TRIM7 inhibitors and uses thereof

Abstract

The present disclosure relates to compositions and methods useful for the treatment of diseases, including Trim7 inhibitors, such as therapies for cancer, including cancer, infectious diseases, and inflammatory diseases that are resistant to anti-checkpoint agents.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 520,551, filed August 18, 2023; U.S. Provisional Patent Application No. 63 / 561,076, filed March 4, 2024; and U.S. Provisional Patent Application No. 63 / 631,138, filed April 8, 2024, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] This disclosure In particular This relates to compositions and methods that can be used to treat diseases, including compounds containing Trim7 inhibitors, such as therapies for cancers including cancers resistant to checkpoint agents, infectious diseases, and inflammatory diseases.

[0004] sequence list

[0005] This application contains a sequence list, which has been submitted in XML format via EFS-Web. An XML copy named “SHK-085PC_116981-5085-WO_Sequence_Listing” was created on August 15, 2024, and is 4,096 bytes in size; its contents are incorporated herein by reference in their entirety. Background Technology

[0006] Drug resistance remains one of the greatest challenges in cancer therapy. It is present in all types of cancer and all treatment modalities, including molecularly targeted therapy, immunotherapy, and chemotherapy. In some patients, the initiation of effective therapy is delayed due to unpredictable responses. Furthermore, it is common for patients with advanced cancer to receive drugs that help shrink their tumors, only to have the cancer subsequently develop resistance to those drugs. Unfortunately, for some patients with cancers resistant to checkpoint therapy, there are few effective treatment options. Therefore, there is a need for approaches to developing new therapies for patients with drug-resistant cancers to improve outcomes for cancer patients. Summary of the Invention

[0007] Therefore, this disclosure provides compositions and methods for treating cancer, including but not limited to cancers resistant to checkpoint agents. Methods for treating infectious diseases and inflammatory diseases are also provided. Methods for selecting cancer treatment for patients are also provided, as well as methods for cancer treatment based on, for example, the expression profile of the Trim7 gene, which is dysregulated in checkpoint-resistant cancers.

[0008] In one embodiment, this disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0009] Formula (I)

[0010] In equation (I): A is selected from , , , , , and ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a-OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; t is 1 or 2; The condition is that the compound of formula (I) is not a compound of any of formulas 1001, 1003, 1004, and 1006-1009:

[0011] In some embodiments, the compound is a compound of formula (I), wherein R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6eR 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, optionally halogenated, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -C(O)R a -C(O)N(R) a )2、-N(R a )2、-N(R a )C(O)R a and -S(O) t R a In some embodiments, the compound is a compound of formula (I), wherein L is a bond or contains one or more linking groups selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b)C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, optionally substituted alkyl, or optionally substituted aryl; optionally, L is a bond and / or -C(O)- and / or -C(H)(CH2). p C(O)NH2 and / or Where p is an integer from 1 to 5, and optionally p is 2; optionally L is... Wherein the alkyl group is substituted or unsubstituted. or .

[0012] In some embodiments, the compound of formula (I) is the compound of formula (10):

[0013] Equation (10)

[0014] In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a-C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

[0015] In some embodiments, the compound of formula (I) is a compound of formula (20) or (21):

[0016] In equations (20) and (21): n3 is an integer from 0 to 5.

[0017] In some embodiments, the compound of formula (I) is a compound of formula (30) or (31):

[0018] In equations (30) and (31): p is an integer from 0 to 5.

[0019] In some embodiments, the compound of formula (I) is the compound of formula (32):

[0020] Equation (32)

[0021] In equation (32): q is an integer from 1 to 3.

[0022] In some embodiments, the compound of formula (I) is the compound of formula (40):

[0023] Equation (40)

[0024] In equation (40): n4 is an integer from 0 to 5.

[0025] In some embodiments, the compound of formula (I) is the compound of formula (50):

[0026] Equation (50)

[0027] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a)C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

[0028] In some embodiments, the compound of formula (I) is the compound of formula (60):

[0029] Equation (60)

[0030] In equation (60): n6 is an integer between 0 and 5.

[0031] In some embodiments, the compound of formula (I) is the compound of formula (70):

[0032] Equation (70)

[0033] In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-Ra -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0034] In some embodiments, compound (70) is a compound of formula (700) or (701):

[0035] In some embodiments, the compound of formula (I) is a compound of formula (80) or formula (81):

[0036] Equation (80)

[0037] In equation (80): R 11a and R 11bEach of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5;

[0038] Equation (81)

[0039] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0040] In some embodiments, the compound of formula (80) is a compound of formula (800) or formula (801), or the compound of formula (81) is a compound of formula (802) or formula (803):

[0041] In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 5b and / or R 5c Each group is independently selected from unsubstituted or substituted alkynyl groups, optionally substituted alkynyl groups, substituted aryl groups, substituted heteroaryl groups, halogenated groups, optionally Br, -N(R) groups. a 2. Optional -NH2 and -N(R) a )C(O)R a Optional , , or Optional of R 5b Selected from , , , , , , , , , , , , , , and Optional of R 5c Selected from , , , , , , , , , and In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 11a and R 11b Each is an unsubstituted alkyl group, or R 11a and R 11b Each independently is , or R 11a Selected from H and unsubstituted alkyl groups and R 11b yes , or R 11aIt is H and R 11b Y is an unsubstituted alkyl group; wherein Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups, and n7 is an integer from 1 to 3, optionally n7 is 1 or 2. In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 11a and R 11b Each independently selected , , , , , , , , , , and Optional of R 11a and R 11b Each independently selected , , , , , , , , and In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and Optional of R 11a Selected from H and -CH3 and R 11b Selected from , , and In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , and In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81), or (800)-(803), wherein R 11a It is H and R 11b It is -CH3 or R in it. 11a and R 11b Each is -CH3. In some embodiments, the compound of formula (I) is a compound of any one of formulas (80), (81) or (800)-(803), wherein n8 is 1.

[0042] In some embodiments, the compound of formula (I) is the compound of formula (82):

[0043] Equation (82)

[0044] In equation (82): R 11a R 11b 、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R)a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0045] In some embodiments, the compound of formula (82) is a compound of formula (804) or (805):

[0046] In some embodiments, the compound of formula (I) is the compound of formula (90):

[0047] Equation (90)

[0048] In equation (90): n is an integer from 1 to 5.

[0049] In some embodiments, the compound of formula (90) is a compound of formula (900), formula (901), or formula (902):

[0050] In some embodiments, the compound of formula (I) is a compound of any one of formulas (90), (900), (901), or (902), wherein R 12 Is it H or -CH3 In some embodiments, the compound of formula (I) is a compound of any one of formulas (90), (900), (901), or (902), wherein R 11a It is H or a substituted alkyl group, optional. Optional In some embodiments, the compound of formula (I) is a compound of any one of formulas (90), (900), (901), or (902), wherein R 10 It is -C(O)R a Optional of R a Selected from unsubstituted alkenyl, substituted alkyl, substituted aryl, and substituted heterocyclic groups, or R 10 It is -S(O) t R a Optionally, where t is 2 and R a It is a substituted aryl group. In some embodiments, the compound of formula (I) is a compound of any one of formulas (90), (900), (901), or (902), wherein R 10 Selected from: , , , , , , , , , and .

[0051] In some embodiments, the compound of formula (I) is a compound of any one of formulas 1002, 1005, 1010-1098, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof.

[0052] On the other hand, this disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient:

[0053] Formula (I)

[0054] In equation (I): A is selected from , , , , , , ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t Ra -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; and t is 1 or 2.

[0055] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), wherein R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, optionally halogenated, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -N(R) a )2、-C(O)Ra -C(O)N(R) a )2、-N(R a )C(O)R a and -S(O) t R a In some embodiments, the pharmaceutical composition comprises a compound of formula (I), wherein L is a bond or comprises one or more linking groups selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R bIndependently, it is hydrogen, optionally substituted alkyl, or optionally substituted aryl; optionally, L is a bond and / or -C(O)- and / or -C(H)(CH2). p C(O)NH2 and / or Where p is an integer from 1 to 5, and optionally p is 2; optionally L is... Wherein the alkyl group is substituted or unsubstituted. or .

[0056] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (10):

[0057] Equation (10)

[0058] In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t Ra -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

[0059] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (20) or (21):

[0060] In equations (20) and (21): n3 is an integer from 0 to 5.

[0061] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (30) or (31):

[0062] In equations (30) and (31): p is an integer from 0 to 5.

[0063] That.

[0064] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (32):

[0065] Equation (32)

[0066] In equation (32): q is an integer from 1 to 3.

[0067] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (40):

[0068] Equation (40)

[0069] In equation (40): n4 is an integer from 0 to 5.

[0070] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (50):

[0071] Equation (50)

[0072] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

[0073] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (60):

[0074] Equation (60)

[0075] In equation (60): n6 is an integer between 0 and 5.

[0076] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (70):

[0077] Equation (70)

[0078] In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a-N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0079] In some embodiments, the pharmaceutical composition comprises a compound of formula (70), which is a compound of formula (700) or (701):

[0080] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (80) or formula (81):

[0081] Equation (80)

[0082] In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)Ra -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5;

[0083] Equation (81)

[0084] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a-OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0085] In some embodiments, the pharmaceutical composition comprises a compound of formula (80), which is a compound of formula (800) or (801), or a compound of formula (81), which is a compound of formula (802) or (803):

[0086] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (82):

[0087] Equation (82)

[0088] In equation (82): R 11a R 11b、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0089] In some embodiments, the pharmaceutical composition comprises a compound of formula (82), which is a compound of formula (804) or (805):

[0090] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of formula (90):

[0091] Equation (90)

[0092] In equation (90): n is an integer from 1 to 5.

[0093] In some embodiments, the pharmaceutical composition comprises a compound of formula (90), which is a compound of formula (900), formula (901), or formula (902):

[0094] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of any one of formulas 1001-1098, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), which is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof.

[0095] In another aspect, this disclosure provides a method for treating a subject in need of cancer, an infectious disease, or an inflammatory disease, the method comprising administering to the subject a pharmaceutical composition comprising a compound of any one of formulas (I), (10), (20), (21), (30)-(32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800)-(805), (900), (901), or (902). In some implementations, the cancer is selected from basal cell carcinoma; bile duct cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancers); glioblastoma; liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney cancer or renal cell carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer). Lung cancer, lung adenocarcinoma, and squamous cell carcinoma of the lung; melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancers; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancers; vulvar cancer; lymphoma, including Hodgkin's and non-Hodgkin's lymphomas. andnon-Hodgkin's lymphoma), and B-cell lymphomas (including low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate / follicular NHL; intermediate diffuse NHL; advanced immunoblastic NHL; advanced lymphoblastic NHL; advanced small non-lytic cell NHL; mass disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorders (PTLD), as well as abnormal angiogenesis, edema (such as edema associated with brain tumors) and Meigs' syndrome associated with scarring nevi).In some implementations, cancer is selected from the group consisting of: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, and Burkitt's lymphoma. Phoma), diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia, and preleukemia, or combinations thereof. In some embodiments, the cancer is resistant to the anti-checkpoint agent. In some embodiments, the anti-checkpoint agent is an antibody, optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA antibodies. In some embodiments, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiplimab (LIBTAYO), atezolizumab (TECENTRIQ), avelumab (BAVENCIO), and durvalumab (IMFINZI). In some embodiments, the infectious disease is a viral infection.In some implementations, the viral infection is caused by a virus selected from the following: human papillomavirus, herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis virus, Zika virus, yellow fever virus, West Nile virus, dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, hepatitis C virus, poliovirus, rhinovirus, enterovirus, coxsackievirus, influenza virus, lentivirus, respiratory syncytial virus, human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2). In some implementations, the inflammatory disease is an autoimmune disease or disorder selected from multiple sclerosis, diabetes, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholecystitis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allogeneic transplant rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome. This includes diseases such as systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, and other autoimmune diseases.

[0096] In another aspect, this disclosure provides a method for treating an anti-checkpoint agent-resistant cancer in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising a compound of any one of formulas (I), (10), (20), (21), (30)-(32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800)-(805), (900), (901), or (902). In some embodiments, the anti-checkpoint agent is an antibody, optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA antibodies. In some implementations, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiplimab (LIBTAYO), atezolizumab (TECENTRIQ), avelumab (BAVENCIO), and durvalumab (IMFINZI).

[0097] In another aspect, this disclosure provides a method for determining cancer treatment for a patient, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then a cancer therapy is selected consisting of a pharmaceutical composition comprising any one of the following formulas: (I), (10), (20), (21), (30)-(32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800)-(805), (900), (901), or (902); and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0098] In another aspect, this disclosure provides a method for selecting patients for cancer treatment, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and (c) A cancer therapy comprising a pharmaceutical composition comprising any one of the following formulas: (I), (10), (20), (21), (30)-(32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800)-(805), (900), (901), or (902); and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0099] In another aspect, this disclosure provides a method for treating cancer, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and (c) Cancer therapy comprising, if Trim7 is upregulated compared to healthy tissue, a prior biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, administration of a pharmaceutical composition comprising any one of the compounds of formulas (I), (10), (20), (21), (30)-(32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800)-(805), (900), (901), or (902); and (d) Optionally administer a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0100] In some embodiments, the biological sample used in any of the above methods is a fresh tissue sample, a frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen. In some embodiments, the biological sample used in any of the above methods is a biopsy sample, optionally wherein the biopsy sample is selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy, and colonoscopy), puncture biopsy (e.g., fine-needle aspiration biopsy, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computed tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy, and ultrasound-assisted biopsy), skin biopsy (e.g., scraping biopsy, puncture biopsy, and incision biopsy), and surgical biopsy. In some embodiments, the biological samples used in any of the above methods include bodily fluids selected from: blood, plasma, serum, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing bodily fluids, free nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological secretions, skin swabs, vaginal swabs, oral swabs, nasal swabs, irrigation or lavage fluids such as catheter lavage fluid or bronchoalveolar lavage fluid, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other bodily fluids, secretions and / or excretions, and / or cells extracted therefrom. In some embodiments, the biological samples used in any of the above methods include at least one tumor cell. In some embodiments, the evaluation used in any of the above methods is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, Western blotting, intracellular Western blotting, immunofluorescence staining, ELISA and fluorescence activated cell sorting (FACS) or combinations thereof.

[0101] In some embodiments, the evaluation used in any of the above methods is performed by contacting the sample with an agent that specifically binds to Trim7. In one embodiment, the agent that specifically binds to one or more proteins comprises an antibody, an antibody-like molecule, or a binding fragment thereof. In some embodiments, the evaluation used in any of the above methods is performed by contacting the sample with one or more agents that specifically bind to Trim7 nucleic acids. In some embodiments, the agent that specifically binds to one or more nucleic acids is a nucleic acid primer or probe.

[0102] Any aspect or implementation disclosed herein may be combined with any other aspect or implementation disclosed herein. Attached Figure Description

[0103] This patent or application document contains at least one color drawing. A published copy of this patent or application with one or more color drawings will be provided by the Patent Office upon request and payment of the necessary fees.

[0104] Figure 1A and Figure 1B The in vitro binding of recombinant human (rh) Trim7 to RACO1 and MSK1, as measured using a Meso Scale Discovery (MSD) platform-based assay, is shown. Figure 1A The binding of RACO1 to human Trim7 was shown and compared with CD47, which was used as a negative control. Figure 1B The binding of MSK1 to human Trim7 was shown and compared with CD47, which was used as a negative control.

