2 < 3 hours), and near-complete elimination from plasma by 9 hours post-administration. This PK profile is hypothesized to improve tolerability by enabling transient target binding followed by daily post-administration recovery time. For further information regarding BET inhibitors, please refer to U.S. Patent Application No. 9,771,363, published on March 23, 2027, titled "Heterocyclic compounds and uses thereof," which is incorporated herein by reference in its entirety.

[0126] v.JAB-8263 JAB-8263 is a potent BET inhibitor with sub-nanomolecular binding affinity. Preclinical studies have shown that JAB-8263 can effectively inhibit tumor growth, including both hematological and solid tumors, at very low concentrations. A multicenter, open-label Phase I / IIa clinical trial is currently underway in China and the United States. For more information on BET inhibitors such as JAB-8263, please refer to U.S. Patent Application No. 11,466,005, published October 11, 2022, and U.S. Patent Application No. 2021 / 0179617, published June 17, 2021, both titled “Tricyclic Compounds,” which are incorporated herein by reference.

[0127] b. The role of the EP300 gene in cancer The EP300 gene, also known as the E1A-binding protein P300, is a gene that codes for a protein involved in various cellular processes, including gene regulation, DNA repair, and cell growth and development.

[0128] The protein encoded by the EP300 gene is a histone acetyltransferase, meaning it can modify the structure of chromatin (the complex of DNA and proteins in the nucleus) by adding acetyl groups to histone proteins. This modification is important for regulating gene expression because it makes DNA more accessible to transcription factors and other cellular mechanisms involved in gene transcription.

[0129] In addition to its role in histone acetylation and gene regulation, the p300 protein interacts with a wide range of other proteins and is involved in various intracellular signaling pathways and molecular interactions. The p300 protein plays a crucial role in embryonic development, cell differentiation, and responses to environmental stimuli.

[0130] Mutations or dysregulations in the EP300 gene are associated with a variety of diseases and conditions, including certain cancers (such as colorectal and hematological malignancies), developmental disorders, and neurological disorders.

[0131] The EP300 protein may play an essential role in regulating cell proliferation and differentiation; therefore, loss-of-function mutations or deletions in the EP300 gene may result in cancer or exacerbate cancer severity or metastasis. Cancers containing mutated or deleted EP300 are thought to account for more than 4% of all cancers. However, loss of function in the EP300 gene has been shown to be particularly common in bladder cancer, lung cancer, and pancreatic cancer (Table 1). Furthermore, studies have shown that tumors with EP300 mutations are associated with pathological T stage and lymph node metastasis, and result in a shortened predicted cumulative survival. Therefore, there is a need to provide treatment for subjects with cancers including those with mutated or deleted EP300.

[0132] The methods provided herein may be useful for treating cancers involving EP300 loss-of-function mutations or EP300 gene deletions.

[0133] In some embodiments, cancers containing EP300 loss-of-function mutations or EP300 deletions include breast cancer, urothelial carcinoma, rectal cancer, thymic carcinoma, sarcoma, or combinations thereof. In some embodiments, cancer includes bladder cancer, rectal cancer, breast cancer, sarcoma, thymic carcinoma, or combinations thereof. In some embodiments, cancer includes bladder cancer. In some embodiments, cancer includes rectal cancer. In some embodiments, cancer includes breast cancer. In some embodiments, the cancer includes sarcoma. In some embodiments, cancer includes thymic carcinoma.

[0134] In some embodiments, cancer includes urothelial carcinoma. In some embodiments, urothelial carcinoma includes bladder cancer. In some embodiments, cancer includes rectal cancer. In some embodiments, cancer includes thymic carcinoma. In some embodiments, cancer includes sarcoma.

[0135] c. Identification of mutations or deletions in a gene (e.g., the EP300 gene) In some embodiments, cancer has been determined to contain mutations or deletions (e.g., in the EP300 gene) (e.g., has been determined to date). In some embodiments, the methods provided herein include the step of determining the presence of mutations or deletions in the EP300 gene (e.g., in a subject). The presence of gene mutations or deletions may be determined before administration of the composition. For example, the determination of mutations or deletions (e.g., previous identifications) may be performed months, weeks, days, hours, or even minutes before administration of the composition (e.g., a composition containing a BET inhibitor). The determination of the presence of mutations in a gene (e.g., loss-of-function mutations) or deletions in a gene (e.g., the EP300 gene) may include, but are not limited to, the identification of gene mutations or deletions by one or more tests discussed herein, and may be carried out in any suitable manner.

[0136] In some embodiments, mutations or deletions in the EP300 gene are the cause or result of cancer. In some embodiments, mutations or deletions in the EP300 gene are not the result of pharmacological inhibition. For example, in such embodiments, mutations or deletions in the EP300 gene are not caused by the administration of a BET inhibitor.

[0137] A mutation (e.g., in the EP300 gene, or a loss-of-function mutation or deletion in the EP300 gene) can be any of the acceptable types of mutations, such as substitution mutations, insertion mutations, deletion mutations, or combinations thereof. In some embodiments, the EP300 mutation is a substitution mutation. In some embodiments, the EP300 mutation is an insertion mutation. In some embodiments, the EP300 mutation is a deletion mutation. In some embodiments, the deletion mutation is a partial deletion mutation. In some embodiments, the deletion mutation is a total deletion mutation. In some embodiments, the mutation may affect one copy of the gene. In some embodiments, the mutation may affect multiple copies of the gene.

[0138] Determining whether a tumor has an EP300 gene mutation may involve identifying the EP300 mutation in DNA extracted from a tumor sample and / or in circulating tumor or tumor cell DNA. In some embodiments, the cancer is determined to contain the mutation before administration of a BET inhibitor (i.e., the cancer is pre-determined to contain the mutation).

[0139] Multiple tests may be used to detect EP300 mutations or deletions. For example, tests may include Sanger sequencing of PCR-amplified EP300 coding regions, or sequencing of tumor DNA using next-generation sequencing (NGS) of whole genome or captured / enriched EP300 coding regions (e.g., whole exome sequencing, or sequencing of a targeted mutation panel including EP300 exons and introns).

[0140] Mutations can also be detected in RNA. Such RNA mutations can be detected using RNA sequencing or DNA techniques that sequence cDNA derived from RNA. Furthermore, mutations can be detected by targeted amplification of the variant and sequenced by next-generation sequencing (NGS) or by array-based readout of gene variants (e.g., using Illumina BeadArray). Tumor DNA may originate from biopsy specimens or be captured from indirect tumor sources such as cell-free DNA from blood.

[0141] The function and quantity of EP300 proteins can be determined by any acceptable method, including, for example, a method for measuring the acetylation level of proteins known to be modified by p300. Methods for quantifying these modifications may include Western blotting, mass spectrometry, protein-binding arrays, or immunohistochemical analysis.

[0142] d. Improving the effectiveness of cancer treatments The methods provided herein may be useful in treating cancer, for example, by increasing inhibition of cancer cells or slowing the progression of cancer. "Increasing inhibition of cancer cells" may mean reducing the survival rate of cancer cells or inhibiting the growth or proliferation of cancer cells.

[0143] In some embodiments, administration of a BET inhibitor enhances the inhibition of cancer cells. In some embodiments, administration of a BET inhibitor enhances the inhibition of cancer cells compared to different treatments. In some embodiments, administration of a BET inhibitor enhances the inhibition of cancer cells in cancers involving loss of function or deletion of the EP300 gene compared to the corresponding administration of the BET inhibitor to cancers without loss of function or deletion.

[0144] e. Administration Administration of a composition containing a BET inhibitor can be achieved by any acceptable means, including, for example, parenteral administration. Acceptable means of parenteral administration include, but are not limited to, subcutaneous, intramuscular, and intravenous administration. In some embodiments, the method includes the step of administering a BET inhibitor. In some embodiments, administration includes the step of administering a BET inhibitor parenterally. In some embodiments, the method includes the step of administering a pharmaceutical composition containing a BET inhibitor (for example, any of the pharmaceutical compositions provided herein).

[0145] In some embodiments, administration includes enteral administration of the BET inhibitor. Acceptable means of enteral administration include, but are not limited to, oral, gastric, and rectal administration.