[0105] Figure 2 The in vitro binding of recombinant human (rh) Trim7 to enterovirus 71 2B or enterovirus 71 2BC proteins, as measured using a Meso Scale Discovery (MSD) platform-based assay, is shown. Recombinant human RACO1 and MSK1 proteins were used as positive controls, and recombinant human CD47 protein was used as a negative control.

[0106] Figure 3A and Figure 3B The results, as measured using a Meso Scale Discovery (MSD) platform, demonstrate the inhibitory effect of enterovirus 71 2BC protein on recombinant human (rh) Trim7 and MSK1. Figure 3A ) and RACO1 ( Figure 3B ) in vitro binding.

[0107] Figure 4 The crystal structure of Trim7 bound to the CVB_2C (319-329) peptide (SVGTTLEALFQ) is shown. The peptide is the C-terminal fragment of the Coxsackievirus B3 (CVB3)_2C protein. The upper left figure shows a schematic diagram of the CVB3 C2 protein, illustrating the position of the CVB_2C (319-329) peptide. The lower left figure shows the crystal structure of the CVB_2C protein, illustrating the CVB_2C (319-329) peptide, and the crystal structure of the Trim7 protein complexed with the CVB_2C (319-329) peptide. The right figure shows the interactions of various amino acids between the CVB_2C (319-329) peptide and the Trim7 protein.

[0108] Figure 5 A schematic diagram of a molecular simulation-based method for identifying Trim7 inhibitors (including compounds of Formula 1) is shown.

[0109] Figure 6 Various docking compounds are shown. Underlined compounds have docking scores better than -7, indicating that their affinity constants may be <100 nM.

[0110] Figure 7 Representative compounds and their docking scores are shown.

[0111] Figure 8A and Figure 8B The docking of compound 1009 is shown. Figure 8A Compound 1001 is shown in the background under the space-filling model of Trim7. Figure 8B The binding of compound 1001 with Trim7 is shown.

[0112] Figure 9A , Figure 9B and Figure 9C An illustration of the Trim7 crystal structure is shown, which in part tells the story of the Trim7 SMI of this disclosure.

[0113] Figure 10 Data confirming the interaction of TRIM7 with RACO-1, STING, MAVS, and CVB3_2C (WT rather than mutant) are provided.

[0114] Figure 11 This illustrates a scheme for an exemplary workflow of screening and prioritizing candidates.

[0115] Figure 12A and Figure 12B Data from cell-based activity assays were provided, indicating that TRIM7 expression in cells leads to target degradation / stabilization. Figure 12A It was demonstrated that overexpression of TRIM7 (+T7) in 293T cell lines expressing CVB3, MAVS, or STING led to their degradation. Figure 12B This assay showed that compound 1028 blocked the stabilization of RACO1 by TRIM7, thereby leading to its degradation. Detailed Implementation

[0116] This article discloses Trim7 inhibitors, which... In particularIt can be used to treat diseases such as cancer (including cancers resistant to checkpoint agents), infectious diseases, and autoimmune therapies. Drug resistance, whether pre-existing (inherent or primary resistance) or acquired (acquired resistance) after treatment, is a cause of repeated cancer recurrence, and cancer is one of the leading causes of death. Therefore, a better understanding of the mechanisms of drug resistance is needed to guide future cancer treatments. Anti-PD-1 resistant tumors have been reported to exhibit paradoxical dysregulation of several IFNγ-induced genes, with Trim7 being a driver gene involved in this paradoxical dysregulation and anti-PD-1 resistance. See International Application PCT / US2021 / 061834, which is incorporated herein by reference in its entirety. Therefore, this document discloses… In particular Trim7 inhibitors can be used to treat cancers resistant to checkpoint agents. Because Trim7 is involved in multiple processes in the pathogenesis of diseases such as tumor growth, innate immunity, and viral infections, the Trim7 inhibitors disclosed herein can be used to treat cancer, infectious diseases, and autoimmune diseases.

[0117] Trim7

[0118] Triple motif (TRIM) proteins are a class of E3 ubiquitin ligases involved in various cellular functions. Many TRIM proteins are induced by type I and type II interferons (IFN-I or IFN-II) or by pathogen stimulation (present in different cell types, including human and mouse primary immune cells). Rajsbaum et al. , Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells. Eur J Immunol . 2008;38(3):619-630;Carthagena et al. , Human TRIM gene expression responds to interferons. PLoS One 2009;4(3):e4894. The common N-terminal region of TRIM proteins contains a RING finger domain, followed by one or two B-box domains and a coiled-coil domain (CC). Each TRIM protein has a specific C-terminal domain that imparts substrate specificity via protein-protein interactions. The C-terminal domains include the PRY and / or SPRY domains (B30.2).

[0119] Tripartite motif containing 7 (Trim7) is known to play roles in tumor cell proliferation, glycogen metabolism, innate immunity (e.g., induced by IFN), and viral pathogenesis. Giraldo et al. ,Envelope protein ubiquitination drives entry and pathogenesis of Zikavirus. Nature 2020. 10.1038 / s41586-020-2457-8; Montori-Grau et al. , GNIP1 E3ubiquitin ligase is a novel player in regulating glycogen metabolism inskeletal muscle. Metabolism 2018;83:177–187; Lu et al. , E3 ubiquitin ligasetripartite motif 7 positively regulates the TLR4-mediated immune response viaits E3 ligase domain in macrophages. Mol Immunol 2019;109:126-133. While not wishing to be bound by theory, it is believed that MSK1 directly phosphorylates Trim7. Trim7 has also been shown to act as an E3 ligase mediating the K63-linked polyubiquitination of the AP-1 coactivator RACO-1, thereby stabilizing the RACO-1 protein. Chakraborty et al. ,The E3 ubiquitin ligase Trim7 mediates c-Jun / AP-1 activation by Rassignaling. Nat Commun 2015;6:6782. Trim7 has been described to negatively regulate responses to DNA viruses through degradation targeting STING. Yang et al. , RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation. PLoS Pathog . 2020;16(3):e1008387.

[0120] Trim7 has been identified as one of the dysregulated genes in an acquired resistance model of anti-PD-1 antibodies. See International Application No. PCT / US2021 / 061834, which is incorporated herein by reference in its entirety.

[0121] Trim7 inhibitor

[0122] As used herein, the term "alkyl" refers to a branched or unbranched hydrocarbon chain having about 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-methylpentyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, etc. "Substituted alkyl" includes alkyl groups optionally substituted with one or more functional groups typically attached to such chains, such as hydroxyl, halogen, mercapto or thio, cyano, alkylthio, carboxyl, nitro, alkoxy, or optionally substituted alkyl, amino, alkenyl, formamido, alkoxycarbonyl, alkynyl, heterocyclic, aryl, heteroaryl, etc., to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl, phenethyl, benzyl, etc.

[0123] The term “halogen” or “halogenated” as used alone or as part of another group in this article refers to chlorine, bromine, fluorine, or iodine.

[0124] The term "alkoxy" refers to alkyl-O-, where the alkyl group is as defined above.

[0125] The term "alkylthio" refers to an alkyl-S- group, where the alkyl group is as defined above.

[0126] The term “alkylamino” refers to –NR'R”, where R' and R” can each independently represent H, alkyl or aryl, all of which are as defined herein.

[0127] The term "alkyl carbonyl" refers to –C(=O)-alkyl, where the alkyl group is as defined above.

[0128] The term "carboxyl group" refers to a portion of –C(=O)OH.

[0129] The term "alkoxycarbonyl" refers to a partially –C(=O)-O-alkyl group, where the alkyl group is as defined above.

[0130] The term “formamide group” refers to the part –C(=O)-NR'R”, where R' and R” can each independently represent H, alkyl or aryl, all of which are as defined herein.

[0131] The term "alkylsulfonyl" refers to a partial –S(=O)2-alkyl group, wherein the alkyl group is as defined above.

[0132] The term "arylsulfonyl" refers to a partial –S(=O)2-aryl group, wherein the aryl group is as defined herein. For example, an arylsulfonyl group can be –S(=O)2-phenyl.

[0133] The term “arylsulfonyloxy” refers to a partial –OS(=O)2-alkyl group, wherein the alkyl group is as defined above.

[0134] The term “amino(monoalkylamino-, dialkylamino-)sulfinyl” refers to the part –S(=O)NR'R”, where R' and R” can each independently represent H, alkyl or aryl, all of which are as defined herein.

[0135] The term “amino(monoalkylamino-, dialkylamino-)sulfonyl” refers to the moiety –S(=O)2NR'R”, where R' and R” can each independently represent H, alkyl or aryl, all of which are as defined herein.

[0136] The term "alkylsulfonylamino" refers to a moiety –NHS(=O)2-alkyl, wherein the alkyl group is as previously defined.

[0137] The term "hydroxysulfonyloxy" refers to part of –OS(=O)2OH.

[0138] The term "alkoxysulfonyloxy" refers to a partial –OS(=O)2O-alkyl, wherein the alkyl group is as defined above.

[0139] The term "alkylsulfonyloxy" refers to a partial –OS(=O)2-alkyl group, wherein the alkyl group is as previously defined.

[0140] The term "hydroxysulfonyl" refers to the part –S(=O)2OH.

[0141] The term "alkoxysulfonyl" refers to a partial –S(=O)2O-alkyl group, wherein the alkyl group is as previously defined.

[0142] The term “alkylsulfonylalkyl” refers to a partial –alkyl-S(=O)2-alkyl, wherein each alkyl group may be as previously defined.

[0143] The term “amino(monoalkylamino-, dialkylamino-)sulfonylalkyl” means “partial –alkyl-S(=O)2-NR'R”, where alkyl is as previously defined, and R' and R” may each independently represent H, alkyl or aryl, all of which are as defined herein.

[0144] The term “amino(monoalkylamino-, dialkylamino-)sulfinylalkyl” means “partial –alkyl-S(=O)-NR'R”, where alkyl is as previously defined, and R' and R” can each independently represent H, alkyl or aryl, all of which are as defined herein.

[0145] Unless otherwise indicated, the term "cycloalkyl" as used alone or as part of another group herein includes a saturated or partially unsaturated cyclic hydrocarbon group (containing one or more double bonds) containing one to three rings, including monocycloalkyl, bicycloalkyl, and tricycloalkyl, containing a total of three to 20 carbon-forming rings, preferably three to ten-forming rings, and which may be fused with one or two aromatic rings as described for aryl, said cycloalkyl including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl. "Substituted cycloalkyl" includes cycloalkyl groups optionally substituted with one or more substituents such as halogen, alkyl, substituted alkyl, alkoxy, hydroxy, aryl, substituted aryl, aryloxy, cycloalkyl, alkylamide, alkylacylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio, and / or any substituent included in the definition of "substituted alkyl".

[0146] Unless otherwise indicated, the term "alkenyl" as used alone or as part of another group herein refers to a straight or branched chain having 2 to 20 carbons in its positive chain, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons, containing one or more double bonds in its positive chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecanetrienyl, etc. "Substituted alkenyl" includes alkenyl groups optionally substituted with one or more substituents, such as those included in the definitions of "substituted alkyl" and "substituted cycloalkyl" above.

[0147] Unless otherwise indicated, the term "alkynyl" as used alone or as part of another group herein refers to a straight or branched chain having 2 to 20 carbons in its positive chain, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons, containing one or more triple bonds in its positive chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, 4-decynyl, 3-undetyynyl, 4-dodecynyl, etc. "Substituted alkynyl" includes alkynyl groups optionally substituted with one or more substituents, such as those included in the definitions of "substituted alkyl" and "substituted cycloalkyl" above.

[0148] Unless otherwise indicated, the term "aryl" or "Ar" as used alone or as part of another group herein refers to a monocyclic, bicyclic, and / or polycyclic aromatic group (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) containing 6 to 10 carbons in the ring moiety, and may optionally include one to three additional rings fused to the carbon ring or heterocycle, such as aryl rings, cycloalkyl rings, heteroaryl rings, or cyclohexaalkyl rings or substituted forms thereof.

[0149] "Substituted aryl" includes aryl groups optionally substituted with one or more functional groups, such as halogen, alkyl, haloalkyl (e.g., trifluoromethyl), alkoxy, haloalkoxy (e.g., difluoromethoxy), alkenyl, alkynyl, cycloalkylalkyl, cyclohexaalkyl, cyclohexaalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, arylalenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalenyl, heteroarylhexaaryl, heteroarylalkyl, heteroarylalenyl, heteroarylhexaaryl, heteroarylalkyl The amino group includes alkyl, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino group comprises one or two substituents (the substituents being optionally substituted alkyl, aryl, or any other substituents described herein)), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylaminocarbonyl, arylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, or arylsulfonylaminocarbonyl and / or any alkyl substituents described herein.

[0150] The term “arylalkyl” refers to –alkyl-aryl, where alkyl and aryl are as defined above.

[0151] Unless otherwise indicated, the term "heteroaryl" as used alone or as part of another group herein refers to a 5- to 7-membered aromatic ring comprising 1, 2, 3, or 4 heteroatoms (such as nitrogen, oxygen, or sulfur), and such ring is fused with an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring (e.g., benzothiophene, indole, quinoline, thiazole, isoxazole, benzothiazole, benzimidazole, isoquinoline, pyridine, pyrimidine, benzopyranone, oxazole, thiazole, pyrazine), and includes possible N-oxides. "Substituted heteroaryl" includes heteroaryl groups optionally substituted with 1 to 4 substituents, such as those included in the definitions of "substituted alkyl" and "substituted cycloalkyl" above. Substituted heteroaryl groups also include fused heteroaryl groups, such as quinoline, isoquinoline, indole, isoindole, carbazole, acridine, benzo[a]pyrene, benzo[a]pyranone, benzimidazole, benzo[a]furan, isobenzo[a]furan, phenanthrene, purine, etc.

[0152] Furthermore, as used herein, the terms "heterocyclo," "heterocycle," "heterocyclyl," or "heterocyclic ring" refer to an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system, which may be saturated or unsaturated, and which consists of a carbon atom and one to four heteroatoms selected from N, O, or S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heterocycles can be attached to any heteroatom or carbon atom to produce a stable structure. Examples of such heterocyclic groups include, but are not limited to: piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, oxopyrrolyl, oxonitrile-heptanyl, heptanyl, pyrroleyl, pyrroleyl, benzothiophene, cronone, benzo[a]pyrene, benzo[a]pyranone, furanyl, thiophene, pyrazolyl, pyrazolylyl, imidazolyl, imidazolinyl, imidazolinyl, pyridinyl, pyrimidinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, morpholinyl, thiazolyl, thiazolinylyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0153] The term “heteroarylalkyl” refers to –alkyl-heteroaryl, where alkyl and heteroaryl are as defined above.