[0146] In some embodiments, administration is performed once a day. In some embodiments, administration is performed twice a day. In some embodiments, administration is performed three times a day.

[0147] f. Pharmaceutical compositions BET inhibitors (e.g., PLX-51107) can be delivered in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a BET inhibitor. The pharmaceutical composition may be useful for treating cancer, for example, any of the cancers disclosed herein (e.g., cancer determined to include loss of function or deletion of the EP300 gene). In some embodiments, the method provided herein includes the step of determining the presence of a mutation or deletion of the EP300 gene (e.g., in a subject).

[0148] The compositions described herein may include, for example, any suitable BET inhibitor, such as any of the BET inhibitors described herein. In some embodiments, the BET inhibitor is a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate of a BET inhibitor described herein. In some embodiments, the pharmaceutical composition comprises a BET inhibitor and a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carriers, two or more pharmaceutically acceptable carriers, three or more pharmaceutically acceptable carriers, etc.). The carrier(s) may be any acceptable or preferred carrier(s) described herein. In some embodiments, the pharmaceutical composition comprising the BET inhibitor is administered in a manner that treats a patient (e.g., loss of function of EP300 or deletion of EP300).

[0149] In certain embodiments, the BET inhibitors described herein are administered as pure chemical substances (i.e., without excipients). In some embodiments, the BET inhibitors described herein are combined with a pharmaceutically suitable or acceptable carrier (which may be referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on a chosen route of administration and standard pharmacopoeia (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, Pennsylvania (2005))).

[0150] In some embodiments, the pharmaceutical composition containing the BET inhibitor is formulated for oral administration. Preferred oral dosage forms include, but are not limited to, tablets, pills, sachets, or capsules.

[0151] In some embodiments, the pharmaceutical composition containing the BET inhibitor is formulated for administration by injection. In some examples, the injectable formulation is an aqueous formulation. In some examples, the injectable formulation is a non-aqueous formulation. In some examples, the injectable formulation is an oil-based formulation, such as sesame oil.

[0152] The dosage of a composition containing a BET inhibitor may vary depending on the subject or patient's condition. Such factors to consider may include overall health status, age, and other factors.

[0153] The pharmaceutical compositions described herein may be administered in a manner suitable for the treatment or prevention of a disease (e.g., cancer). The appropriate dose, as well as the preferred duration and frequency of administration, may be determined by factors relating to the patient's condition, such as the type and severity of the patient's disease, the patient's age, weight, and body surface area. Alternatively, the appropriate dose, as well as the preferred duration and frequency of administration, may be determined by factors relating to the composition, such as the specific form of the active ingredient and the method of administration. In some cases, the appropriate dose is determined by factors relating to both the patient's condition and the composition. Generally, the appropriate dose and treatment regimen may provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes such as a higher frequency of complete or partial remission, or longer disease-free survival and / or overall survival). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose may depend on the patient's body mass, weight, or blood volume.

[0154] II. Kits for treating cancer Furthermore, in some embodiments, the Specified Provisions provide a kit for treating cancer, which includes a test for determining loss of function or deletion of the EP300 gene. In some embodiments, the above BET inhibitors include ABBV-075, ABBV-744, Apabetalon, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, and OMT-001. This includes OMT-002, OTX-015, Perablecib, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, ZEN-3694, CPI-0610, INCB0543294, JAB-8263, INCB057643, CC-90010, Alloblecib, GSK778, GSK046, Mibeblecib, Trotablecib, Molyblecib, Perablecib, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitors include AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or combinations thereof. In some embodiments, the BET inhibitor is OTX-015, PLX-51107, PLX-2853, or a combination thereof.In some embodiments, the BET inhibitor is JAB-8263. In some embodiments, the BET inhibitor includes AZD-5153. In some embodiments, the BET inhibitor includes BI-894999. In some embodiments, the BET inhibitor includes BMS-986158. In some embodiments, the BET inhibitor includes GSK525762. In some embodiments, the BET inhibitor includes INCB054329. In some embodiments, the BET inhibitor includes TEN-010. In some embodiments, the BET inhibitor includes PLX-51107. In some embodiments, the BET inhibitor includes PLX-2853. In some embodiments, the BET inhibitor includes OTX-015. In some embodiments, the BET inhibitor includes JAB-8263. In some embodiments, the BET inhibitor includes INCB057643. In some embodiments, the BET inhibitor includes CC-90010. In some embodiments, the BET inhibitor includes alloblesib. In some embodiments, the BET inhibitor includes ODM-207. In some embodiments, the BET inhibitor includes GSK778. In some embodiments, the BET inhibitor includes GSK046. In some embodiments, the BET inhibitor includes ABBV-744. In some embodiments, the BET inhibitor includes mibeblesib. In some embodiments, the BET inhibitor includes trotaburesib. In some embodiments, the BET inhibitor includes molyblesib. In some embodiments, the BET inhibitor includes virabresib. In some embodiments, the BET inhibitor includes perabresib. In some embodiments, the BET inhibitor includes a compound of formula IV. In some embodiments, the BET inhibitor includes compound 5. In some embodiments, the BET inhibitor includes compound 9.

[0155] In some embodiments, the cancers include breast cancer, urothelial carcinoma, rectal cancer, thymic carcinoma, sarcoma, or combinations thereof. In some embodiments, the urothelial carcinoma includes bladder cancer. In some embodiments, the methods provided herein include the step of determining the presence of mutations or deletions of the EP300 gene (for example, in a subject).

[0156] definition As used in this specification and the appended claims, the following terms have the meanings set forth below, unless otherwise specified.

[0157] The singular forms (e.g., "a," "and," and "the") include multiple referents unless explicitly stated otherwise in the context. For example, a reference to "an agent" includes the plural of such agents, and a reference to "the cell" includes one or more cells and their equivalents known to those skilled in the art. Where a range is used herein for physical properties such as molecular weight, or for chemical properties such as chemical formula, it is intended to include all combinations and partial combinations of the range, as well as specific embodiments within it.

[0158] The term "about" when referring to a number or range of numbers means that the number or range referred to is an approximation within the range of experimental variation (or statistical experimental error). Therefore, the number or range, in some cases, includes the specified value, and also includes ±20% of the specified value or range, and more specifically, values ​​within ±10%, ±5%, ±2%, and ±1% of the specified value or range.

[0159] In the context of a disease, a substance, or the activity or function of a substance associated with a disease, the terms “associated” or “associated with” mean that the disease is caused (in whole or in part) by the activity or function of the substance or substance, that the symptoms of the disease are caused (in whole or in part) by the activity or function of the substance or substance, or that the side effects (e.g., toxicity) of a compound are caused (in whole or in part) by the activity or function of the substance or substance.

[0160] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude, in other particular embodiments, embodiments such as compositions, compositions, methods, or processes of any substance described herein, from “consisting of” or “consisting essentially of” the described features.

[0161] "Disease" or "illness" refers to a condition or health state of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, disease refers to cancer, as used herein.

[0162] As defined herein, terms such as “inhibition,” “inhibit,” and “inhibiting,” when made in relation to protein-inhibitor interactions, mean adversely affecting (e.g., reducing) the activity or function of a protein (e.g., BET) compared to the activity or function of the protein in the absence of the inhibitor. Thus, inhibition includes, at least partially, partially, or completely, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downmodulating signaling or enzymatic activity or the amount of a protein. Inhibition and such terms, when referred to in such context, may refer to the reduction of a disease or the symptoms of a disease.

[0163] The compounds disclosed herein, in some embodiments, contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers defined as (R) or (S) from the viewpoint of absolute stereochemistry. Unless otherwise specified, all stereoisomers of the compounds disclosed herein are intended to be considered by this disclosure. Where the compounds described herein contain an alkene double bond, unless otherwise specified, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are also intended to be included. The term “geometric isomer” refers to the E or Z geometric isomer (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-isomers, meta-isomers, and para-isomers around a benzene ring.

[0164] As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and / or postpone the onset of a disease (such as cancer). This delay can be of varying lengths depending on the disease being treated and / or the individual's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in that the individual does not develop the disease. For example, late-stage cancers, such as the onset of metastasis, can be delayed.

[0165] The terms "selective," "selectivity," "specific," "specifically," and "specificity" of a compound refer to the ability of a compound to produce a specific effect, or the ability of a compound to identify a specific molecular target, such as inhibition of a particular molecular target (e.g., BD2). For example, a selective BD2 inhibitor may have at least three times higher selectivity for BD2 compared to BD1 in cells. As a further example, a selective BET inhibitor may have at least three times higher selectivity for BET compared to other targets in cells (e.g., Plk1).

[0166] As used herein, compounds providing inhibitory properties (e.g., BET inhibitors) include small molecule compounds and biological products (e.g., those derived from biomaterials such as antibodies, proteins, peptide fragments, etc.) unless otherwise explicitly indicated by the context.

[0167] A "tautomer" refers to a molecule in which proton transfer is possible from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. Under conditions where tautomerization is possible, a chemical equilibrium exists between the tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibrium include:

[0168] [ka]

[0169] "Pharmacologically acceptable salts" include both acid-addition salts and base-addition salts. A pharmaceutically acceptable salt of any one of the BET inhibitors described herein is intended to encompass all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base-addition salts.

[0170] A "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, or phosphorous acid, which retains the biological efficacy and properties of the free base and is not biologically or otherwise undesirable. It also includes salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Salts of amino acids such as alginates, glucons, and galacturons are also intended (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a desired acid in an amount sufficient to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0171] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid and is not undesirable from a biological or other standpoint. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al., (cited above).

[0172] A "pharmaceutically acceptable solvate" refers to a solvent-addition type composition. In some embodiments, the solvate contains either a stoichiometric or nonstoichiometric amount of solvent and is formed during a process using a pharmaceutically acceptable solvent such as water or ethanol. If the solvent is water, a hydrate is formed; if the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein are readily prepared or formed during the processes described herein. The compounds provided herein exist in either a non-solvated or solvated form.

[0173] The terms “subject,” “individual,” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia, namely non-human primates such as humans, chimpanzees and other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; household animals such as rabbits, dogs, and cats; and laboratory animals (including rodents such as rats, mice, and guinea pigs). In one aspect, a mammal is a human being.

[0174] As used herein, “mutation” may refer to a change in a polynucleotide sequence that results in an alteration of protein function. Changes in protein function can occur through alterations in the protein encoded by the polynucleotide sequence. These changes may occur through alterations in the protein’s amino acid sequence, or through alterations in the protein’s quantity (e.g., expression level), or both. A mutation can be a nucleotide substitution, such as a single nucleotide substitution, insertion, or deletion, which can ultimately alter the splicing of messenger RNA (mRNA), the level of mRNA, and / or the amino acid sequence of the protein encoded by the mRNA. Mutations can also occur in regions that regulate protein expression levels or processing.

[0175] As used herein, “loss of function” can be caused by 1) an amino acid sequence change resulting in the loss or reduction of one or more normal functions of a protein, or 2) a decrease in the amount of EP300 protein. These changes can be caused by genetic changes (changes to genomic DNA), changes to normal mRNA production and processing (e.g., due to changes in gene expression regulation such as mutations in the regulatory regions of genes, or by splice changes or silencing of gene expression, such as epigenetic silencing), and / or changes in protein translation resulting in inaccurate protein sequence synthesis or abnormal protein folding.

[0176] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are interchangeable. These terms refer to an approach to obtain beneficial or desired outcomes, including but not limited to therapeutic and / or preventive benefits. Terms such as “therapeutic effect” may include the eradication or improvement of the underlying disease being treated. A therapeutic benefit may also be achieved by the eradication or improvement of one or more symptoms associated with an underlying disorder, such that improvement may be observed in the patient, even though the patient may still suffer from the underlying disorder. To achieve a preventive benefit, a composition may be administered to a patient at risk of developing a particular disease, or to a patient who reports one or more physiological symptoms of the disease, even if the disease has not been diagnosed. [Examples]

[0177] While preferred embodiments of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternative forms to those described herein may be employed in carrying out the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

[0178] Example 1 - Identification of mutations in the EP300 gene Experiments were conducted to identify potential loss-of-function mutations and deletions in EP300. Genomic DNA was extracted from FFPE-preserved tumor biopsy tissue. Exomes, including all coding exons, were enriched using targeted capture. NGS libraries were constructed and indexed using the Illumina TruSeq Exome Kit (catalog no. 20020614) and then sequenced on the Illumina HiSeq platform. Somatic mutations were then called (e.g., by the method described in PMID 24192750 or PMID 33106175). Genomic variants (SNVs and indels) were identified using GATK (PMID 20644199), and somatic mutations were called using Mutect2 (PMID 23396013) and Varscan (PMID 19542151). Mutations were filtered into functional / deleterious variants based on their ability to cause amino acid substitutions or protein-coding changes, using the predicted functional effect inferred by MutationTaster (PMID 20676075), the "deleterious" flag inferred by SIFT (PMID 12824425), and / or the "probably damaging" flag inferred by Polyphen-2 (PMID 23315928). Loss-of-function (LOF) mutations may include hotspot mutations.

[0179] Shallow deletions (e.g., loss of a single copy) and deep deletions (e.g., complete loss (zero copies)) of one or more regions of EP300 overlapping with part or all of the coding exon can also constitute a LOF event for EP300. Deletions and complete loss of the EP300 gene were called from exome data using Control-FREEC (PMID 22155870). Decreased or lost EP300 gene expression at the protein level was confirmed using Western blotting and immunohistochemical analysis in FFPE-preserved tumor biopsies.

[0180] Example 2 - Frequency of EP300 changes in various cancers Table 1 below shows the estimated frequency of some EP300 loss-of-function events across cancers, obtained from Project GENIE (Genomics Evidence Neoplasia Information Exchange).

[0181] [Table 1]

[0182] Example 3. Cell assay To test the effects of BET inhibitors on cells with the LOF mutation in EP300, cells with and without the LOF mutation in EP300 were treated with BET inhibitors.

[0183] Isogeneic pairs of cancer cell lines differing only in the mutational state of EP300 (presence or absence of EP300 loss of function) were generated. EP300 was knocked out in KP4 cells using the Synthego CRISPR Gene Knockout v2 kit (where EP300 is wild-type and present in two copies; PMID 23550210). EP300 knockout was confirmed by Sanger sequencing and Synthego analysis software. Cells were seeded three times at 2000 cells / well in 96-well plates and treated with different concentrations of BET inhibitors across a 3-fold dilution gradient from 50 μM to sub-nanomolar concentrations. Cell viability was determined by Cell Titer Glo 4–11 days after the start of treatment.

[0184] The curve shows a dose-dependent response to the BET inhibitor, where higher concentrations in EP300 knockout cells lead to a greater decrease in cell viability and overall increased sensitivity (i.e., EP300 LOF results in the same decrease in viability at lower drug concentrations compared to EP300 wild-type).

[0185] Figures 1-9 show the inhibitory effects of various compounds in different cell lines having wild-type EP300 or EP300 knockout. As shown in these figures, cell lines with the LOF mutation in EP300 showed increased sensitivity to multiple BET inhibitors. Figures 1A-1B show the effects of AZD-5153 in cancer cells having wild-type EP300 and cancer cells with EP300 knockout. Figure 1A shows the effect of AZD-5153 in H2009 cells, a lung cancer cell line, and Figure 1B shows the effect of AZD-5153 in SW780 cells, a bladder cancer cell line.

[0186] Figures 2A and 2B show the effects of BI-2536 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 2A shows the effect of BI-2536 on SW780 cells, a bladder cancer cell line, and Figure 2B shows the effect of BI-2536 on KP4 cells, a pancreatic cancer cell line.

[0187] Figure 3 shows the effects of BI-894999 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0188] Figures 4A and 4B show the effects of BMS-986158 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 4A shows the effects of BMS-986158 on SW780 cells, a bladder cancer cell line, and Figure 4B shows the effects of BMS-986158 on KP4 cells, a pancreatic cancer cell line.

[0189] Figures 5A and 5B show the effects of GSK525762 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 5A shows the effects of GSK525762 on SW780 cells, a bladder cancer cell line, and Figure 5B shows the effects of GSK525762 on KP4 cells, a pancreatic cancer cell line.