[0154] As used herein, the terms “optionally substituted” or “substituted” may indicate that the referred chemical moiety (e.g., alkyl, aryl, and heteroaryl) may be unsubstituted or may be substituted by one or more groups, including but not limited to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, hydroxyl, amino, substituted amino, alkoxy, substituted alkoxy, halogen, carboxyl, nitro, alkoxycarbonyl, substituted alkoxycarbonyl, formamido, substituted formamido, alkylamino, substituted alkylamino, monoalkylaminosulfinyl, substituted monoalkylaminosulfinyl, dialkylaminosulfinyl, substituted Dialkylaminosulfinyl, monoalkylaminosulfinyl, substituted monoalkylaminosulfinyl, dialkylaminosulfinyl, substituted dialkylaminosulfinyl, alkylsulfonylamino, substituted alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, substituted alkoxysulfonyloxy, alkylsulfonyloxy, substituted alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, substituted alkoxysulfonyl, alkylsulfonylalkyl, substituted alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, substituted monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, substituted dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, substituted monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, substituted dialkylaminosulfinylalkyl, etc. The chemical portions of formulas (I), (10), (20), (21), (30), (31), (32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800), (801), (802), (803), (804), (805), (900), (901), (902), or formulas 1001-1098, or pharmaceutically acceptable salts thereof, may optionally be substituted, including alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclic, and heteroaryl, as described herein. For example, optionally substituted alkyl groups may include both propyl and 2-chloropropyl. Additionally, "optionally substituted" also includes embodiments in which one or more named substituents have multiple substituents rather than a simple single substituent. For example, the optionally substituted aryl group may include both phenyl and 3-ethyl-5-methyl-6-bromo-phenyl.

[0155] The compounds of this disclosure can be administered in the form of salts, which are also within the scope of this disclosure. Pharmaceutically acceptable (i.e., non-toxic and physiologically compatible) salts are preferred. If the compounds of this disclosure, for example, have at least one basic center, they can form acid addition salts. For example, these compounds are formed with strong inorganic acids (such as mineral acids, such as sulfuric acid, phosphoric acid, or hydrohalic acid), strong organic carboxylic acids (such as alkane carboxylic acids with 1 to 4 carbon atoms (which are unsubstituted or substituted, such as halogenated, for example, acetic acid), such as saturated or unsaturated dicarboxylic acids (such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid), such as hydroxycarboxylic acids (such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid), such as amino acids (such as aspartic acid and glutamic acid or lysine or arginine) or benzoic acid), or organic sulfonic acids (such as (C1-C4) alkyl sulfonic acids or aryl sulfonic acids, which are unsubstituted or substituted, such as halogenated, for example, methanesulfonic acid or p-toluenesulfonic acid). If desired, corresponding acid addition salts with multiple basic centers can also be formed. In the implementation plan, pharmaceutically acceptable salts are selected from valproic acid, maleic acid, tartaric acid, oxalic acid, pamoic acid, phosphonic acid, benzoic acid, citric acid, salicylic acid, succinic acid, mesylic acid, malic acid, and... for Toluenesulfonic acid. In the implementation scheme, the pharmaceutically acceptable salt is selected from valproic acid, maleic acid, tartaric acid, oxalic acid, and pamoic acid.

[0156] Compounds of this disclosure having at least one acidic group (e.g., a carboxylic acid) can also form salts with suitable bases. Representative examples of such salts include metal salts, such as alkali metal or alkaline earth metal salts, such as sodium, potassium, or magnesium salts; or salts containing ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine; monohydroxy, dihydroxy, or trihydroxy lower alkylamines, such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine; or monohydroxy, dihydroxy, or trihydroxy lower alkylamines, such as monoethanolamine, diethanolamine, or triethanolamine. Corresponding inner salts may also be formed.

[0157] For example, certain salts of the compounds described herein containing a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, or nitrate. Furthermore, certain salts of the compounds described herein containing an acidic group include sodium, potassium, and magnesium salts, as well as pharmaceutically acceptable organic amines.

[0158] All stereoisomers of the compounds disclosed herein, whether in mixtures or in pure or substantially pure form, shall be considered within the scope of this disclosure. The compounds of this disclosure may have an asymmetric center on any carbon atom, including any of the substituents. Therefore, the compounds of this disclosure may exist as enantiomers or diastereomers, or mixtures thereof. Furthermore, where the stereocenter present in the compounds of this disclosure is represented as a racemic mixture, it should be understood that said stereocenter may encompass racemic mixtures of R and S isomers, S isomers, and R isomers. Processes for preparing such compounds may utilize racemic, enantiomeric, or diastereomers as starting materials. When preparing diastereomeric or enantiomeric products, they can be separated by conventional methods, including chromatography, chiral HPLC, fractional crystallization, or distillation. Some of the compounds disclosed herein have groups including alkenyl, imino, etc., which can exist in trans (E) or cis (Z) conformations. In this case, all their geometries, both E and Z, cis and trans, and mixtures thereof, are within the scope of this disclosure. Therefore, when preparing such geometric isomers, they can be separated by conventional methods (e.g., chromatography, HPLC, distillation, or crystallization).

[0159] In one aspect, this disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0160] Formula (I)

[0161] In equation (I): A is selected from , , , , , and ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R aEach time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; and t is 1 or 2; the condition is that the compound of formula (I) is not a compound of any of formulas 1001, 1003, 1004 and 1006-1009:

[0162] In the implementation plan, R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -C(O)R a -N(R) a )2、-N(R a )C(O)R a and -S(O) t R a In the embodiments, the aryl group is a halogenated aryl group. In the embodiments, L is a bond or contains one or more linking groups selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1-10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted aryl group, wherein p is an integer from 1 to 5. In an embodiment, p is 2. In an embodiment, L is a bond. In an embodiment, L is -C(O)-. In an embodiment, L is -C(H)(CH2). p C(O)NH2. In the implementation scheme, L is... In the implementation plan, L is... Wherein the alkyl group is substituted or unsubstituted. In the embodiments, L is... In the implementation plan, L is... In the implementation plan, L is... .

[0163] In the implementation plan, A is In the implementation scheme, compound (I) is compound (10):

[0164] Equation (10)

[0165] In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(Ra )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2. In the implementation scheme, n 2 The value is 2. In the implementation plan, R... 1a It is a C1-6 alkyl group. In the embodiments, R 1a It is -CH3. In the implementation plan, R 2 It is H. In the implementation plan, R 9a R 9b R 9c R 9d and R 9e Each is independently selected from hydrogen and halogenated. In the embodiments, the halogenated form is F or Cl. In the embodiments, R... 9a R 9b R 9c R 9d and R 9e Each is hydrogen. In the implementation plan, R 9a R 9d and R 9e Each is hydrogen. In the implementation plan, R 9b It is Cl. In the implementation plan, R 9c It is F.

[0166] In the implementation plan, A is In the embodiments, the compound of formula (I) is a compound of formula (20) or (21):

[0167] In equations (20) and (21): n3 is an integer from 0 to 5. In the implementation, n3 is 2. In the implementation, R4a It is H. In the implementation plan, R 4b It is H. In the implementation plan, R 3 It is a C1-6 alkyl group. In the embodiments, R 3 It is -CH3.

[0168] In the embodiments, the compound of formula (I) is the compound of formula (20), or a pharmaceutically acceptable salt thereof. In the embodiments, the compound of formula (I) is the compound of formula (21), or a pharmaceutically acceptable salt thereof.

[0169] In the implementation plan, A is In the embodiments, the compound of formula (I) is a compound of formula (30) or (31):

[0170] In equations (30) and (31): p is an integer from 0 to 5. In the implementation, p is 2. In the implementation, R 5a R 5b R 5c R 5d and R 5e Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH3. 。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 5a R 5c R 5d and R 5e Each is hydrogen. In the implementation plan, R 5d It is -CH3.

[0171] In the embodiments, the compound of formula (I) is the compound of formula (30), or a pharmaceutically acceptable salt thereof. In the embodiments, the compound of formula (I) is the compound of formula (31), or a pharmaceutically acceptable salt thereof.

[0172] In the implementation scheme, the compound of formula (I) is the compound of formula (32):

[0173] Equation (32).

[0174] In equation (32): q is an integer from 1 to 3. In the implementation scheme, q is 1. In the implementation scheme, R 5a R 5b R 5c and R 5d Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH3. 。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 5a R 5b R 5c and R 5d Each is hydrogen.

[0175] In the implementation scheme, the compound of formula (I) is the compound of formula (70):

[0176] Equation (70)

[0177] In equation (70): R11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl. In the embodiments, R 5a and R 5d Each is hydrogen.

[0178] In the embodiments, the compound of formula (70) is a compound of formula (700) or (701):

[0179] In an embodiment, the compound of formula (70) is a compound of formula (700), or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (70) is a compound of formula (701), or a pharmaceutically acceptable salt thereof.

[0180] In the implementation plan, R 5b Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5c Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation scheme, the halogen is Br. In the implementation scheme, the substituted aryl group is... In some implementations, the substituted aryl group is... In the implementation plan, -N(R) a )2 is -NH 2。 In the embodiments, the alkynyl group is optionally unsubstituted. In the embodiments, -N(R a )C(O)R a yes , , or .

[0181] In the implementation plan, R 11a and R 11b Each independently is Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2. In the embodiments, R 11a and R 11b Each independently selected , , , , , , , , , , and .

[0182] In some implementation schemes, R 11a Selected from H and unsubstituted alkyl groups and R 11b yes In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and .

[0183] In the implementation plan, R 11a It is H and R 11b It is an unsubstituted alkyl group. In the embodiments, R 11a It is H and R 11b It is -CH3. In the implementation plan, R 11a and R 11b Each is independently an unsubstituted alkyl group. In the embodiments, R 11a and R 11b Each is -CH3.

[0184] In the implementation scheme, the compound of formula (I) is the compound of formula (80):

[0185] Equation (80)

[0186] In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-Ra -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5. In the implementation scheme, R 5a and R 5d Each is hydrogen. In the implementation scheme, n8 is 1.

[0187] In the implementation scheme, the compound of formula (I) is the compound of formula (81):

[0188] Equation (81)

[0189] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11bEach of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl. In the embodiments, R 5a and R 5d Each is hydrogen.

[0190] In the embodiments, the compound of formula (80) is a compound of formula (800) or formula (801), or the compound of formula (81) is a compound of formula (802) or formula (803):

[0191] In one embodiment, the compound of formula (80) is a compound of formula (800), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (80) is a compound of formula (801), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (81) is a compound of formula (802), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of formula (81) is a compound of formula (803), or a pharmaceutically acceptable salt thereof.

[0192] In the implementation plan, R 5b Selected from unsubstituted or substituted alkynyl groups, substituted heteroaryl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5b Selected from substituted aryl and -N(R) a )C(O)R a In the implementation plan, R 5c Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5c It is a substituted aryl group. In the embodiment, the halogenation is Br. In the embodiment, the substituted aryl group is... In the implementation scheme, the substituted aryl group is... In the implementation scheme, the substituted aryl group is... In the implementation scheme, the substituted aryl group is... In the implementation plan, -N(R) a )2 is -NH 2。 In the embodiments, the alkynyl group is optionally unsubstituted. In the embodiments, -N(R a )C(O)R a yes In the implementation plan -N(R) a )C(O)R a yes In the implementation plan, R 5b Selected from , , , , , , , , , , , and In the implementation plan, R 5b Selected from , , , , , , and In the implementation plan, R 5c Selected from , , , , , , , , , and In the implementation plan, R 5c Selected from , , , and In the embodiment, n8 is 1. In the embodiment, Alk is a C1-C5 alkyl group. In the embodiment, Alk is a C1-C3 alkyl group. In the embodiment, Alk is methyl. In the embodiment, Alk is an aryl-substituted C1-C5 alkyl group. In the embodiment, Alk is... .

[0193] In the implementation plan, R 11a and R 11b Each is independently an unsubstituted alkyl group. In the embodiments, R 11a and R 11b Each is independently a C1-C5 alkyl group. In the embodiments, R 11a and R 11b Each is independently a C1-C3 alkyl group. In the embodiments, R 11a and R 11b Each is independently a methyl group. In the implementation scheme, R 11a and R 11b Each independently is Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2. In the embodiments, R 11a and R 11b Each independently selected , , , , , , , , , , , and In the implementation plan, R 11a and R 11b Each independently selected , , , , , , , , , , and In the implementation plan, R 11a and R 11b Each independently selected , , , , , , , and .

[0194] In the implementation plan, R 11a Selected from H and unsubstituted alkyl groups, optionally methyl, and R 11b yes In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , and .

[0195] In the implementation plan, R 11a It is H and R 11b It is an unsubstituted alkyl group. In the embodiments, R 11a It is H and R 11b It is -CH3. In the implementation plan, R 11a and R 11b Each is independently an unsubstituted alkyl group. In the embodiments, R 11a and R 11b Each is -CH3.

[0196] In the implementation scheme, the compound of formula (I) is the compound of formula (82):

[0197] Equation (82)

[0198] In equation (82): R 11a R 11b 、 R 11c and R11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0199] In the embodiments, the compound of formula (82) is a compound of formula (804) or (805):

[0200] In one embodiment, the compound of formula (82) is the compound of formula (804), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (82) is the compound of formula (805), or a pharmaceutically acceptable salt thereof.

[0201] In the implementation plan, R 5b and / or R 5c Each independently is -OR a , where R a It is an unsubstituted alkyl group, optionally wherein -OR a It is -OCH3. In the implementation scheme, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is an independent cyclohexyl group. In the implementation plan, R... 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is an alkyl group that has been substituted with a cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently a -CH2- substituted with a cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each independently is .

[0202] In the implementation plan, A is In the implementation scheme, compound (I) is compound (90):

[0203] Equation (90)

[0204] In equation (90): n is an integer from 1 to 5.

[0205] In the implementation scheme, the compound of formula (90) is a compound of formula (900), formula (901), or formula (902):

[0206] In one embodiment, the compound of formula (90) is a compound of formula (900), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (90) is a compound of formula (901), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of formula (90) is a compound of formula (902), or a pharmaceutically acceptable salt thereof.

[0207] In the implementation plan, R 12 It is H. In the implementation plan, R 12 It is -CH3.

[0208] In the implementation plan, R 11a It is H. In the implementation plan, R 11a It is a substituted alkyl group. In the embodiments, R 11a It is an alkyl group substituted with an aryl group. In the embodiments, R 11a yes In the implementation plan, R 11a yes In the implementation plan, R 10 It is -C(O)R a In the implementation plan, R 10 It is -C(O)R a , where R a It is an unsubstituted alkenyl group. In the embodiments, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted alkyl group. In the embodiments, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted aryl group. In the implementation scheme, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted heterocyclic group. In the implementation, R 10 yes In the implementation plan, R 10 It is -S(O) t R a In the implementation plan, R 10It is -S(O) t R a Where t is 2. In the implementation scheme, R 10 It is -S(O) t R a， Where t is 2 and R a It is a substituted aryl group. In the implementation scheme, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes .

[0209] In the embodiments, the compound of formula (I) is a compound of any one of 1002, 1005, 1010-1098, or a pharmaceutically acceptable salt thereof:

[0210] In the embodiments, the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof:

[0211] In the implementation plan, A is In the implementation scheme, compound (I) is compound (40):

[0212] Equation (40)

[0213] In equation (40): n4 is an integer from 0 to 5. In the implementation, n4 is 0. In the implementation, R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and unsubstituted or substituted alkyl groups. In embodiments, the alkyl group is an alkyl group substituted with an amide group, and the amide group is an amide group. In embodiments, R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and , where r is an integer from 0 to 4. In the implementation, r is 0. In the implementation, R 6a R 6c R 6d and R 6e Each is hydrogen. In the implementation plan, R 6b It is -C(O)NH2.