[0190] Figure 6 shows the effect of INCB054329 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0191] Figures 7A to 7D show the effects of OTX-015 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 7A shows the effect of OTX-015 on RT11284 cells, a bladder cancer cell line. Figure 7B shows the effect of OTX-015 on KP4 cells, a pancreatic cancer cell line. Figure 7C shows the effect of OTX-015 on SW780 cells, a bladder cancer cell line. Figure 7D shows the effect of OTX-015 on Calu1 cells, a lung cancer cell line.

[0192] Figures 8A to 8C show the effects of PLX-51107 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 8A shows the effects of PLX-51107 on RT11284 cells, a bladder cancer cell line. Figure 8B shows the effects of PLX-51107 on Calu1 cells, a lung cancer cell line. Figure 8C shows the effects of PLX-51107 on KP4 cells, a pancreatic cancer cell line.

[0193] Figure 9 shows the effect of TEN-010 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells with EP300 knocked out. Figure 10 shows the effect of JQ1 on KP4 pancreatic cells with wild-type EP300 and KP4 pancreatic cells with EP300 knocked out.

[0194] The results of this experiment demonstrate synthetic lethality between BET inhibitors and EP300 loss-of-function mutations for drugs whose primary targets include BRD2, BRD3, and / or BRD4.

[0195] Example 4. Xenotransplantation test using a patient-derived xenotransplant model. To investigate the potential use of BET inhibitors (e.g., PLX-51107 and virabreciv) to treat tumors with EP300-LOF, patient-derived xenograft (PDX) models with predicted LOF mutations in EP300 were identified from the NCI Patient-Derived Model Repository (PDMR) and Jackson Labs (JAX). Analysis of whole-exome sequencing data to identify LOF EP300 mutations was performed using methods such as those described in Example 1. GATK and Samtools were used to call probable somatic single-nucleotide variants (SNVs) and indels, which were then filtered for their likelihood of inducing protein functional changes and further distinguished from gain-of-function (GOF) mutations by their absence in sequence or structural hotspot regions.

[0196] PDX samples containing the EP300 LOF mutation, selected using the criteria described above, were cut to a uniform size and subcutaneously transplanted into the bilateral flanks of 5-week-old NSG mice obtained from JAX. A 3×8 (3 treatments, 8 replicates) experimental design was used for each study (i.e., each model). The tumor volume was approximately 150 mm². 3 Tumors were measured every other day until a certain value was reached. BET inhibitors were administered orally once daily (1-20 mg / kg). Tumor size was recorded daily, and body weight was measured every 7 days to monitor drug toxicity. Tumor volume was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2(W)2 × (L). The tumor was once 500mm 3 Mice were sacrificed upon reaching a certain stage. Differential outcomes were determined by Logrank-Kaplan-Meier survival analysis or by comparing growth dynamics over time.

[0197] Oral treatment of mice with the EP300-LOF mutant PDX model with either PLX-51107 or 20 mg / kg of virabrecib resulted in a significant reduction in tumor growth (Figure 11). No significant changes in body weight were observed in mice treated with PLX-51107 or virabrecib (Figure 12).

[0198] Example 5. Xenotransplantation study of compound VII (e.g., compound 9) using a patient-derived xenotransplant model. To investigate the potential use of a compound of formula VII (e.g., compound 9) to treat tumors with EP300-LOF, the technique presented in Example 4 ("Xenograft Study Using a Patient-Derived Xenograft Model") is used with a compound of formula VII (e.g., compound 9) at concentrations that model clinically meaningful exposure levels.

[0199] Mice carrying the EP300-LOF mutant PDX model are orally treated with a compound of formula VII (e.g., compound 9). The treated mice achieve a significant reduction in tumor growth, accompanied by a non-significant reduction in body weight.

[0200] Example 6. Patient Selection Targets with EP300 LOFs are identified using tumor-derived FFPE biopsy samples. Sequencing data is generated using next-generation sequencing (NGS) of a target gene panel containing all exons of EP300. Mutations are called using the method described in Example 1.

[0201] Example 7. Cell assay To test the effects of BET inhibitors on cells with the LOF mutation in EP300, cells with and without the LOF mutation in EP300 were treated with BET inhibitors.

[0202] Isogenic pairs of cancer cell lines differing only in the mutational state of EP300 (presence or absence of EP300 function loss) are generated. EP300 is knocked out in KP4 cells using the Synthego CRISPR Gene Knockout v2 kit (where EP300 is wild-type and present in two copies; PMID 23350210). EP300 knockout is confirmed by Sanger sequencing and Synthego analysis software. Cells are seeded three times at 2000 cells / well in 96-well plates and treated with different concentrations of BET inhibitors across a 3-fold dilution gradient from 50 μM to sub-nanomolar concentrations. Cell viability is determined by Cell Titer Glo 4–11 days after the start of treatment.

[0203] The curve shows a dose-dependent response to the BET inhibitor, where higher concentrations in EP300 knockout cells lead to a greater decrease in cell viability and overall increased sensitivity (i.e., EP300 LOF results in the same decrease in viability at lower drug concentrations compared to EP300 wild-type).

[0204] Figures 13–44 show the inhibitory effects of various compounds in different cell lines having wild-type EP300 or in which EP300 is knocked out. As shown in these figures, cell lines with the LOF mutation in EP300 showed increased sensitivity to multiple BET inhibitors.

[0205] Figure 13 shows the effect of AZD-5153 on lung cancer cell lines containing wild-type EP300 and on H2009 cells, a lung cancer cell line in which EP300 is knocked out.

[0206] Figure 14 shows the effects of TEN-010 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0207] Figures 15-17 show the effects of INCB057643 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 15 shows the effects of INCB057643 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out. Figure 16 shows the effects of INCB057643 on SW780 bladder cancer cells with wild-type EP300 and SW780 bladder cancer cells in which EP300 has been knocked out. Figure 17 shows the effects of INCB057643 on HCC827 lung cancer cells with wild-type EP300 and HCC827 lung cancer cells in which EP300 has been knocked out.

[0208] Figure 18 shows the effects of CC-90010 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0209] Figure 19 shows the effect of BI-2536 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells with EP300 knocked out. BI-2536 is a potent Plk1 inhibitor with more than 40-fold selectivity for Plk1 compared to BRD4. The efficacy of BET inhibitors against synthetic lethality is demonstrated compared to Plk1 inhibitors, including BI-2536 as a negative control.

[0210] Figures 20-22 show the effects of PLX-51107 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 20 shows the effects of PLX-51107 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out. Figure 21 shows the effects of PLX-51107 on Calu1 lung cancer cells with wild-type EP300 and Calu1 lung cancer cells in which EP300 has been knocked out. Figure 22 shows the effects of PLX-51107 on SW780 bladder cancer cells with wild-type EP300 and SW780 bladder cancer cells in which EP300 has been knocked out.

[0211] Figures 23 and 24 show the effects of alloblesib on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 23 shows the effects of alloblesib on Calu1 lung cancer cells with wild-type EP300 and Calu1 lung cancer cells in which EP300 has been knocked out. Figure 24 shows the effects of alloblesib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0212] Figure 25 shows the effects of ODM-207 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0213] Figures 26 and 27 show the effects of GSK778 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 26 shows the effects of GSK778 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out. Figure 27 shows the effects of GSK778 on Calu1 lung cancer cells with wild-type EP300 and Calu1 lung cancer cells in which EP300 has been knocked out.

[0214] Figure 28 shows the effects of GSK046 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0215] Figures 29-30 show the effects of ABBV-744 on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 29 shows the effects of ABBV-744 on Calu1 lung cancer cells with wild-type EP300 and Calu1 lung cancer cells in which EP300 has been knocked out. Figure 30 shows the effects of ABBV-744 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0216] Figure 31 shows the effects of compound 5 on KP4 pancreatic cancer cells with wild-type EP300 and on KP4 pancreatic cancer cells in which EP300 was knocked out.

[0217] Figure 32 shows the effects of mibeblesib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0218] Figure 33 shows the effects of ZEN-3694 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0219] Figure 34 shows the effect of trotaburesib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0220] Figures 35 and 36 show the effects of molyblesib on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 35 shows the effects of molyblesib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out. Figure 36 shows the effects of molyblesib on SW780 bladder cancer cells with wild-type EP300 and SW780 bladder cancer cells in which EP300 has been knocked out.