[0214] In the implementation plan, A is In the implementation plan, R 8 It is an unsubstituted or substituted aryl group. In the embodiments, the compound of formula (I) is the compound of formula (50):

[0215] Equation (50)

[0216] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a-OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2. In the implementation, n5 is 3. In the implementation, R 7a R 7b R 7c R 7d R 10a R 10b R 10c R 10d and R 10e Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH3. 。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 7a R 7b R 7c and R 7d Each is hydrogen. In the implementation plan, R 10a R 10b R 10d and R 10e Each is hydrogen. In the implementation plan, R 10c It is F.

[0217] In the implementation plan, A is In the implementation scheme, compound (I) is compound (60):

[0218] Equation (60)

[0219] In equation (60): n6 is an integer from 0 to 5. In the implementation scheme, n6 is 1. In the implementation scheme, R 9 It is H.

[0220] In embodiments, the compounds of this disclosure (e.g., compounds of formula (I), (10), (20), (21), (30), (31), (32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800), (801), (802), (803), (804), (805), (900), (901), (902), or formulas 1001-1098) are non-covalent inhibitors of Trim7. In a non-limiting example, the non-covalent inhibitor does not form a covalent bond with the Trim7 gene product (e.g., a covalent bond with an amino acid of the Trim7 gene product). In embodiments, the compounds of this disclosure (e.g., compounds of formula (I), (10), (20), (21), (30), (31), (32), (40), (50), (60), (70), (80), (81), (82), (90), (700), (701), (800), (801), (802), (803), (804), (805), (900), (901), (902), or formulas 1001-1098) are covalent inhibitors of Trim7. In a non-limiting example, the covalent inhibitor forms and / or is capable of forming a covalent bond with the Trim7 gene product (e.g., a covalent bond with an amino acid of the Trim7 gene product). Non-limiting examples of covalent Trim7 inhibitors include compounds containing one or more moieties capable of forming a covalent bond with the Trim7 gene product, including but not limited to alkenes, such as alkenes that are Michael receptors as understood by those skilled in the art. Non-limiting examples of alkenes include the -C(O)-CH=CH2 moiety.

[0221] pharmaceutical composition

[0222] This disclosure includes a pharmaceutical composition comprising a Trim7 inhibitor of any aspect or embodiment disclosed herein.

[0223] In one aspect, this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient:

[0224] Formula (I)

[0225] In equation (I): A is selected from , , , , , and ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a-C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; and t is 1 or 2.

[0226] In the implementation plan, R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R9 R 10 R 11a R 11b and R 11c Each is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -C(O)R a -C(O)N(R) a )2、-N(R a )2、-N(R a )C(O)R a and -S(O) t R a In the embodiments, the aryl group is a halogenated aryl group. In the embodiments, L is a bond or contains one or more linking groups selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R bS(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted aryl group, wherein p is an integer from 1 to 5. In an embodiment, p is 2. In an embodiment, L is a bond. In an embodiment, L is C(O)-. In an embodiment, L is -C(H)(CH2). p C(O)NH2. In the implementation scheme, L is... In the implementation plan, L is... Wherein the alkyl group is substituted or unsubstituted. In the embodiments, L is... In the implementation plan, L is... In the implementation plan, L is... .

[0227] In the implementation plan, A is In the implementation scheme, compound (I) is compound (10):

[0228] Equation (10)

[0229] In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a-C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2. In the implementation scheme, n 2 The value is 2. In the implementation plan, R... 1a It is a C1-6 alkyl group. In the embodiments, R 1a It is -CH3. In the implementation plan, R 2 It is H. In the implementation plan, R 9a R 9b R 9c R 9d and R 9e Each is independently selected from hydrogen and halogenated. In the embodiments, the halogenated form is F or Cl. In the embodiments, R... 9a R 9b R 9c R 9d and R 9e Each is hydrogen. In the implementation plan, R 9a R 9d and R 9e Each is hydrogen. In the implementation plan, R 9bIt is Cl. In the implementation plan, R 9c It is F.

[0230] In the implementation plan, A is In the embodiments, the compound of formula (I) is a compound of formula (20) or (21):

[0231] In equations (20) and (21): n3 is an integer from 0 to 5. In the implementation, n3 is 2. In the implementation, R4a It is H. In the implementation plan, R 4b It is H. In the implementation plan, R 3 It is a C1-6 alkyl group. In the embodiments, R 3 It is -CH3.

[0232] In the embodiments, the compound of formula (I) is the compound of formula (20), or a pharmaceutically acceptable salt thereof. In the embodiments, the compound of formula (I) is the compound of formula (21), or a pharmaceutically acceptable salt thereof.

[0233] In the implementation plan, A is In the embodiments, the compound of formula (I) is a compound of formula (30) or (31):

[0234] In equations (30) and (31): p is an integer from 0 to 5. In the implementation, p is 2. In the implementation, R 5a R 5b R 5c R 5d and R 5e Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH 3。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 5a R 5c R 5d and R 5e Each is hydrogen. In the implementation plan, R 5d It is -CH3.

[0235] In the embodiments, the compound of formula (I) is the compound of formula (30), or a pharmaceutically acceptable salt thereof. In the embodiments, the compound of formula (I) is the compound of formula (31), or a pharmaceutically acceptable salt thereof.

[0236] In the implementation scheme, the compound of formula (I) is the compound of formula (32):

[0237] Equation (32).

[0238] In equation (32): q is an integer from 1 to 3. In the implementation scheme, q is 1. In the implementation scheme, R 5a R 5b R 5c and R 5d Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH 3。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 5a R 5b R 5c and R 5d Each is hydrogen.

[0239] In the implementation scheme, the compound of formula (I) is the compound of formula (70):

[0240] Equation (70)

[0241] In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a)2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl. In the embodiments, R 5a and R 5d Each is hydrogen. In the embodiments, the compound of formula (70) is a compound of formula (700) or (701):

[0242] In an embodiment, the compound of formula (70) is a compound of formula (700), or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (70) is a compound of formula (701), or a pharmaceutically acceptable salt thereof.

[0243] In the implementation plan, R 5b Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5c Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation scheme, the halogenation is Br. In the implementation scheme, -N(R) a )2 is -NH 2。 In the embodiments, the alkynyl group is optionally unsubstituted. In the embodiments, -N(R a )C(O)R a yes In the implementation plan -N(R) a )C(O)R a yes In the implementation plan -N(R) a )C(O)R a yes In the implementation plan -N(R) a )C(O)R a yes In one implementation, the substituted aryl group is In one implementation, the substituted aryl group is .

[0244] In the implementation plan, R 11a and R 11b Each independently is Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2. In the embodiments, R 11a and R 11b Each independently selected , , , , , , , , , , and .

[0245] In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and .

[0246] In the implementation plan, R 11a It is H and R 11b It is an unsubstituted alkyl group. In one embodiment, R 11a It is H and R 11b It is -CH3. In the implementation plan, R 11a and R 11b Each is independently an unsubstituted alkyl group. In one embodiment, R 11a and R11b Each is -CH3.

[0247] In the embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein 5b Or R 5c It is -N(R) a )C(O)R a In the embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein R 5b Or R 5c yes In the embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein R 11a yes n7 is 1, and Y is an optionally substituted phenyl group and R 11b Selected from H, alkyl, tetrahydropyran and Where n7 is 1, and Y is an optionally substituted phenyl group. In embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein R 11a and R 11b Both are independent n7 is 1, and Y is an optionally substituted phenyl group, and at least one optionally substituted phenyl group is substituted with one or more halogens, alkyl groups, or CX3 groups, wherein X is a halogen selected from F, Cl, Br, and I. In embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein R 11a and R 11b Both are independent n7 is 1, and Y is an optionally substituted phenyl group, and both optionally substituted phenyl groups are substituted with one or more alkoxy groups, optionally -OCH3.

[0248] In the embodiments, the compound of formula (I) is a compound of formula (700) or formula (701), wherein: R 5b Or R 5c It is -N(R) a )C(O)R a Optional , R 11a yes Where n7 is 1, and Y is an optionally substituted phenyl group and R 11b Selected from H, alkyl, tetrahydropyran and Where n7 is 1, and Y is an optionally substituted phenyl group, or R 11a and R 11b Each independently is Where n7 is 1, and Y is an optionally substituted phenyl group, wherein at least one optionally substituted phenyl group is substituted by one or more halogens, alkyl groups, or CX3 groups, wherein X is a halogen selected from F, Cl, Br, and I, or R 11a and R 11b Each independently is , where n7 is 1, and Y is an optionally substituted phenyl group, wherein each optionally substituted phenyl group is independently substituted by one or more alkoxy groups, optionally -OCH3.

[0249] In the embodiments, the compound of formula (700) or formula (701) is a compound of any one of formulas 1020-1027, 1029, 1030, 1078-1081, or a pharmaceutically acceptable salt thereof.

[0250] In the implementation scheme, the compound of formula (I) is the compound of formula (80):

[0251] Equation (80)

[0252] In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NRa )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5. In the implementation scheme, R 5a and R 5d Each is hydrogen. In the implementation scheme, n8 is 1.

[0253] In the implementation scheme, the compound of formula (I) is the compound of formula (81):

[0254] Equation (81)

[0255] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a)2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl. In the embodiments, R 5a and R 5d Each is hydrogen.

[0256] In the embodiments, the compound of formula (80) is a compound of formula (800), formula (801), formula (802) or formula (803):

[0257] In one embodiment, the compound of formula (80) is a compound of formula (800), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (80) is a compound of formula (801), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (81) is a compound of formula (802), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of formula (81) is a compound of formula (803), or a pharmaceutically acceptable salt thereof.

[0258] In the implementation plan, R 5b Selected from unsubstituted or substituted alkynyl groups, substituted heteroaryl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5bSelected from substituted aryl and -N(R) a )C(O)R a In the implementation plan, R 5c Selected from unsubstituted or substituted alkynyl groups, substituted aryl groups, halogenated groups, and -N(R) groups. a )2 and -N(R a )C(O)R a In the implementation plan, R 5c It is a substituted aryl group. In the embodiment, the halogenation is Br. In the embodiment, the substituted aryl group is... In the implementation scheme, the substituted aryl group is... In the implementation scheme, the substituted aryl group is... In the implementation plan, -N(R) a )2 is NH 2。 In the embodiments, the alkynyl group is optionally unsubstituted. In the embodiments, -N(R a )C(O)R a yes In the implementation plan -N(R) a )C(O)R a yes In the implementation plan, R 5b Selected from , , , , , , , , , , , and In the implementation plan, R 5b Selected from , , , , , , and In the implementation plan, R 5c Selected from , , , , , , , , , and In the implementation plan, R 5c Selected from , , , and In the embodiment, n8 is 1. In the embodiment, Alk is a C1-C5 alkyl group. In the embodiment, Alk is a C1-C3 alkyl group. In the embodiment, Alk is methyl. In the embodiment, Alk is an aryl-substituted C1-C5 alkyl group. In the embodiment, Alk is... .

[0259] In the implementation plan, R 11a and R 11b Each is independently an unsubstituted alkyl group. In the embodiments, R 11a and R 11b Each is independently a C1-C5 alkyl group. In the embodiments, R 11a and R 11b Each is independently a C1-C3 alkyl group. In the embodiments, R 11a and R 11b Each is independently a methyl group. In the implementation scheme, R 11a and R 11b Each independently is Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2. In the embodiments, R 11a and R 11b Each independently selected , , , , , , , , , , , and In the implementation plan, R 11a and R 11b Each independently selected , , , , , , , , , , and In the implementation plan, R 11a and R 11b Each independently selected , , , , , , , and .

[0260] In the implementation plan, R 11a Selected from H and unsubstituted alkyl groups, optionally methyl, and R 11b yes In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , and In the implementation plan, R 11a Selected from H and -CH3 and R 11b Selected from and .

[0261] In the implementation scheme, the compound of formula (I) is the compound of formula (82):

[0262] Equation (82)

[0263] In equation (82): R 11a R 11b 、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R aEach time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0264] In the embodiments, the compound of formula (82) is a compound of formula (804) or (805):

[0265] In one embodiment, the compound of formula (82) is the compound of formula (804), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (82) is the compound of formula (805), or a pharmaceutically acceptable salt thereof.

[0266] In the implementation plan, R 5b and / or R 5c Each independently is -OR a , where R a It is an unsubstituted alkyl group, optionally wherein -OR a It is -OCH3. In the implementation scheme, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is an independent cyclohexyl group. In the implementation plan, R... 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is an alkyl group that has been substituted with a cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently a -CH2- substituted with a cycloalkyl group. In the embodiments, R 11a and R 11c Each is hydrogen, R 11b and R 11d Each independently is .

[0267] In the embodiments, the compound of formula (800) or formula (801) is a compound of any one of formulas 1035-1037, 1040-1045, 1047-1051, 1053, 1055-1074, 1082, 1083, or a pharmaceutically acceptable salt thereof.

[0268] In the embodiments, the compound of formula (802) or formula (803) is a compound of any one of formulas 1046, 1052, 1054, 1075-1077, or a pharmaceutically acceptable salt thereof.

[0269] In the embodiments, the compound of formula (804) or formula (805) is a compound of formula 1072, 1073, or a pharmaceutically acceptable salt thereof. In the embodiments, A is... In the implementation scheme, compound (I) is compound (90):

[0270] Equation (90)

[0271] In equation (90): n is an integer from 1 to 5.

[0272] In the implementation scheme, the compound of formula (90) is a compound of formula (900), formula (901), or formula (902):

[0273] In one embodiment, the compound of formula (90) is a compound of formula (900), or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (90) is a compound of formula (901), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of formula (90) is a compound of formula (902), or a pharmaceutically acceptable salt thereof.

[0274] In the implementation plan, R 12 It is H. In the implementation plan, R 12 It is -CH3.

[0275] In the implementation plan, R 11a It is H. In the implementation plan, R 11a It is a substituted alkyl group. In the embodiments, R 11a It is an alkyl group substituted with an aryl group. In the embodiments, R 11a yes or In the implementation plan, R 10 It is -C(O)R a In the implementation plan, R 10 It is -C(O)R a , where R aIt is an unsubstituted alkenyl group. In the embodiments, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted alkyl group. In the embodiments, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted aryl group. In the implementation scheme, R 10 yes In the implementation plan, R 10 It is -C(O)R a , where R a It is a substituted heterocyclic group. In the implementation, R 10 yes In the implementation plan, R 10 It is -S(O) t R a In the implementation plan, R 10 It is -S(O) t R a Where t is 2. In the implementation scheme, R 10 It is -S(O) t R a , where t is 2 and R a It is a substituted aryl group. In the implementation scheme, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes In the implementation plan, R 10 yes .

[0276] In the implementation scheme, the compound of formula (900), formula (901) or formula (902) is a compound of any one of formulas 1084-1098, or a pharmaceutically acceptable salt thereof.

[0277] In the embodiments, the compound of formula (I) is a compound of any one of 1002, 1005, 1010-1098, or a pharmaceutically acceptable salt thereof:

[0278] In the embodiments, the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof:

[0279] In the implementation plan, A is In the implementation scheme, compound (I) is compound (40):

[0280] Equation (40)

[0281] In equation (40): n4 is an integer from 0 to 5. In the implementation, n4 is 0. In the implementation, R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and unsubstituted or substituted alkyl groups. In embodiments, the alkyl group is an alkyl group substituted with an amide group, and the amide group is an amide group. In embodiments, R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and , where r is an integer from 0 to 4. In the implementation, r is 0. In the implementation, R 6a R 6c R 6d and R 6e Each is hydrogen. In the implementation plan, R 6b It is -C(O)NH2.

[0282] In the implementation plan, A is In the implementation plan, R8 It is an unsubstituted or substituted aryl group. In the embodiments, the compound of formula (I) is the compound of formula (50):

[0283] Equation (50)

[0284] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R aEach time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2. In the implementation, n5 is 3. In the implementation, R 7a R 7b R 7c R 7d R 10a R 10b R 10c R 10d and R 10e Each is independently selected from hydrogen, unsubstituted or substituted alkyl groups, and halogenated groups. In the embodiments, the alkyl group is -CH 3。 In the implementation scheme, the halogen is F or Cl. In the implementation scheme, R 7a R 7b R 7c and R 7d Each is hydrogen. In the implementation plan, R 10a R 10b R 10d and R 10e Each is hydrogen. In the implementation plan, R 10c It is F.

[0285] In the implementation plan, A is In the implementation scheme, compound (I) is compound (60):

[0286] Equation (60)

[0287] In equation (60): n6 is an integer from 0 to 5. In the implementation scheme, n6 is 1. In the implementation scheme, R 9 It is H.

[0288] In the implementation scheme, the compound of formula (I) is a compound of any of 1001-1074, or a pharmaceutically acceptable salt thereof.

[0289] In the embodiments, the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for topical, skin, intradermal, intramuscular, intraperitoneal, intra-articular, intravenous, subcutaneous, intra-arterial, or transdermal administration. In some embodiments, the pharmaceutical composition is formulated for topical administration.

[0291] In the embodiments, any Trim7 inhibitor (and / or additives) disclosed herein are included in various formulations. Any Trim7 inhibitor (and / or additives) described herein may be in the form of a solution, suspension, emulsion, drops, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, or any other suitable form. In the embodiments, the composition is in the form of a capsule (…). See For example, U.S. Patent No. 5,698,155. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences The references cited in 1447-1676 (edited. Alfonso R. Gennaro, 19th edition, 1995) are incorporated herein by reference.

[0292] In embodiments, the Trim7 inhibitors disclosed herein may have a sufficiently basic functional group capable of reacting with inorganic or organic acids, or a carboxyl group capable of reacting with inorganic or organic bases to form a pharmaceutically acceptable salt. As is well known in the art, pharmaceutically acceptable acid addition salts are formed from pharmaceutically acceptable acids. Such salts include, for example, those formed from... Journal of Pharmaceutical Science , 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use Pharmaceutically acceptable salts are listed in PH Stahl and CGWermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated in their entirety by reference.

[0293] In the embodiments, the compositions disclosed herein are in the form of pharmaceutically acceptable salts.

[0294] Furthermore, any Trim7 inhibitor disclosed herein may be administered to a subject as a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or mediator. Such pharmaceutical compositions may optionally contain a suitable amount of a pharmaceutically acceptable excipient to provide a form suitable for appropriate administration. Pharmaceutical excipients may be liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical excipients may be, for example, saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, and colorants may be used. In embodiments, the pharmaceutically acceptable excipient is sterile when administered to a subject. Water is a useful excipient when any of the agents disclosed herein is administered intravenously. Saline solutions, dextran solutions, and glycerol solutions may also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. If desired, any agent disclosed herein may also contain small amounts of wetting agents, emulsifiers, or pH buffers.

[0295] This disclosure includes disclosed Trim7 inhibitors in various formulations of pharmaceutical compositions. Any Trim7 inhibitor disclosed herein may be in the form of a solution, suspension, emulsion, drops, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, or any other suitable form. DNA or RNA constructs encoding protein sequences may also be used. In embodiments, the composition is in the form of a capsule (…). Refer to For example, U.S. Patent No. 5,698,155. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences The references cited in 1447-1676 (edited. Alfonso R. Gennaro, 19th edition, 1995) are incorporated herein by reference.

[0296] If necessary, pharmaceutical compositions containing Trim7 inhibitors may also contain solubilizers. Furthermore, suitable media or delivery devices known in the art can be used to deliver the agent. The combination therapies outlined herein may be delivered together in a single delivery media or delivery device. Pharmaceutical compositions for administration may optionally contain a local anesthetic, such as, for example, lidocaine, to reduce pain at the injection site.

[0297] Pharmaceutical compositions containing the Trim7 inhibitors of this disclosure are readily available in unit dosage forms and can be prepared by any method known in the pharmaceutical field. Such methods generally involve the step of combining a therapeutic agent with a carrier consisting of one or more additional components. Typically, pharmaceutical compositions are prepared by uniformly and tightly combining a therapeutic agent with a liquid carrier, a finely divided solid carrier, or both, and then, if desired, shaping the product into a dosage form of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

[0298] In the implementation scheme, any Trim7 inhibitor disclosed herein is formulated into a pharmaceutical composition suitable for the administration mode disclosed herein according to standard procedures.

[0299] Administration, dosing and treatment regimens

[0300] In one embodiment, any Trim7 inhibitor (and / or adjuvant) described herein is formulated according to conventional procedures into a composition suitable for the administration mode described herein.

[0301] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or local, particularly to the ear, nose, eye, or skin. In some embodiments, administration is oral or via parenteral injection. In most cases, administration results in the release of any of the agents described herein into the bloodstream.

[0302] Any Trim7 inhibitor (and / or adjuvant) described herein may be administered orally. Such Trim7 inhibitors (and / or adjuvants) may also be administered via any other convenient route, such as intravenous infusion or bolus, via an epithelial or mucosal skin liner (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered in combination with another bioactive agent. Administration may be systemic or local. Different delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and are suitable for administration.

[0303] In certain implementations, local application to the area requiring treatment may be necessary. In one implementation, for example, in cancer treatment, the Trim7 inhibitor (and / or adjunct) is administered to the tumor microenvironment (e.g., cells, molecules, extracellular matrix, and / or blood vessels surrounding and / or nourishing tumor cells, including, for example, tumor vessels; tumor-infiltrating lymphocytes; fibroblast reticulum cells; endothelial progenitor cells (EPCs); cancer-associated fibroblasts; pericytes; other stromal cells; components of the extracellular matrix (ECM); dendritic cells; antigen-presenting cells; T cells; regulatory T cells; macrophages; neutrophils; and other immune cells located near the tumor) or lymph nodes, and / or targeted to the tumor microenvironment or lymph nodes. In various implementations, such as in cancer treatment, the Trim7 inhibitor (and / or adjunct) is administered intratumorally.

[0304] Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, and intra-articular injections and infusions) include, for example, solutions, suspensions, dispersions, emulsions, etc. They may also be manufactured as sterile solid compositions (e.g., lyophilized compositions) that can be dissolved or suspended in a sterile injectable medium before use. They may contain, for example, suspending agents or dispersants known in the art.

[0305] The dosage and dosing regimen of any Trim7 inhibitor (and / or adjuvant) described herein may depend on various parameters, including but not limited to the disease being treated, the subject's overall health condition, and the administering physician's judgment. Any Trim7 inhibitor described herein may be administered to subjects in need before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). In various implementations, any Trim7 inhibitor and additional agent described herein may be administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0306] In various embodiments, this disclosure relates to the co-administration of a Trim7 inhibitor that induces an innate immune response and another Trim7 inhibitor that induces an adaptive immune response. In such embodiments, the Trim7 inhibitor that induces an innate immune response may be administered before, simultaneously with, or after the administration of the Trim7 inhibitor that induces an adaptive immune response. For example, the Trim7 inhibitor may be administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks. In an exemplary implementation, the Trim7 inhibitor that induces an innate immune response and the Trim7 inhibitor that induces an adaptive immune response are administered one week apart, or every other week. i.e. First, administer a Trim7 inhibitor that induces an innate immune response, then administer a Trim7 inhibitor that induces an adaptive immune response one week later, and so on.

[0307] The dosage of any Trim7 inhibitor (and / or adjuvant) described herein may depend on several factors, including the severity of the disease, whether the disease is being treated or prevented, and the age, weight, and health status of the subject being treated. Additionally, pharmacogenomic information (the effect of genotype on the pharmacokinetics, pharmacodynamics, or efficacy profile of a particular subject) can influence the dosage used. Furthermore, the exact individual dosage may be adjusted to some extent based on a variety of factors, including the specific combination of agents administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the specific disease being treated, the severity of the disease, and the anatomical location of the disease. Some variations in dosage can be expected.

[0308] For administration of any Trim7 inhibitor (and / or additional agent) described herein via parenteral injection, the dosage may be from about 0.1 mg to about 250 mg daily, from about 1 mg to about 20 mg daily, or from about 3 mg to about 5 mg daily. Generally, when administered orally or parenterally, the dosage of any agent described herein may be from about 0.1 mg to about 1500 mg daily, or from about 0.5 mg to about 10 mg daily, or from about 0.5 mg to about 5 mg daily, or from about 200 mg to about 1200 mg daily (e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg daily).

[0309] In the implementation scheme, the Trim7 inhibitor (and / or adjuvant) described herein is administered via parenteral injection at a dose of about 0.1 mg to about 1500 mg per treatment, or about 0.5 mg to about 10 mg per treatment, or about 0.5 mg to about 5 mg per treatment, or about 200 mg to about 1200 mg per treatment (e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg per treatment).

[0310] In the implementation plan, the appropriate dose of the Trim7 inhibitor (and / or adjunct) is in the range of about 0.01 mg / kg to about 100 mg / kg body weight, or about 0.01 mg / kg to about 10 mg / kg body weight of the subject, for example, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.4 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.4 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 ... mg / kg, approximately 1.5 mg / kg, approximately 1.6 mg / kg, approximately 1.7 mg / kg, approximately 1.8 mg / kg, 1.9 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg body weight, including all values ​​and ranges in between.

[0311] In another embodiment, delivery may be via a small capsule, particularly a liposome ( See Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in Therapy of Infectious Disease and Cancer Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0312] Any Trim7 inhibitor (and / or adjuvant) described herein may be administered via a controlled release or sustained release method or by a delivery device well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. These dosage forms are suitable for using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide controlled or sustained release of one or more active ingredients, thereby providing the desired release profile in different proportions. The controlled or sustained release of the active ingredient can be stimulated by various conditions, including but not limited to pH changes, temperature changes, stimulation by light of an appropriate wavelength, enzyme concentration or availability, water concentration or availability, or other physiological conditions or compounds.

[0313] In another embodiment, polymeric materials (see, Medical Applications of Controlled Release Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985. Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).

[0314] In another embodiment, the controlled-release system can be placed adjacent to the target area to be treated, thereby requiring only a portion of the systemic dose. See For example ， Goodson, at Medical Applications of Controlled Release , ibid (Volume 2, pp. 115-138 (1984)). Available in Langer, 1990.Science Other controlled release systems discussed in the review in 249:1527-1533.

[0315] Any Trim7 inhibitor (and / or adjuvant) described herein may be administered independently as one to four times daily, one to four times monthly, one to six times annually, or once every two, three, four, or five years. Administration may continue for a duration of one day, one month, two months, three months, six months, one year, two years, or three years, and may even continue for the subject's lifetime.

[0316] Dosing regimens for any Trim7 inhibitor (and / or adjuvant) described herein may be selected based on a number of factors, including subject type, race, age, weight, sex, and medical condition; severity of the disease to be treated; route of administration; renal or hepatic function of the subject; individual pharmacogenetic composition; and the specific compound of this disclosure used. Any Trim7 inhibitor (and / or adjuvant) described herein may be administered as a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily. Furthermore, any Trim7 inhibitor (and / or adjuvant) described herein may be administered continuously rather than intermittently throughout the entire dosing regimen.

[0317] Diseases; treatment methods and patient selection

[0318] In one aspect, this disclosure relates to a method for treating a subject in need of cancer, an infectious disease, or an inflammatory disease, said method comprising administering to the subject a pharmaceutical composition of any of the embodiments disclosed herein. In the embodiments, the cancer is selected from basal cell carcinoma; biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancers); glioblastoma; liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney cancer or renal cell carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma); black... Pigmented sarcoma; multiple myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancers; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; gastric cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancers; vulvar cancer; lymphoma, including Hodgkin's and non-Hodgkin's lymphomas, and B-cell lymphomas (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) lymphomas. NHL; intermediate / follicular NHL; intermediate diffuse NHL; advanced immunoblastic NHL; advanced lymphoblastic NHL; advanced small non-lytic cell NHL; massive disease NHL; mantle cell lymphoma; AIDS-associated lymphoma; and Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorders (PTLD), as well as abnormal angiogenesis, edema (such as edema associated with brain tumors), and Megs syndrome associated with scarring nevi.

[0319] In the implementation plan, cancer is defined as blood cancer selected from the group consisting of: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia, and preleukemia, or a combination thereof.

[0320] In the implementation scheme, the cancer exhibits resistance to anti-checkpoint agents. In the implementation scheme, the anti-checkpoint agent is an antibody. In the implementation scheme, the anti-checkpoint agent is an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibody. In the implementation scheme, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiplimab (LIBTAYO), atezolizumab (TECENTRIQ), avelumab (BAVENCIO), and durvalumab (IMFINZI).

[0321] In the implementation plan, the infectious disease is a viral infection. In the implementation plan, the viral infection is caused by a virus selected from the following: human papillomavirus (HPV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis virus, Zika virus, yellow fever virus, West Nile virus, dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, hepatitis C virus, poliovirus, rhinovirus, enterovirus, Coxsackie virus, influenza virus, lentivirus, respiratory syncytial virus, human parainfluenza virus, lubra virus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2).

[0322] In the implementation plan, inflammatory diseases are autoimmune diseases or disorders selected from multiple sclerosis, diabetes, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpassuia syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholecystitis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allogeneic transplant rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Wright's syndrome, Graves' disease, and other autoimmune diseases.

[0323] In one aspect, this disclosure relates to a method for treating an anti-checkpoint agent-resistant cancer in a subject of need, the method comprising administering to the subject a pharmaceutical composition of any of the embodiments disclosed herein. In the embodiments, the anti-checkpoint agent is an antibody. In the embodiments, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pildizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiprimab (LIBTAYO), atezolizumab (TECENTRIQ), avelumab (BAVENCIO), and durvalumab (IMFINZI).

[0324] In one aspect, this disclosure relates to methods for treating viral infections, including but not limited to acute or chronic viral infections such as respiratory infections, human papillomavirus infections, herpes simplex virus (HSV) infections, human immunodeficiency virus (HIV) infections, and viral infections of internal organs (such as hepatitis virus infections). In embodiments, the viral infection is caused by viruses of the Flaviviridae family. In embodiments, Flaviviridae viruses are selected from Zika virus, yellow fever virus, West Nile virus, dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, and hepatitis C virus. In embodiments, the viral infection is caused by viruses of the Picornaviridae family (e.g., poliovirus, rhinovirus, enterovirus, Coxsackievirus). In embodiments, the viral infection is caused by members of the Orthomyxoviridae family (e.g., influenza virus). In embodiments, the viral infection is caused by members of the Retroviridae family (e.g., lentivirus). In embodiments, the viral infection is caused by members of the Paramyxoviridae family (e.g., respiratory syncytial virus, human parainfluenza virus, Rubra virus (e.g., mumps virus), measles virus, and human metapneumovirus). In one implementation, the viral infection is caused by a member of the Bunyaviridae family (e.g., hantavirus). In another implementation, the viral infection is caused by a member of the Reoviridae family (e.g., rotavirus).