[0221] Figures 37 to 40 show the effects of virabrecib on cancer cells with wild-type EP300 and cancer cells in which EP300 has been knocked out. Figure 37 shows the effects of virabrecib on Calu1 lung cancer cells with wild-type EP300 and Calu1 lung cancer cells in which EP300 has been knocked out. Figure 38 shows the effects of virabrecib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out. Figure 39 shows the effects of virabrecib on SW780 bladder cancer cells with wild-type EP300 and SW780 bladder cancer cells in which EP300 has been knocked out. Figure 40 shows the effects of virabrecib on SW1271 lung cancer cells with wild-type EP300 and SW1271 lung cancer cells in which EP300 has been knocked out.

[0222] Figure 41 shows the effect of INCB054329 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0223] Figure 42 shows the effects of BI-894999 on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 was knocked out.

[0224] Figure 43 shows the effects of perabrecib on KP4 pancreatic cancer cells with wild-type EP300 and KP4 pancreatic cancer cells in which EP300 has been knocked out.

[0225] Figure 44 shows the effect of C177(JQ1) on KP4 cell pancreatic cancer cells with wild-type EP300 and on KP4 cell pancreatic cancer cells in which EP300 was knocked out.

[0226] The results of this experiment demonstrate synthetic lethality between BET inhibitors and EP300 loss-of-function mutations for drugs whose primary targets include BRD2, BRD3, and / or BRD4.

[0227] Example 8. Xenotransplantation test using a patient-derived xenotransplantation model. To investigate the potential use of BET inhibitors (e.g., PLX-51107 and virabreciv) to treat tumors with EP300-LOF, patient-derived xenograft (PDX) models with predicted LOF mutations in EP300 were identified from the NCI Patient-Derived Model Repository (PDMR) and Jackson Labs (JAX). For these experiments, PDX models J000108112 (Figures 46A-46D) and TM00244 (Figures 47A-47D) were examined. Analysis of whole exome sequencing data to identify LOF EP300 mutations was performed using methods such as those described in Example 1. GATK and Samtools were used to call probable somatic single nucleotide variants (SNVs) and indels, which were then filtered for their likelihood of inducing protein function changes and further distinguished from gain-of-function (GOF) mutations by their absence in sequence or structural hotspot regions.

[0228] PDX samples containing the EP300 LOF mutation, selected using the criteria described above, were cut to a uniform size and subcutaneously transplanted into the bilateral flanks of 5-week-old NSG mice obtained from JAX. A 3×8 (3 treatments, 8 replicates) experimental design was used for each study (i.e., each model). The tumor volume was approximately 150 mm². 3 Tumors were measured every other day until a certain value was reached. BET inhibitors were administered once daily by forced oral administration (20 mg / kg). Tumor size was recorded daily, and body weight was measured every 7 days to monitor drug toxicity. Tumor volume was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2(W)2 × (L). The tumor was once 500mm 3 Mice were sacrificed upon reaching a certain stage. Differential outcomes were determined by Logrank-Kaplan-Meier survival analysis or by comparing growth dynamics over time.

[0229] Oral treatment of mice carrying the EP300-LOF mutant PDX model J000108112 with either PLX-51107 or virabrecib resulted in a significant reduction in tumor growth (Figure 46A). No significant changes in body weight were observed in mice treated with PLX-51107 or virabrecib (Figure 46B). Treatment with PLX-51107 and virabrecib were graphed separately in Figures 46C and 46D. The results demonstrate that BET inhibitors reduced growth in the EP300-LOF mutant PDX model J000108112 mice.

[0230] Oral treatment of mice carrying the EP300-LOF mutant PDX model TM00244 with either PLX-51107 or virabrecib resulted in a significant reduction in tumor growth (Figure 47A). No significant changes in body weight were observed in mice treated with PLX-51107 or virabrecib (Figure 47B). Treatment with PLX-51107 and virabrecib were graphed separately in Figures 47C and 47D. The results demonstrate that BET inhibitors reduced growth in the EP300-LOF mutant PDX model TM00244 mice.

[0231] Example 9. CRISPR Pharmacogenetic Screening To test the effects of synthetic lethality, CRISPR pharmacogenetic screening was performed to knock out a given gene and investigate changes in cell fitness upon treatment with a BET inhibitor, e.g., virabrecib. Each gene knockout was achieved via 3-4 different guide RNAs in KP4 cells (Figure 45A) and MDAMB231 cells (Figure 45B). A volcano plot was generated showing the effect size and significance of driver gene perturbations in pooled CRISPR virabrecib pharmacogenetic screening. Each circle (point) on the plot represents a loss-of-function mutation (knockout) of a specific driver gene. Points to the left of zero indicate an interaction where the presence of virabrecib, rather than a vehicle control, leads to a decrease in the fitness of cells with the gene perturbation. The y-axis shows the effect size and significance of the interaction, factored by the agreement between genetic perturbations.

[0232] EP300 in the upper left of both Figure 45A and Figure 45B showed potent and significant sensitization to vilabrecib. The results further demonstrate how synthetic lethality exists between cells with EP300 loss-of-function mutations or deletions and BET inhibitors.

[0233] Example 10. Cell assay using a compound of formula VII (e.g., compound 9) To test the effect of compound 9 on cells with the EP300 LOF mutation, cells with and without the EP300 LOF mutation were treated with the compound of formula (VII) (e.g., compound 9) using the technique presented in Example 3. The results of this experiment demonstrate synthetic lethality between the compound of formula (VII) (e.g., compound 9) and the EP300 loss-of-function mutation or deletion.

[0234] The examples and embodiments described herein are for illustrative purposes only, and various improvements or modifications suggested to those skilled in the art should be included within the spirit and scope of this application and the appended claims.

Claims

1. A method for treating cancer in a subject requiring treatment for cancer, wherein the method is: The step includes administering the pharmaceutical composition to the subject, a. The pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, b. The aforementioned cancers have been determined to involve loss of function or deletion of the EP300 gene, c. The patient, 【Chemistry 1】 or 【Chemistry 2】 They are not receiving both at the same time. d. If the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1.

2. A method for treating cancer in a subject requiring treatment for cancer, wherein the method is: The step includes administering the pharmaceutical composition to the subject, The pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor. The aforementioned cancers have been determined to involve a decrease in the amount or activity of p300 compared to wild-type p300. The patient, 【Transformation 3】 or 【Chemistry 4】 They are not receiving both at the same time. If the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1.

3. The method according to claim 1, wherein the loss of function is caused by a gene mutation.

4. The method according to claim 1 or 2, wherein the subject has not previously received compound 1 or compound 2.

5. The BET inhibitors mentioned above include ABBV-075, ABBV-744, Apabetalon, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB 054329, INCB57643, JQ1, LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OT The method according to any one of claims 1 to 4, comprising X-015, perabrecib, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, ZEN-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, allobrecib, GSK778, GSK046, mibeblecib, trotabrecib, molyblecib, perabrecib, or a combination thereof.

6. The method according to claim 5, wherein the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or a combination thereof.

7. The method according to claim 5, wherein the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, allobrecib, ODM-207, GSK778, GSK046, ABBV-744, mibeblecib, trotabrecib, molyblecib, virabrecib, perabrecib, or a combination thereof.

8. The BET inhibitor is defined by formula (I): 【Transformation 5】 The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein the formula includes, R １ (C) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, or halo, methyl, ethyl, methoxy, and ethoxy. １ -C ３ ) is alkyl, The method according to any one of claims 1 to 4, wherein X is a halo if present.

9. R １ is, (C １ -C ２ The method according to claim 7, wherein the alkyl, cyano, or fluoro

10. R １ The method according to claim 9, wherein is methyl.

11. R １ The method according to claim 9, wherein is fluoro.

12. R １ is cyano, the method according to claim 9.

13. The BET inhibitor is defined by formula (II): 【Transformation 6】 The compound, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, or deuterated analog thereof, wherein the formula includes, R １ (C) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, methyl, ethyl, methoxy, and ethoxy. １ -C ３ The method according to any one of claims 1 to 4, wherein the alkyl group is alkyl.