[0325] In one aspect, this disclosure relates to methods for treating parasitic infections, such as protozoan or worm infections. In an embodiment, the parasitic infection is transmitted via a protozoan parasite. In an embodiment, the oritiziab parasite is selected from intestinal protozoa, tissue protozoa, or blood protozoa. Examples of illustrative protozoan parasites include, but are not limited to, Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodesiense, Trypanosomatida crusi, Leishmania mexicana, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum. *Trichomonas vaginalis* and *Histomonas meleagridis*. In this embodiment, the parasitic infection is transmitted via helmintic parasites, such as nematodes (e.g., Adenophorea). In this embodiment, the parasites are selected from the Secementea class (e.g., *Trichuris trichiura*, *Ascaris lumbricoides*, *Enterobius vermicularis*, *Ancylostoma duodenale*, *Necator americanus*, *Strongyloides stercoralis*, *Wuchereria bancrofti*, *Dracunculus medinensis*). In this embodiment, the parasites are selected from flukes (e.g., schistosomes, liver flukes, intestinal flukes, and lung flukes).In the implementation scheme, the parasites are selected from: Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola gigantica, Heterophyes, and Paragonimus westermani. In the implementation scheme, the parasites are selected from tapeworms (e.g., Taenia solium, Taenia saginata, Hymenolepis nana, and Echinococcus granulosus).

[0326] In one aspect, this disclosure relates to a method of treating bacterial infections. In an embodiment, the bacterial infection is caused by Gram-positive bacteria, Gram-negative bacteria, aerobic bacteria, and / or anaerobic bacteria. In an embodiment, the bacteria are selected from, but are not limited to, Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, and Proteus. s), Campylobacter, Citrobacter, Neisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, and other organisms. In the implementation scheme, the bacteria are selected from, but are not limited to, *Pseudomonas aeruginosa*, *Pseudomonas fluorescens*, *Pseudomonas acidovorans*, *Pseudomonas alcaligenes*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Burkholderia cepacia*, *Aeromonas hydrophilia*, *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhi*, *Salmonella paratyphi*, and *Salmonella enteritidis*. enteritidis, Shigella dysenteriae, Shigella flexneri* *Flexneri*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, *Francisella tularensis*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providencia alcalifaciens*, *Providencia rettgeri*, *Providencia stuartii*, *Acinetobacter baumannii* Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi *Ducreyi*, *Pasteurella multocida*, *Pasteurella haemolytica*, *Branhamella**Helicobacter pylori*, *Campylobacter fetus*, *Campylobacter jejuni*, *Campylobacter coli*, *Borrelia burgdorferi*, *Vibrio cholerae*, *Vibrio parahaemolyticus*, *Legionella pneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Kingella*, *Moraxella*, *Gardnerella vaginalis*, *Bacteroides fragilis*, *Bacteroides dignitaries* Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae agalactiae, Streptococcus pyogenes, Enterococcus faecalisThe following bacteria are listed: *Staphylococcus faecalis*, *Enterococcus faecium*, *Staphylococcus aureus*, *Staphylococcus epidermidis*, *Staphylococcus saprophyticus*, *Staphylococcus intermedius*, *Staphylococcus hyicus subsp. hyicus*, *Staphylococcus haemolyticus*, *Staphylococcus hominis*, or *Staphylococcus saccharolyticus*.

[0327] In one aspect, this disclosure relates to methods for treating one or more autoimmune diseases or conditions. In embodiments, treating an autoimmune disease or condition may involve using a Trim7 inhibitor of this disclosure to modulate the immune system to promote immunosuppression rather than immune stimulation. Exemplary autoimmune diseases or conditions that can be treated with the Trim7 inhibitor of this invention include those diseases or conditions in which the body's own antigens become targets of an immune response, such as, for example, rheumatoid arthritis, systemic lupus erythematosus, diabetes, ankylosing spondylitis, Sjögren's syndrome, inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), multiple sclerosis, sarcoidosis, psoriasis, Graves' disease, Hashimoto's thyroiditis, hypersensitivity reactions (e.g., type I hypersensitivity reactions caused by allergies, hay fever, asthma, and acute edema), and vasculitis.

[0328] Methods for determining a cancer treatment for a patient; methods for selecting a patient for a cancer treatment; and treatment methods

[0329] In one aspect, this disclosure relates to a method for determining cancer treatment for a patient, the method comprising: (a) obtaining a biological sample from a subject; (b) assessing the expression of Trim7 in the biological sample; and (c) if the Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to anti-checkpoint agents, selecting a cancer therapy comprising a pharmaceutical composition of any embodiment disclosed herein; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agents. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibodies.

[0330] In one aspect, this disclosure relates to a method for selecting a patient for cancer treatment, the method comprising: (a) obtaining a biological sample from a subject; (b) assessing the expression of Trim7 in the biological sample; and (c) selecting a cancer therapy comprising a pharmaceutical composition comprising any embodiment disclosed herein if the Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to anti-checkpoint agents; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agents. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibodies.

[0331] In one aspect, this disclosure relates to a method of treating cancer, the method comprising: (a) obtaining a biological sample from a subject; (b) assessing the expression of Trim7 in the biological sample; and (c) administering a pharmaceutical composition of any embodiment disclosed herein if the Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to anti-checkpoint agents; and (d) optionally administering a second cancer therapy comprising an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agents. In embodiments, the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibodies.

[0332] In the implementation scheme, the biological sample is a fresh tissue sample, a frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen. In the implementation scheme, the biological sample is a biopsy sample, optionally selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy, and colonoscopy), puncture biopsy (e.g., fine-needle aspiration biopsy, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computed tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy, and ultrasound-assisted biopsy), skin biopsy (e.g., curettage biopsy, puncture biopsy, and incision biopsy), and surgical biopsy. In the implementation plan, biological samples include body fluids selected from: blood, plasma, serum, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing body fluids, free nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological secretions, skin swabs, vaginal swabs, oral swabs, nasal swabs, irrigation or lavage fluids such as catheter lavage fluid or bronchoalveolar lavage fluid, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other body fluids, secretions and / or excretions, and / or cells extracted therefrom. In the implementation plan, biological samples include at least one tumor cell.

[0333] In the implementation scheme, evaluation is performed using DNA sequencing, RNA sequencing, immunohistochemical staining, Western blotting, intracellular Western blotting, immunofluorescence staining, ELISA, and fluorescence activated cell sorting (FACS), or combinations thereof. In the implementation scheme, evaluation is performed by contacting the sample with an agent that specifically binds to Trim7. In the implementation scheme, the agent that specifically binds to one or more proteins comprises an antibody, an antibody-like molecule, or a binding fragment thereof. In the implementation scheme, evaluation is performed by contacting the sample with one or more nucleic acids that specifically bind to Trim7. In the implementation scheme, the agent that specifically binds to one or more nucleic acids is a nucleic acid primer or probe.

[0334] Combination therapies and conjugations

[0335] In embodiments, this disclosure provides Trim7 inhibitors and methods, the methods further comprising administering an additional agent to a subject. In embodiments, this disclosure relates to co-administration and / or co-formulation. Any compositions described herein may be co-formulated and / or co-administered.

[0336] In the implementation scheme, any Trim7 inhibitor described herein acts synergistically with another agent when administered together, and is administered at a lower dose than is typically used when such agents are used as monotherapy.

[0337] In embodiments including, but not limited to, cancer applications, this disclosure relates to chemotherapeutic agents as adjunctive agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; azacyclopropanes such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); polyacetyl (e.g., bulbatacin and bulbatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (Including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, naphthylambucil, chlorphosphamide, estradiol, ifosfamide, nitrogen mustard, nitrogen mustard oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine. Nitrosamine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ-II and calicheamicin ω-II). SeeFor example, Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clophosphonate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophore. Chromophores, aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin (Including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid Drugs containing: nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as folate, methotrexate, pteroxate, and trimethoprim; and purine analogs such as fludarabine, 6-mercaptopurine, thioimide, and thioguanine.Pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, and fluorouridine; androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; antiadrenergic drugs, such as minoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglucuronolactone; aldehyde phosphoramide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonicacid; triaziquone; 2,2',2''-trichlorotriethylamine;Trichothecene toxins (e.g., T-2 toxin, verrucosporin A, baculosporin A, and serpentin); urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromoeusine; piperobromethane; gacytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE paclitaxel nanoparticle formulations without cremophor (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE docetaxel (Rhone-Poulenc Rorer, Antony, France; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including irinotecan combined with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; comprehendingin; leucovorin (LV); oxaliplatin, including oxaliplatin regimens (FOLFOX); lapatinib (TYKERB); inhibitors of cell proliferation reducing PKC-α, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)), and VEGF-A, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Additionally, the treatment may further include the use of radiation. Furthermore, the treatment may further include the use of photodynamic therapy.

[0338] In embodiments including but not limited to cancer applications, the additional agent of the present invention is one or more immunomodulatory agents selected from agents that block, reduce, and / or inhibit the binding of PD-1 and PD-L1 or PD-L2 and / or PD-1 with PD-L1 or PD-L2 (by means of non-limiting examples, one or more of the following: nivolumab (ONO-4538 / BMS-936558, MDX1106, OPDIVO, BRISTOL MYERS SQUIBB), pembrolizumab (KEYTRUDA, Merck), MK-3475 (MERCK), BMS 936559 (BRISTOL MYERS SQUIBB), atezolizumab (TECENTRIQ, GENENTECH, MPDL328OA (ROCHE)), and agents that increase and / or stimulate the binding of CD137 (4-1BB) and / or CD137 (4-1BB) with one or more 4-1BB ligands (by means of non-limiting examples, urelumab). (BMS-663513 and anti-4-1BB antibody), and agents that block, reduce and / or inhibit the activity of CTLA-4 and / or the binding of CTLA-4 to one or more of AP2M1, CD80, CD86, SHP-2 and PPP2R5A and / or the binding of OX40 to OX40L (by means of non-limiting examples, GBR 830 (GLENMARK), MEDI6469 (MEDIMMUNE)).

[0339] In embodiments including, but not limited to, applications for infectious diseases, this disclosure relates to anti-infective agents as additional agents. In embodiments, the anti-infective agent is an antiviral agent, including but not limited to abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, darunavir, delavirendine, didanosine, docosanol, efavirenz, elvitegravir, emtricitabine, enfuvirtide, etravirine, famciclovir, and foscarnet. In the implementation plan, the anti-infective agent is an antibacterial agent, including but not limited to cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole); fluoroquinolone antibiotics (ciprofloxacin, levaquin, ofloxacin, gatifloxacin, avelox, and norfloxacin); and tetracycline antibiotics (tetracycline...). cline), minocycline, oxytetracycline, and doxycycline; penicillin antibiotics (amoxicillin, ampicillin, penicillin V, diclofenac, carbenicillin, vancomycin, and methicillin); monobactam antibiotics (aztreonam); and carbapenem antibiotics (ertapenem, doripenem, imipenem / cilastatin, and meropenem).In the implementation plan, the anti-infective agents include antimalarial agents (e.g., chloroquine, quinine, mefloquine, primaquine, doxycycline, artemether / lumefantrine, atovaquone / proguanil, and sulfadoxine / pyrimethamine), metronidazole, tinidazole, ivermectin, pyrantel pamoate, and albendazole.

[0340] In embodiments including, but not limited to, autoimmune applications, the additional agent is an immunosuppressant. In embodiments, the immunosuppressant is an anti-inflammatory agent, such as a steroidal anti-inflammatory agent or a nonsteroidal anti-inflammatory agent (NSAID). Steroids, particularly corticosteroids and their synthetic analogues, are well known in the art. Examples of corticosteroids that can be used with the present disclosure include, but are not limited to, hydroxytriamcinolone, α-methyldexamethasone, β-methylbetamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, hydroxyprednisolone, dexamethasone, difluralasone diacetate, diflucolone valerate, fluadrenolone, fluclomethasone valerate, flumethasone tervalerate, fluosinolone acetonide, fluocinolone acetate, and flucortine. butylesters), fluocortolone, fluprednidene / fluprednylidene, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone, cortisone, todoxacin, flucetonide, flurandrenolone, difluorosone diacetate, fluradrenolone acetal Acetone, methylhydroxysalicylic acid, ancinarizine, ancinarizine, betamethasone and its balanced esters, chlorprednisolone, clocortelone, clescinolone, diclomethasone, difluprednisolone, flucloronide, flunisolone, fluorometholone, fluperazine, fluprednisolone, hydrocortisone, methylprednisolone, peramisone, prednisolone, prednisolone, beclomethasone dipropionate. Products that can be used in this disclosure (NSAIDS) include, but are not limited to, salicylic acid, acetylsalicylic acid, methyl salicylate, ethylene glycol salicylate, salicylamide, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenadine, phenylbutazone, and indomethacin.In the implementation scheme, the immunosuppressant can be a cell inhibitor, such as analkylating agent, antimetabolite (e.g., imidazothiopurine, methotrexate), cytotoxic antibiotic, antibody (e.g., basiliximab, daclizumab, and muromonab), antiimmunophilic agent (e.g., cyclosporine, tacrolimus, sirolimus), interferon, opioid, TNF-binding protein, mycophenolate mofetil, and small biological agents (e.g., fingolimod, myriocin).

[0341] In the implementation scheme, including but not limited to, the additional agent is a kras inhibitor (e.g., a kras G12C inhibitor). In the implementation scheme, the kras inhibitor is selected from BI2865, MRTX113, sotorasib (AMG510), and adagrasib (MRTX849).

[0342] In the implementation scheme, including but not limited to, the additional agent is a braf inhibitor. In the implementation scheme, the braf inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0343] In the implementation scheme, including but not limited to, the additional agent is a MEK inhibitor. In the implementation scheme, the MEK inhibitor is selected from binimetinib (MEK162), cobimetinib (XL518), selumetinib, and trametinib (GSK1120212).

[0344] In the implementation scheme, the Trim7 inhibitors (and / or adjuvants) described herein include modified derivatives. i.e. By covalently attaching any type of molecule to the composition such that the covalent attachment does not prevent the composition from being active. For example, but not limited to, derivatives include those already... In particularCompositions modified by glycosylation, esterification, acetylation, polyethylene glycolation, phosphorylation, amidation, derivatization via known protecting / blocking groups, proteolytic cleavage, or linkage with cellular ligands or other proteins. Any of these chemical modifications can be performed using known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, and the metabolic synthesis of turicamycin. Additionally, the derivative may contain one or more non-classical amino acids. In further embodiments, the Trim7 inhibitors (and / or additional agents) described herein further include cytotoxic agents, including, in exemplary embodiments, toxins, chemotherapeutic agents, radioisotopes, and agents that induce apoptosis or cell death. Such agents may be conjugated to the compositions described herein.

[0345] The Trim7 inhibitors (and / or adjuvants) described herein can therefore be post-translational modified to add an effector moiety (such as a chemical linker), a detectable moiety (such as, for example, fluorescent dyes, enzymes, substrates, bioluminescent substances, radioactive substances, and chemiluminescent moieties), or a functional moiety (such as, for example, streptavidin, avidin, biotin, cytotoxins, cytotoxic agents, and radioactive substances).