14. R １ The method according to claim 13, wherein is methyl.

15. The BET inhibitor is defined by formula (III): 【Transformation 7】 The compound comprises, or a pharmaceutically acceptable salt thereof, in the formula, The method according to any one of claims 1 to 4, wherein X is a halo if present.

16. The BET inhibitor is compound 3: 【Transformation 8】 The method according to any one of claims 1 to 4 and 7 to 15, or comprising a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

17. The BET inhibitor is defined by formula (Va): 【Chemistry 9】 This includes compounds having, or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs thereof, During the ceremony, R ２ H is, R ４ H is, R ６ H is, R ７ H, -OH, C １－６ Alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, R １ This is 1 to 3 R ｊ A heteroaryl compound that has been optionally substituted with the base compound. R ｊ are each independently halogen, -CN, -OH, -NH ２ , -NO ２ , -C(O)OH, -C(S)OH, -C(O)NH ２ , -C(S)NH ２ , -S(O) ２ NH ２ , -NHC(O)NH ２ , -NHC(S)NH ２ , -NHS(O) ２ NH ２ , -C(NH)NH ２ , -CH=C(R ｋ )(R ｋ ), -OR ｋ , -SR ｋ , -OC(O)R ｋ , -OC(S)R ｋ , -P(=O)HR ｋ , -P(=O)R ｋ R ｋ , -PH(=O)OR ｋ , -P(=O)(OR ｋ ) ２ , -OP(=O)(OR ｋ ) ２ , -C(O)H, -O(CO)OR ｋ , -C(O)R ｋ , -C(S)R ｋ , -C(O)OR ｋ , -C(S)OR ｋ , -S(O)R ｋ , -S(O) ２ R ｋ , -C(O)NHR ｋ , -C(S)NHR ｋ , -C(O)NR ｋ R ｋ , -C(S)NR ｋ R ｋ , -S(O) ２ NHR ｋ , -S(O) ２ NR ｋ R ｋ , -C(NH)NHR ｋ , -C(NH)NR ｋ R ｋ , -NHC(O)R ｋ , -NHC(S)R ｋ , -NR ｋ C(O)R ｋ , -NR ｋ C(S)R ｋ , -NHS(O) ２ R ｋ , -NR ｋ S(O) ２ R ｋ , -NHC(O)NHR ｋ , -NHC(S)NHR ｋ , -NR ｋ C(O)NH ２ , -NR ｋ C(S)NH ２ , -NR ｋ C(O)NHR ｋ , -NR ｋ C(S)NHR ｋ , -NHC(O)NR ｋ R ｋ , -NHC(S)NR ｋ R ｋ , -NR ｋ C(O)NR ｋ R ｋ , -NR ｋ C(S)NR ｋ R ｋ , -NHS(O) ２ NHR ｋ , -NR ｋ S(O) ２ NH ２ , -NR ｋ S(O) ２ NHR ｋ , -NHS(O) ２ NR ｋ R ｋ , -NR ｋ S(O) ２ NR ｋ R ｋ , -NHR ｋ , or -NR ｋ R ｋ is selected from, R ｋ These are H and C, which are independent of each other. １－６ Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl, Two R's ｋ When the group is bonded to the same carbon or nitrogen atom, it forms a 3-6 membered carbocyclic ring or a 3-8 membered heterocyclic ring having 1-2 heteroatoms as ring members selected from O, N, or S, and the nitrogen or sulfur ring atom is optionally oxidized. R ３ H, halogen, -CN, and C substituted by any choice １－６ Alkyl, optionally substituted deuterated C １－６ Alkyl, optionally substituted aryl, optionally substituted aryl-C １－４ Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C １－４ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkyl-C １－４ Alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkyl-C １－４ It is alkyl, R ５ D, halogen, C １－６ Alkyl, C １－４ Haloalkyl, C １－４ One or two R selected independently of haloalkoxy or -CN １１ Replaced by arbitrary selection in the base 【Chemistry 10】 And, The method according to any one of claims 1 to 4, wherein the wavy line in the formula indicates a bond point to the remainder of the molecule.

18. The BET inhibitor is compound 4: 【Chemistry 11】 The method according to claim 17, or comprising a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

19. The BET inhibitor is compound 9: 【Chemistry 12】 The method according to any one of claims 1 to 4, or comprising a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

20. The method according to any one of claims 1 to 19, wherein the cancer includes bladder cancer, lung cancer, gynecological cancer, adrenocortical cancer, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, nerve sheath tumor, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or a combination thereof.

21. The method according to any one of claims 1 to 20, wherein the cancer includes lung cancer.

22. The method according to claim 21, wherein the lung cancer includes non-small cell lung cancer.

23. The method according to claim 22, wherein the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof.

24. The method according to claim 23, wherein the non-small cell lung cancer includes squamous cell carcinoma.

25. The method according to claim 23, wherein the non-small cell lung cancer includes large cell carcinoma.

26. The method according to claim 23, wherein the non-small cell lung cancer includes adenocarcinoma.

27. The method according to claim 21, wherein the lung cancer includes small cell lung cancer.

28. The method according to any one of claims 21 to 27, wherein the BET inhibitor includes AZD-5153, INCB57643, OTX-015, PLX-51107, or a combination thereof.

29. The method according to any one of claims 1 to 20, wherein the cancer includes bladder cancer.

30. The method according to claim 29, wherein the bladder cancer includes carcinoma.

31. The method according to claim 30, wherein the carcinoma includes urothelial carcinoma.

32. The method according to any one of claims 29 to 31, wherein the BET inhibitor includes AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or a combination thereof.

33. The method according to any one of claims 1 to 20, wherein the cancer includes pancreatic cancer.

34. The method according to claim 33, wherein the BET inhibitor includes BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or a combination thereof.

35. The method according to claim 20, wherein the skin cancer includes melanoma.

36. The method according to claim 20, wherein the CNS cancer includes glioma.

37. The method according to claim 20, wherein the CNS cancer includes neuroepithelial tumors.

38. The method according to claim 20, wherein the lymphoma includes non-Hodgkin lymphoma.

39. The method according to claim 20, wherein the lymphoma includes diffuse large B-cell lymphoma.

40. The method according to claim 20, wherein the lymphoma includes follicular lymphoma.

41. The method according to claim 20, wherein the lymphoma includes marginal zone lymphoma.

42. The method according to claim 20, wherein the lymphoma includes a mature B-cell tumor.

43. The method according to claim 20, wherein the gastrointestinal cancers include gastrointestinal stromal tumors, esophageal and gastric cancers, gastrointestinal neuroendocrine tumors, small intestine cancers, anal cancers, colon cancers, or combinations thereof.

44. The method according to claim 20, wherein the gastrointestinal cancer includes gastrointestinal stromal tumors.

45. The method according to claim 20, wherein the gastrointestinal cancer includes esophageal and gastric cancer.

46. The method according to claim 20, wherein the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors.

47. The method according to claim 20, wherein the gastrointestinal cancer includes small intestine cancer.

48. The method according to claim 20, wherein the gastrointestinal cancer includes anal cancer.

49. The method according to claim 20, wherein the gastrointestinal cancer includes colon cancer.

50. The method according to claim 49, wherein the colon cancer includes colorectal cancer.

51. The method according to claim 20, wherein the gynecological cancer includes cervical cancer.

52. The method according to claim 20, wherein the gynecological cancer includes ovarian cancer.

53. The method according to claim 20, wherein the gynecological cancer includes sex cord-stromal tumors.

54. The method according to claim 20, wherein the gynecological cancer includes vaginal cancer.

55. The method according to claim 20, wherein the cancer includes uterine cancer.

56. The method according to claim 55, wherein the uterine cancer includes endometrial cancer or uterine sarcoma.

57. The method according to claim 56, wherein the uterine cancer includes endometrial cancer.

58. The method according to claim 57, wherein the endometrial cancer includes endometrial cancer of the uterine body.

59. The method according to claim 55, wherein the uterine cancer includes uterine sarcoma.

60. The method according to claim 59, wherein the uterine sarcoma includes uterine carcinosarcoma.

61. The method according to any one of claims 1 to 60, wherein the BET inhibitor inhibits one or more of the following bromodomains: BRD2, BRD3, and BRD4.

62. The method according to claim 61, wherein the BET inhibitor inhibits BRD4 and BRD2.

63. The method according to claim 61, wherein the BET inhibitor inhibits BRD3 and BRD4.

64. The method according to claim 61, wherein the BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

65. The method according to claim 61, wherein the BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

66. The method according to any one of claims 1 to 65, wherein the BET inhibitor includes a selective BET inhibitor.

67. The method according to claim 66, wherein the selective BET inhibitor inhibits one or more of the following bromodomains: BRD2, BRD3, and BRD4.

68. The method according to claim 67, wherein the selective BET inhibitor is selective for BRD4 and BRD2.

69. The method according to claim 67, wherein the selective BET inhibitor is selective for BRD2, BRD3, and BRD4.

70. The method according to claim 67, wherein the selective BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

71. The method according to claim 70, wherein the selective BET inhibitor comprises GSK778.

72. The method according to claim 67, wherein the selective BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

73. The method according to claim 72, wherein the selective BET inhibitor comprises GSK046, ABBV-744, compound 9, or any combination thereof.

74. The method according to any one of claims 1 to 73, wherein the loss of function or deletion is to the EP300 gene.

75. A method for treating cancer in a subject requiring treatment for cancer, wherein the method is: The step includes administering the pharmaceutical composition to the subject, a. The pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor, b. The aforementioned cancers have been determined to involve loss of function or deletion of the EP300 gene, The aforementioned BET inhibitor is given by formula IV: 【Chemistry 13】 This includes compounds thereof, pharmaceutically acceptable salts thereof, or stereoisomers thereof. During the ceremony, R １ is hydrogen, deuterium, -C １－６ Alkyl, or -C ３－８ Selected from carbocyclic structures, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C １－８ Alkyl, -C １－８ Alkoxy, -NH ２ ,-NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , or -C ３－８ Selected from carbocyclic structures, R ２ is hydrogen, deuterium, halogen, -OR ２１ , -NR ２１ R ２２ -CN, -SR ２１ , -SOR ２１ , -SO ２ R ２１ , -SO ２ NR ２１ R ２２ , -C １－８ Alkyl, 【Chemistry 14】 carboxyl, -COOR ２１ , -CONR ２１ R ２２ , -NR ２１ COR ２２ , -NR ２１ SO ２ R ２２ , or -C ３＿８ Selected from carbocyclic structures, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently and optionally substituted with deuterium, halogen, -OH, -CN, or -NH ２ , -C １－８ Alkyl, -C １－８ Alkoxy, C ３－８ Selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O, R ２１ and R ２２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, -OH, NH ２ -CN, -C １－８ Alkyl, -C １－８ Alkoxy, -C １－８ Alkylene-C ３－８ Carbocyclic, or -C ３－８ Selected from carbocyclic structures, R ２３ and R ２４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－８ Selected from alkyl groups, A is, 【Chemistry 15】 Selected from, Y １ is N or CR Ｙ１ Selected from, Y ２ O, S, CR Ｙ１ R Ｙ２ , or NR Ｙ２ Selected from, R Ｙ１ and R Ｙ２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, halogen, -OH, NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, R ３ and R ４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－６ Selected from alkyl groups, each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent independently substituted with deuterium, halogen, -OH, or -NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, n is selected from 0, 1, 2, 3, 4, 5, or 6. W １ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－６ Alkyl, -C １－６ Alkoxy, -C １－３ Alkylene-C １－３ A five-membered heteroaryl compound containing one, two, or three heteroatoms selected from alkoxy, phenyl, N, or O; a six-membered heteroaryl compound containing one, two, or three heteroatoms selected from N, or O; a three-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a four-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a five-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a six-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a three-membered carbocyclic compound; a four-membered carbocyclic compound; a five-membered carbocyclic compound; or a six-membered carbocyclic compound, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent being deuterium, halogen, or -NH ２ , -CN, -OH, -NO ２ carboxyl, -C １－３ Alkyl, or -C １－３ Selected from alkoxy, W ２ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－３ Alkyl, -C １－３ A five-membered heteroaryl containing one, two, or three heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S; a six-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; a seven-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; an eight-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; a nine-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; and a ten-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S. , selected from a three-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a four-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a five-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a six-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a three-membered carbocyclic formula; a four-membered carbocyclic formula; a five-membered carbocyclic formula; or a six-membered carbocyclic formula, each independently and optionally substituted with one, two, three, four, or five substituents, each substituent being deuterium, halogen, -NH ２ , -CN, -OH, -NO ２ Selected from carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, Z represents hydrogen, deuterium, halogen, and -NH ２ -CN, -OH, carboxyl, -C １－６ Alkyl, or -C １－６ A method selected from alkoxy.

76. A method for treating cancer in a subject requiring treatment for cancer, wherein the method is: The step includes administering the pharmaceutical composition to the subject, The pharmaceutical composition comprises a bromodomain and an extraterminal domain (BET) inhibitor. The aforementioned cancers have been determined to involve a decrease in the amount or activity of p300 compared to wild-type p300. The aforementioned BET inhibitor is given by formula IV: 【Chemistry 16】 This includes compounds thereof, pharmaceutically acceptable salts thereof, or stereoisomers thereof. During the ceremony, R １ is hydrogen, deuterium, -C １－６ Alkyl, or -C ３－８ Selected from carbocyclic structures, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C １－８ Alkyl, -C １－８ Alkoxy, -NH ２ ,-NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , or -C ３－８ Selected from carbocyclic structures, R ２ is hydrogen, deuterium, halogen, -OR ２１ , -NR ２１ R ２２ -CN, -SR ２１ , -SOR ２１ , -SO ２ R ２１ , -SO ２ NR ２１ R ２２ , -C １－８ Alkyl, 【Chemistry 17】 carboxyl, -COOR ２１ , -CONR ２１ R ２２ , -NR ２１ COR ２２ , -NR ２１ SO ２ R ２２ , or -C ３＿８ Selected from carbocyclic structures, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently and optionally substituted with deuterium, halogen, -OH, -CN, or -NH ２ , -C １－８ Alkyl, -C １－８ Alkoxy, C ３－８ Selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O, R ２１ and R ２２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, -OH, NH ２ -CN, -C １－８ Alkyl, -C １－８ Alkoxy, -C １－８ Alkylene-C ３－８ Carbocyclic, or -C ３－８ Selected from carbocyclic structures, R ２３ and R ２４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－８ Selected from alkyl groups, A is, [Chemistry 18] Selected from, Y １ is N or CR Ｙ１ Selected from, Y ２ O, S, CR Ｙ１ R Ｙ２ , or NR Ｙ２ Selected from, R Ｙ１ and R Ｙ２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, halogen, -OH, NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, R ３ and R ４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－６ Selected from alkyl groups, each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent independently substituted with deuterium, halogen, -OH, or -NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, n is selected from 0, 1, 2, 3, 4, 5, or 6. W １ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－６ Alkyl, -C １－６ Alkoxy, -C １－３ Alkylene-C １－３ A five-membered heteroaryl compound containing one, two, or three heteroatoms selected from alkoxy, phenyl, N, or O; a six-membered heteroaryl compound containing one, two, or three heteroatoms selected from N, or O; a three-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a four-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a five-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a six-membered heterocyclic compound containing one, two, or three heteroatoms selected from N, or O; a three-membered carbocyclic compound; a four-membered carbocyclic compound; a five-membered carbocyclic compound; or a six-membered carbocyclic compound, each independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent being deuterium, halogen, or -NH ２ , -CN, -OH, -NO ２ carboxyl, -C １－３ Alkyl, or -C １－３ Selected from alkoxy, W ２ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－３ Alkyl, -C １－３ A five-membered heteroaryl containing one, two, or three heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S; a six-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; a seven-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; an eight-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; a nine-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S; and a ten-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S. , selected from a three-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a four-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a five-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a six-membered heterocyclic formula containing one, two, or three heteroatoms selected from N, O, or S; a three-membered carbocyclic formula; a four-membered carbocyclic formula; a five-membered carbocyclic formula; or a six-membered carbocyclic formula, each independently and optionally substituted with one, two, three, four, or five substituents, each substituent being deuterium, halogen, -NH ２ , -CN, -OH, -NO ２ Selected from carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, Z represents hydrogen, deuterium, halogen, and -NH ２ -CN, -OH, carboxyl, -C １－６ Alkyl, or -C １－６ A method selected from alkoxy.