[0346] Subjects and / or animals

[0347] In one implementation, the subject and / or animal is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or a non-human primate, such as a monkey, chimpanzee, or baboon. In another implementation, the subject and / or animal is a non-mammal, such as, for example, zebrafish. In yet another implementation, the subject and / or animal may contain fluorescently labeled cells (e.g., with GFP). In yet another implementation, the subject and / or animal is a transgenic animal containing fluorescent cells.

[0348] In this implementation, the subject and / or animal is a human. In this implementation, the human is a young child. In this implementation, the human is an adult. In this implementation, the human is an elderly person. In this implementation, the human may be referred to as a patient.

[0349] In some implementations, the age of a person is in the range of about 0 months to about 6 months, about 6 months to about 12 months, about 6 months to about 18 months, about 18 months to about 36 months, about 1 to about 5 years, about 5 to about 10 years, about 10 to about 15 years, about 15 to about 20 years, about 20 to about 25 years, about 25 to about 30 years, about 30 to about 35 years, about 35 to about 40 years, about 40 to about 45 years, about 45 to about 50 years, about 50 to about 55 years, about 55 to about 60 years, about 60 to about 65 years, about 65 to about 70 years, about 70 to about 75 years, about 75 to about 80 years, about 80 to about 85 years, about 85 to about 90 years, about 90 to about 95 years, or about 95 to about 100 years.

[0350] In one implementation, the subjects are non-human animals, and therefore this disclosure relates to veterinary use. In a specific implementation, the non-human animal is a domestic pet. In another specific implementation, the non-human animal is livestock.

[0351] Kit

[0352] This disclosure provides kits that simplify the administration of any of the agents described herein. Exemplary kits of this disclosure include unit dosage forms of any of the compositions described herein. In one embodiment, the unit dosage form is a container, such as a pre-filled syringe, which may be sterile and contains any of the agents described herein and a pharmaceutically acceptable carrier, diluent, excipient, or mediator. The kit may further include a label or printed instruction indicating the use of any of the agents described herein. The kit may also include a lid speculum, a local anesthetic, and a cleanser for the application site. The kit may further include one or more additional agents described herein. In one embodiment, the kit includes a container containing an effective amount of a composition of this disclosure and an effective amount of another composition, such as those compositions described herein.

[0353] This disclosure also provides some of the following implementation schemes: Implementation Scheme 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0354] Formula (I)

[0355] In equation (I): A is selected from , , , , , and ; L is a linking group; R1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O)t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; t is 1 or 2; The condition is that the compound of formula (I) is not a compound of any of formulas 1001, 1003, 1004, and 1006-1009:

[0356] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11cEach of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, optionally halogenated, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -C(O)R a -C(O)N(R) a )2、-N(R a )2、-N(R a )C(O)R a and -S(O) t R a .

[0357] Implementation Scheme 3. A compound as described in Implementation Scheme 1 or 2, wherein L is a bond or comprises one or more linking groups, said linking groups being selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(Rb )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, optionally substituted alkyl, or optionally substituted aryl; optionally, L is a bond and / or -C(O)- and / or -C(H)(CH2). p C(O)NH2 and / or Where p is an integer from 1 to 5, and optionally p is 2; optionally L is... The alkyl group is either substituted or unsubstituted. or .

[0358] Implementation Scheme 4. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (10):

[0359] Equation (10)

[0360] In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a)C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

[0361] Implementation Scheme 5. The compound as described in Implementation Scheme 4, wherein n 2 The value is 2.

[0362] Implementation Scheme 6. The compound as described in Implementation Scheme 4 or 5, wherein R 1a It is a C1-6 alkyl group, optionally -CH3.

[0363] Implementation Scheme 7. The compound as described in any one of Implementation Schemes 4-6, wherein R 2 It is H.

[0364] Implementation Scheme 8. The compound as described in any one of Implementation Schemes 4-7, wherein R 9a R 9b R 9c R 9d and R 9e Each is independently selected from hydrogen and halogenated, optionally from F or Cl.

[0365] Implementation Scheme 9. The compound as described in any one of Implementation Schemes 4-8, wherein R 9a R 9b R 9c R 9d and R9e Each is hydrogen.

[0366] Implementation Scheme 10. The compound as described in any one of Implementation Schemes 4-8, wherein R 9a R 9d and R 9e Each is hydrogen, and R is chosen to be hydrogen. 9b It is Cl and / or R 9c It is F.

[0367] Implementation Scheme 11. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (20) or (21):

[0368] In equations (20) and (21): n3 is an integer from 0 to 5.

[0369] Implementation Scheme 12. The compound as described in Implementation Scheme 11, wherein n3 is 2.

[0370] Implementation Scheme 13. The compound as described in Implementation Scheme 11 or 12, wherein R 4a It is H.

[0371] Implementation Scheme 14. The compound as described in any one of Implementation Schemes 11-13, wherein R 4b It is H.

[0372] Implementation Scheme 15. The compound as described in any one of Implementation Schemes 11-13, wherein R 3 It is a C1-6 alkyl group, optionally -CH3.

[0373] Implementation Scheme 16. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (30) or formula (31):

[0374] In equations (30) and (31): p is an integer from 0 to 5.

[0375] Implementation Scheme 17. The compound as described in Implementation Scheme 16, wherein p is 2.

[0376] Implementation Scheme 18. The compound as described in Implementation Scheme 16 or 17, wherein R 5a R 5b R 5c R 5d and R 5eEach is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0377] Implementation Scheme 19. The compound as described in any one of Implementation Schemes 16-18, wherein R 5a R 5c R 5d and R 5e Each is hydrogen, and R is chosen to be hydrogen. 5d It is -CH3.

[0378] Implementation Scheme 20. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (32):

[0379] Equation (32)

[0380] In equation (32): q is an integer from 1 to 3.

[0381] Implementation Scheme 21. The compound as described in Implementation Scheme 20, wherein q is 1.

[0382] Implementation Scheme 22. The compound as described in Implementation Scheme 20 or 21, wherein R 5a R 5b R 5c and R 5d Each is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0383] Implementation Scheme 23. The compound as described in any one of Implementation Schemes 19-21, wherein R 5a R 5c R 5d and R 5e Each is hydrogen.

[0384] Implementation Scheme 24. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (40):

[0385] Equation (40)

[0386] In equation (40): n4 is an integer from 0 to 5.

[0387] Implementation Scheme 25. The compound as described in Implementation Scheme 24, wherein n4 is 0.

[0388] Implementation Scheme 26. The compound as described in Implementation Scheme 24 or 25, wherein R6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and unsubstituted or substituted alkyl groups, optionally alkyl groups substituted with amide groups, and amide groups.

[0389] Implementation Scheme 27. The compound as described in any one of Implementation Schemes 24-26, wherein R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and , where r is an integer from 0 to 4, and r is optionally 0.

[0390] Implementation Scheme 28. The compound as described in any one of Implementation Schemes 24-27, wherein R 6a R 6c R 6d and R 6e Each is hydrogen, R can be chosen arbitrarily. 6b It is -C(O)NH2.

[0391] Implementation Scheme 29. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (50):

[0392] Equation (50)

[0393] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a-C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

[0394] Implementation Scheme 30. The compound as described in Implementation Scheme 29, wherein n5 is 3.

[0395] Implementation Scheme 31. The compound as described in Implementation Scheme 29 or 30, wherein R 7a R 7b R 7c R 7d R 10a R 10b R 10c R 10d and R 10e Each is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0396] Implementation Scheme 32. The compound as described in any one of Implementation Schemes 29-31, wherein R 7a R 7b R 7c and R 7dEach is hydrogen.

[0397] Implementation Scheme 33. The compound as described in any one of Implementation Schemes 29-31, wherein R 10a R 10b R 10d and R 10e Each is hydrogen, and R is chosen to be hydrogen. 10c It is F.

[0398] Implementation Scheme 34. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (60):

[0399] Equation (60)

[0400] In equation (60): n6 is an integer between 0 and 5.

[0401] Implementation Scheme 35. The compound as described in Implementation Scheme 34, wherein n6 is 1.

[0402] Implementation Scheme 36. The compound as described in Implementation Scheme 34, wherein R 9 It is H.

[0403] Implementation Scheme 37. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (70):

[0404] Equation (70)

[0405] In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a-OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0406] Implementation Scheme 38. The compound as described in Implementation Scheme 37, wherein the compound of formula (70) is a compound of formula (700) or (701):

[0407] Implementation Scheme 39. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (80) or formula (81):

[0408] Equation (80)

[0409] In equation (80): R 11a and R 11bEach of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5;

[0410] Equation (81)

[0411] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0412] Implementation Scheme 40. The compound of implementation scheme 39, wherein the compound of formula (80) is a compound of formula (800) or formula (801), or the compound of formula (81) is a compound of formula (802) or formula (803):

[0413] Implementation Scheme 41. The compound as described in Implementation Scheme 37 or 39, wherein R 5a and R 5d Each is hydrogen.

[0414] Implementation Scheme 42. The compound as described in any one of Implementation Schemes 37-41, wherein R 5b and / or R 5c Each group is independently selected from unsubstituted or substituted alkynyl groups, optionally substituted alkynyl groups, substituted aryl groups, substituted heteroaryl groups, halogenated groups, optionally Br, -N(R) groups. a 2. Optional -NH2 and -N(R) a )C(O)R a Optional , , or Optional of R 5b Selected from , , , , , , , , , , , , , , and Optional of R 5c Selected from , , , , , , , , , and .

[0415] Implementation Scheme 43. The compound as described in any one of Implementation Schemes 37-42, wherein R 11a and R 11b Each is an unsubstituted alkyl group, or R 11a and R 11bEach independently is , or R 11a Selected from H and unsubstituted alkyl groups and R 11b yes , or R 11a It is H and R 11b Y is an unsubstituted alkyl group, wherein Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2.

[0416] Implementation Scheme 44. The compound as described in Implementation Scheme 43, wherein 11a and R 11b Each independently selected , , , , , , , , , , and Optional of R 11a and R 11b Each independently selected , , , , , , , , and .

[0417] Implementation Scheme 45. The compound as described in Implementation Scheme 43, wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and Optional of R 11a Selected from H and -CH3 and R 11bSelected from , , and .

[0418] Implementation Scheme 46. The compound as described in Implementation Scheme 43, wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , and .

[0419] Implementation Scheme 47. The compound as described in Implementation Scheme 43, wherein R 11a It is H and R 11b It is -CH3 or R in it. 11a and R 11b Each is -CH3.

[0420] Implementation Scheme 48. The compound as described in any one of Implementation Schemes 39-47, wherein n8 is 1.

[0421] Implementation Scheme 49. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (82):

[0422] Equation (82)

[0423] In equation (82): R 11a R 11b 、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R)a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0424] Implementation Scheme 50. The compound as described in Implementation Scheme 49, wherein the compound of formula (82) is a compound of formula (804) or (805):

[0425] Implementation Scheme 51. The compound as described in Implementation Scheme 49 or 50, wherein R 5b and / or R 5c Each independently is -OR a , where R a It is an unsubstituted alkyl group, optionally wherein -OR a It is -OCH3.

[0426] Implementation Scheme 52. The compound as described in any one of Implementation Schemes 49-51, wherein R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group, optionally cyclohexyl; or R 11a and R 11c Each is hydrogen, R 11b and R11d Each is independently an alkyl group substituted with a cycloalkyl group, optional. .

[0427] Implementation Scheme 53. The compound of any one of Implementation Schemes 1-3, wherein the compound of formula (I) is a compound of formula (90):

[0428] Equation (90)

[0429] In equation (90): n is an integer from 1 to 5.

[0430] Implementation Scheme 54. The compound as described in Implementation Scheme 53, wherein the compound of formula (90) is a compound of formula (900), formula (901), or formula (902):

[0431] Implementation Scheme 55. The compound as described in Implementation Scheme 53 or 54, wherein R 12 It is H or -CH3.

[0432] Implementation Scheme 56. The compound as described in any one of Implementation Schemes 53-55, wherein R 11a It is H or a substituted alkyl group, optional. Optional .

[0433] Implementation Scheme 57. The compound as described in any one of Implementation Schemes 53-56, wherein R 10 It is -C(O)R a Optional of R a Selected from unsubstituted alkenyl, substituted alkyl, substituted aryl, and substituted heterocyclic groups, or R 10 It is -S(O) t R a Optionally, where t is 2 and R a It is a substituted aryl group.

[0434] Implementation Scheme 58. The compound as described in any one of Implementation Schemes 53-57, wherein R 10 Selected from: , , , , , , , , , and .

[0435] Implementation Scheme 59. The compound of any one of Implementation Schemes 1-3 or 37-58, wherein the compound of formula (I) is a compound of any one of formulas 1002, 1005, 1010-1098, or a pharmaceutically acceptable salt thereof.

[0436] Implementation Scheme 60. The compound of any one of Implementation Schemes 1-3 or 37-59, wherein the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof: Implementation Scheme 61. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient:

[0437] Formula (I)

[0438] In equation (I): A is selected from , , , , , , ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; and t is 1 or 2.

[0439] Implementation Scheme 62. The pharmaceutical composition as described in Implementation Scheme 61, wherein R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, optionally halogenated, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -N(R) a )2、-C(O)R a -C(O)N(R) a )2、-N(R a )C(O)R a and -S(O) t R a .

[0440] Embodiment 63. A pharmaceutical composition as described in Embodiment 61 or 62, wherein L is a bond or comprises one or more linking groups, said linking groups being selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl-10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, optionally substituted alkyl, or optionally substituted aryl; optionally, L is a bond and / or -C(O)- and / or -C(H)(CH2). p C(O)NH2 and / or Where p is an integer from 1 to 5, optionally p is 2, optionally L is The alkyl group is either substituted or unsubstituted. or .

[0441] Implementation Scheme 64. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (10):

[0442] Equation (10)

[0443] In equation (10): R 9a R 9b R9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

[0444] Implementation Scheme 65. The pharmaceutical composition as described in Implementation Scheme 64, wherein n 2 The value is 2.

[0445] Implementation Scheme 66. The pharmaceutical composition as described in Implementation Scheme 64 or 65, wherein R 1a It is a C1-6 alkyl group, optionally -CH3.

[0446] Implementation Scheme 67. The pharmaceutical composition as described in any one of Implementation Schemes 64-66, wherein R 2 It is H.

[0447] Implementation Scheme 68. The pharmaceutical composition as described in any one of Implementation Schemes 64-67, wherein R 9a R 9b R 9c R 9d and R 9e Each is independently selected from hydrogen and halogenated, optionally from F or Cl.

[0448] Implementation Scheme 69. The pharmaceutical composition as described in any one of Implementation Schemes 64-68, wherein R 9a R 9b R 9c R 9d and R 9e Each is hydrogen.

[0449] Implementation Scheme 70. The pharmaceutical composition as described in any one of Implementation Schemes 64-69, wherein R 9a R 9d and R 9e Each is hydrogen, and R is chosen to be hydrogen. 9b It is Cl and / or R 9c It is F.

[0450] Implementation Scheme 71. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (20) or (21):

[0451] In equations (20) and (21): n3 is an integer from 0 to 5.

[0452] Implementation Scheme 72. The pharmaceutical composition as described in Implementation Scheme 71, wherein n3 is 2.

[0453] Implementation Scheme 73. The pharmaceutical composition as described in Implementation Scheme 71 or 72, wherein R 4a It is H.

[0454] Implementation Scheme 74. The pharmaceutical composition as described in any one of Implementation Schemes 71-73, wherein R 4b It is H.