77. The method according to claim 75, wherein the loss of function is caused by a gene mutation.

78. The BET inhibitor is compound 5: 【Chemistry 19】 The method according to claim 75 or 76, comprising, or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

79. The BET inhibitor is compound 6: 【Chemistry 20】 The method according to claim 75 or 76, comprising, or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

80. The BET inhibitor is compound 7: 【Chemistry 21】 The method according to claim 75 or 76, comprising, or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

81. The BET inhibitor is compound 8: 【Chemistry 22】 The method according to claim 75 or 76, comprising, or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof.

82. The method according to claim 75 or 76, wherein the cancers include bladder cancer, lung cancer, gynecological cancer, adrenocortical cancer, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, nerve sheath tumor, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or a combination thereof.

83. The method according to claim 82, wherein the cancer includes lung cancer.

84. The method according to claim 83, wherein the lung cancer includes non-small cell lung cancer.

85. The method according to claim 84, wherein the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof.

86. The method according to claim 85, wherein the non-small cell lung cancer includes squamous cell carcinoma.

87. The method according to claim 85, wherein the non-small cell lung cancer includes large cell carcinoma.

88. The method according to claim 85, wherein the non-small cell lung cancer includes adenocarcinoma.

89. The method according to claim 84, wherein the lung cancer includes small cell lung cancer.

90. The method according to claim 82, wherein the cancer includes bladder cancer.

91. The method according to claim 90, wherein the bladder cancer includes carcinoma.

92. The method according to claim 91, wherein the carcinoma includes urothelial carcinoma.

93. The method according to claim 82, wherein the cancer includes pancreatic cancer.

94. The method according to claim 82, wherein the skin cancer includes melanoma.

95. The method according to claim 82, wherein the CNS cancer includes glioma.

96. The method according to claim 82, wherein the CNS cancer includes neuroepithelial tumors.

97. The method according to claim 82, wherein the lymphoma includes non-Hodgkin lymphoma.

98. The method according to claim 82, wherein the lymphoma includes diffuse large B-cell lymphoma.

99. The method according to claim 82, wherein the lymphoma includes follicular lymphoma.

100. The method according to claim 82, wherein the lymphoma includes marginal zone lymphoma.

101. The method according to claim 82, wherein the lymphoma includes a mature B-cell tumor.

102. The method according to claim 82, wherein the gastrointestinal cancers include gastrointestinal stromal tumors, esophageal and gastric cancers, gastrointestinal neuroendocrine tumors, small intestine cancers, anal cancers, colon cancers, or combinations thereof.

103. The method according to claim 82, wherein the gastrointestinal cancer includes gastrointestinal stromal tumors.

104. The method according to claim 82, wherein the gastrointestinal cancer includes esophageal and gastric cancer.

105. The method according to claim 82, wherein the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors.

106. The method according to claim 82, wherein the gastrointestinal cancer includes small intestine cancer.

107. The method according to claim 82, wherein the gastrointestinal cancer includes anal cancer.

108. The method according to claim 82, wherein the gastrointestinal cancer includes colon cancer.

109. The method according to claim 108, wherein the colon cancer includes colorectal cancer.

110. The method according to claim 82, wherein the gynecological cancer includes cervical cancer.

111. The method according to claim 82, wherein the gynecological cancer includes ovarian cancer.

112. The method according to claim 82, wherein the gynecological cancer includes sex cord-stromal tumors.

113. The method according to claim 82, wherein the gynecological cancer includes vaginal cancer.

114. The method according to claim 82, wherein the cancer includes uterine cancer.

115. The method according to claim 114, wherein the uterine cancer includes endometrial cancer or uterine sarcoma.

116. The method according to claim 115, wherein the uterine cancer includes endometrial cancer.

117. The method according to claim 116, wherein the endometrial cancer includes endometrial cancer of the uterine body.

118. The method according to claim 114, wherein the uterine cancer includes uterine sarcoma.

119. The method according to claim 118, wherein the uterine sarcoma includes uterine carcinosarcoma.

120. The method according to claim 75, wherein the subject has NUT midline carcinoma.

121. The method according to claim 75, wherein the subject has castration-resistant prostate cancer.

122. The method according to claim 75, wherein the subject has a solid tumor or a humoral tumor.

123. The method according to claim 75, wherein the subject has humoral carcinoma selected from myelofibrosis.

124. The method according to claim 75, wherein the subject has humoral cancer selected from myeloma and leukemia.

125. The method according to claim 75, wherein the subject has humoral cancer selected from leukemia.

126. The method according to claim 124, wherein the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

127. The method according to claim 75, wherein the loss of function or deletion is to the EP300 gene.

128. R １ is hydrogen, deuterium, -C １－６ Alkyl, or -C ３－８ Selected from carbocyclic structures, each independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently substituted with deuterium, halogen, OH, -CN, or -C １－８ Alkyl, or -C １－８ Selected from alkoxy, R ２ is hydrogen, deuterium, halogen, -C １－８ Alkyl, 【Chemistry 23】 carboxyl, -COOR ２１ , or -CONR ２１ R ２２ They are selected from, and each of these is independently substituted with one, two, three, four, five, or six substituents as it appears, and each of the substituents is independently substituted with deuterium, halogen, -OH, -CN, -NH ２ , -C １－８ Alkyl, -C １－８ Alkoxy, C ３－８ Selected from a carbocyclic structure or a six-membered heterocyclic structure containing one, two, or three heteroatoms selected from N and O, R ２１ and R ２２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, -OH, NH ２ -CN, -C １－８ Alkyl, or -C ３－８ Selected from carbocyclic structures, R ２３ and R ２４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－８ Selected from alkyl groups, A is, 【Chemistry 24】 Selected from, Y １ is N or CR Ｙ１ Selected from, Y ２ O, S, CR Ｙ１ R Ｙ２ , or NR Ｙ２ Selected from, R Ｙ１ and R Ｙ２ Each of these elements appears independently, and each time it appears, it is hydrogen, deuterium, halogen, -OH, NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, R ３ and R ４ Each of these elements, independently, appears as hydrogen, deuterium, or -C each time. １－６ Selected from alkyl groups, each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, each substituent independently substituted with deuterium, halogen, -OH, or -NH ２ -CN, -C １－６ Alkyl, or -C １－６ Selected from alkoxy, n is selected from 0, 1, or 2. W １ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－６ Alkyl, -C １－６ Selected from a six-membered heterocyclic formula containing one, two, or three heteroatoms selected from alkoxy, N, and O, each of which is independently and optionally substituted with one, two, three, four, five, or six substituents, each substituent being deuterium, halogen, or -NH ２ , -CN, -OH, -NO ２ carboxyl, -C １－３ Alkyl, or -C １－３ Selected from alkoxy, W ２ is hydrogen, deuterium, -F, -CI, -NH ２ -CN, -OH, carboxyl, -C １－３ Alkyl, -C １－３ Selected from a five-membered heteroaryl containing one, two, or three heteroatoms selected from alkoxy, phenyl, naphthyl, N, O, or S, and a six-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S, each independently optionally substituted with one, two, three, four, or five substituents, each substituent being deuterium, halogen, -NH ２ , -CN, -OH, -NO ２ Selected from carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy, Z represents hydrogen, deuterium, halogen, and -NH ２ -CN, -OH, or -C １－６ The method according to claim 75 or 76, selected from alkoxys.

129. The compound of formula IV is (S)-2-(6-(3,5-dimethylisoxazole-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(3,5-dimethylisoxazole-4-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridine-2-yl)butyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-((3-methylpyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(3,5-dimethylisoxazole-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxamide, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-amine, 2-(4-((3-fluoropyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazole-5-yl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-fluoropyridine-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, 2-(6-(1,4-dimethyl-1H-1,2,3-triazole-5-yl)-4-((3-methoxypyridine-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)propan-2-ol, and The method according to claim 75 or 76, selected from 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-yl)methyl)morpholine.

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