[0455] Implementation Scheme 75. The pharmaceutical composition as described in any one of Implementation Schemes 71-74, wherein R 3 It is a C1-6 alkyl group, optionally -CH3.

[0456] Implementation Scheme 76. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (30) or (31):

[0457] In equations (30) and (31): p is an integer from 0 to 5.

[0458] Implementation Scheme 77. The pharmaceutical composition as described in Implementation Scheme 76, wherein p is 2.

[0459] Implementation Scheme 78. The pharmaceutical composition as described in Implementation Scheme 76 or 77, wherein R 5a R 5b R 5c R 5d and R 5e Each is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0460] Implementation Scheme 79. The pharmaceutical composition as described in any one of Implementation Schemes 76-78, wherein R 5a R 5c R 5d and R 5e Each is hydrogen, and R is chosen to be hydrogen. 5d It is -CH3.

[0461] Implementation Scheme 80. A pharmaceutical composition as described in any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (32):

[0462] Equation (32)

[0463] In equation (32): q is an integer from 1 to 3.

[0464] Implementation Scheme 81. The pharmaceutical composition as described in Implementation Scheme 80, wherein q is 1.

[0465] Implementation Scheme 82. The pharmaceutical composition as described in Implementation Scheme 80 or 81, wherein R 5aR 5b R 5c and R 5d Each is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0466] Implementation Scheme 83. The pharmaceutical composition as described in any one of Implementation Schemes 80-82, wherein R 5a R 5b R 5c and R 5d Each is hydrogen.

[0467] Implementation Scheme 84. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (40):

[0468] Equation (40)

[0469] In equation (40): n4 is an integer from 0 to 5.

[0470] Implementation Scheme 85. The pharmaceutical composition as described in Implementation Scheme 84, wherein n4 is 0.

[0471] Implementation Scheme 86. The pharmaceutical composition as described in Implementation Scheme 84 or 85, wherein R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and unsubstituted or substituted alkyl groups, optionally alkyl groups substituted with amide groups, and amide groups.

[0472] Implementation Scheme 87. The pharmaceutical composition as described in any one of Implementation Schemes 84-86, wherein R 6a R 6b R 6c R 6d and R 6e Each is independently selected from hydrogen and , where r is an integer from 0 to 4, and r is optionally 0.

[0473] Implementation Scheme 88. The pharmaceutical composition as described in any one of Implementation Schemes 84-87, wherein R 6a R 6c R 6d and R 6e Each is hydrogen, R can be chosen arbitrarily. 6b It is -C(O)NH2.

[0474] Implementation Scheme 89. A pharmaceutical composition as described in any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (50):

[0475] Equation (50)

[0476] In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R aEach time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

[0477] Implementation Scheme 90. The pharmaceutical composition as described in Implementation Scheme 89, wherein n5 is 3.

[0478] Implementation Scheme 91. The pharmaceutical composition as described in Implementation Scheme 89 or 90, wherein R 7a R 7b R 7c R 7d R 10a R 10b R 10c R 10d and R 10e Each is independently selected from hydrogen, unsubstituted or substituted alkyl, optional -CH3, and halogenated, optional F or Cl.

[0479] Implementation Scheme 92. The pharmaceutical composition as described in any one of Implementation Schemes 89-91, wherein R 7a R 7b R 7c and R 7d Each is hydrogen.

[0480] Implementation Scheme 93. The pharmaceutical composition as described in any one of Implementation Schemes 89-92, wherein R 10a R 10b R 10d and R 10e Each is hydrogen, and R is chosen to be hydrogen. 10c It is F.

[0481] Implementation Scheme 94. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (60):

[0482] Equation (60)

[0483] In equation (60): n6 is an integer between 0 and 5.

[0484] Implementation Scheme 95. The pharmaceutical composition as described in Implementation Scheme 94, wherein n6 is 1.

[0485] Implementation Scheme 96. The pharmaceutical composition as described in Implementation Scheme 94 or 95, wherein R 9 It is H.

[0486] Implementation Scheme 97. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (70):

[0487] Equation (70)

[0488] In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0489] Implementation Scheme 98. The pharmaceutical composition of Implementation Scheme 97, wherein the compound of formula (70) is a compound of formula (700) or (701):

[0490] Implementation Scheme 99. A pharmaceutical composition as described in any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (80) or formula (81):

[0491] Equation (80)

[0492] In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(Ra )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5;

[0493] Equation (81)

[0494] In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a)C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0495] Implementation Scheme 100. The pharmaceutical composition of Implementation Scheme 99, wherein the compound of formula (80) is a compound of formula (800) or formula (801), or the compound of formula (81) is a compound of formula (802) or formula (803):

[0496] Implementation Scheme 101. The pharmaceutical composition as described in Implementation Scheme 97 or 99, wherein R 5a and R 5d Each is hydrogen.

[0497] Implementation Scheme 102. The pharmaceutical composition as described in any one of Implementation Schemes 97-101, wherein R 5b and / or R 5c Each group is independently selected from unsubstituted or substituted alkynyl groups, optionally substituted alkynyl groups, substituted aryl groups, substituted heteroaryl groups, halogenated groups, optionally Br, -N(R) groups. a 2. Optional -NH2 and -N(R) a )C(O)R a Optional , , or Optional of R 5b Selected from , , , , , , , , , , , , , , and Optional of R 5c Selected from , , , , , , , , , and .

[0498] Implementation Scheme 103. The pharmaceutical composition as described in any one of Implementation Schemes 97-102, wherein R 11a and R 11b Each is an unsubstituted alkyl group, or R 11a and R 11b Each independently is , or R 11a Selected from H and unsubstituted alkyl groups and R 11b yes , or R 11a It is H and R 11b Y is an unsubstituted alkyl group, wherein Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2.

[0499] Implementation Scheme 104. The pharmaceutical composition as described in Implementation Scheme 103, wherein 11a and R 11b Each independently selected , , , , , , , , , , and Optional of R 11a and R 11b Each independently selected , , , , , , , , and .

[0500] Implementation Scheme 105. The pharmaceutical composition as described in Implementation Scheme 103, wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and Optional of R 11a Selected from H and -CH3 and R 11b Selected from , , , and .

[0501] Implementation Scheme 106. The pharmaceutical composition as described in Implementation Scheme 103, wherein R 11a It is H and R 11b It is -CH3 or R in it. 11a and R 11b Each is -CH3.

[0502] Implementation Scheme 107. The pharmaceutical composition as described in any one of Implementation Schemes 103-106, wherein n8 is 1.

[0503] Implementation Scheme 108. A pharmaceutical composition as described in any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (82):

[0504] Equation (82)

[0505] In equation (82): R 11a R 11b 、 R 11c and R 11dEach of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

[0506] Implementation Scheme 109. The pharmaceutical composition of Implementation Scheme 108, wherein the compound of formula (82) is a compound of formula (804) or (805):

[0507] Implementation Scheme 110. The pharmaceutical composition as described in Implementation Scheme 108 or 109, wherein R 5b and / or R 5c Each independently is -OR a , where R a It is an unsubstituted alkyl group, optionally wherein -OR a It is -OCH3.

[0508] Implementation Scheme 111. The pharmaceutical composition as described in any one of Implementation Schemes 108-110, wherein R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an unsubstituted cycloalkyl group, optionally cyclohexyl; or R 11a and R 11c Each is hydrogen, R 11b and R 11d Each is independently an alkyl group substituted with a cycloalkyl group, optional. .

[0509] Implementation Scheme 112. The pharmaceutical composition of any one of Implementation Schemes 61-63, wherein the compound of formula (I) is a compound of formula (90):

[0510] Equation (90)

[0511] In equation (90): n is an integer from 1 to 5.

[0512] Implementation Scheme 113. The pharmaceutical composition of Implementation Scheme 112, wherein the compound of formula (90) is a compound of formula (900), formula (901), or formula (902):

[0513] Implementation Scheme 114. The pharmaceutical composition as described in Implementation Scheme 112 or 113, wherein R 12 It is H or -CH3.

[0514] Implementation Scheme 115. The pharmaceutical composition as described in any one of Implementation Schemes 112-114, wherein R 11a It is H or a substituted alkyl group, optional. or .

[0515] Implementation Scheme 116. The pharmaceutical composition as described in any one of Implementation Schemes 112-115, wherein R 10 It is -C(O)R aOptional of R a Selected from unsubstituted alkenyl, substituted alkyl, substituted aryl, and substituted heterocyclic groups, or R 10 It is -S(O) t R a Optionally, where t is 2 and R a It is a substituted aryl group.

[0516] Implementation Scheme 117. The pharmaceutical composition as described in any one of Implementation Schemes 112-116, wherein R 10 Selected from: , , , , , , , , , and .

[0517] Implementation Scheme 118. The pharmaceutical composition of Implementation Scheme 61, wherein the compound of formula (I) is a compound of any one of 1001-1098, or a pharmaceutically acceptable salt thereof: Implementation Scheme 119. The pharmaceutical composition of Implementation Scheme 61, wherein the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof: Implementation Scheme 120. A method for treating a subject in need of cancer, an infectious disease, or an inflammatory disease, the method comprising administering to the subject any of the pharmaceutical compositions described in any of Implementation Schemes 61-119.

[0518] Implementation Scheme 121. The method as described in Implementation Scheme 120, wherein the cancer is selected from basal cell carcinoma; bile duct cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancers); glioblastoma; liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney cancer or renal cell carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma of the lung). Cancers include: cell carcinoma; melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancers; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancers; vulvar cancer; lymphomas, including Hodgkin's and non-Hodgkin's lymphomas, and B-cell lymphomas (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) lymphomas. NHL; intermediate / follicular NHL; intermediate diffuse NHL; advanced immunoblastic NHL; advanced lymphoblastic NHL; advanced small non-lytic cell NHL; massive disease NHL; mantle cell lymphoma; AIDS-associated lymphoma; and Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorders (PTLD), as well as abnormal angiogenesis, edema (such as edema associated with brain tumors), and Megs syndrome associated with scarring nevi.

[0519] Implementation Plan 122. As described in embodiment 120 or 121, the cancer is a blood cancer selected from the group consisting of: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia and preleukemia, or combinations thereof.

[0520] Implementation Scheme 123. The method of any one of Implementation Schemes 120-122, wherein the cancer-resistant checkpoint agent is resistant.

[0521] Implementation Scheme 124. The method of any one of Implementation Schemes 120-123, wherein the anti-checkpoint agent is an antibody, optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and anti-CTLA antibodies.

[0522] Implementation Scheme 125. The method of Implementation Scheme 124, wherein the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pildizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiprimab (LIBTAYO), atezolizumab (TECENTRIQ), averumab (BAVENCIO), and durvalumab (IMFINZI).

[0523] Implementation Scheme 126. The method as described in Implementation Scheme 120, wherein the infectious disease is a viral infection.

[0524] Implementation Scheme 127. The method of implementation scheme 126, wherein the viral infection is caused by a virus selected from: human papillomavirus, herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis virus, Zika virus, yellow fever virus, West Nile virus, dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, hepatitis C virus, poliovirus, rhinovirus, enterovirus, Coxsackie virus, influenza virus, lentivirus, respiratory syncytial virus, human parainfluenza virus, Rubra virus (e.g., mumps virus), measles virus, human metapneumovirus, Hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2).

[0525] Implementation Scheme 128. The method as described in Implementation Scheme 120, wherein the inflammatory disease is an autoimmune disease or disorder selected from multiple sclerosis, diabetes, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpassuia syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allogeneic transplant rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Wright's syndrome, Graves' disease, and other autoimmune diseases.

[0526] Implementation Scheme 129. A method for treating a subject with checkpoint agent-resistant cancer, the method comprising administering to the subject any of the pharmaceutical compositions described in any of Implementation Schemes 61-119.

[0527] Implementation Scheme 130. The method of Implementation Scheme 129, wherein the anti-checkpoint agent is an antibody, optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and anti-CTLA antibodies.

[0528] Implementation Scheme 131. The method of Implementation Scheme 130, wherein the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pildizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), cimiprimab (LIBTAYO), atezolizumab (TECENTRIQ), averumab (BAVENCIO), and durvalumab (IMFINZI).

[0529] Implementation Scheme 132. A method for determining cancer treatment for a patient, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then a cancer therapy comprising the pharmaceutical composition of any one of embodiments 61-119 is selected; and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0530] Implementation Scheme 133. A method for selecting patients for cancer treatment, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then a cancer therapy comprising the pharmaceutical composition of any one of embodiments 61-119 is selected; and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0531] Implementation Scheme 134. A method for treating cancer, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; and (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then administer cancer therapy comprising the pharmaceutical composition of any one of embodiments 61-119; and (d) Optionally administer a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

[0532] Implementation Scheme 135. The method of any one of Implementation Schemes 132-134, wherein the biological sample is a fresh tissue sample, a frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

[0533] Implementation Scheme 136. The method of any one of Implementation Schemes 132-135, wherein the biological sample is a biopsy sample, optionally wherein the biopsy sample is selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy, and colonoscopy), puncture biopsy (e.g., fine needle aspiration biopsy, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computed tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy, and ultrasound-assisted biopsy), skin biopsy (e.g., scraping biopsy, puncture biopsy, and incision biopsy), and surgical biopsy.

[0534] Implementation Scheme 137. The method of any one of Implementation Schemes 132-136, wherein the biological sample comprises a body fluid selected from: blood, plasma, serum, tears, saliva, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing body fluids, free nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological secretions, skin swabs, vaginal swabs, oral swabs, nasal swabs, irrigation or lavage fluids such as catheter lavage fluid or bronchoalveolar lavage fluid, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other body fluids, secretions and / or excretions, and / or cells extracted therefrom.

[0535] Implementation Scheme 138. The method of any one of Implementation Schemes 132-137, wherein the biological sample comprises at least one tumor cell.

[0536] Implementation Scheme 139. The method of any one of Implementation Schemes 132-138, wherein the evaluation is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, Western blotting, intracellular Western blotting, immunofluorescence staining, ELISA and fluorescence activated cell sorting (FACS) or a combination thereof.

[0537] Implementation Scheme 140. The method of any one of Implementation Schemes 132-139, wherein the evaluation is performed by contacting the sample with an agent that specifically binds to Trim7.

[0538] Implementation Scheme 141. The method of Implementation Scheme 140, wherein the agent that specifically binds to one or more proteins comprises an antibody, an antibody-like molecule, or a binding fragment thereof.

[0539] Implementation Scheme 142. The method of any one of Implementation Schemes 132-141, wherein the evaluation is performed by contacting the sample with one or more agents of nucleic acids specifically bound to Trim7.

[0540] Implementation Scheme 143. The method as described in Implementation Scheme 142, wherein one or more of the agents that specifically bind to the nucleic acids are nucleic acid primers or probes.

[0541] Any aspect or implementation described herein may be combined with any other aspect or implementation disclosed herein.

[0542] This disclosure will be further described in the following embodiments, which do not limit the scope of this disclosure as described in the claims.

[0543] Example

[0544] The embodiments provided herein are intended to illustrate the advantages and benefits of this disclosure and to further assist those skilled in the art in preparing or using the Trim7 inhibitors of this disclosure. Embodiments are also provided herein to more fully illustrate preferred aspects of this disclosure. These embodiments should in no way be construed as limiting the scope of this disclosure as defined in the appended claims. The embodiments may include or incorporate any variations, aspects, or embodiments of this disclosure described above. The foregoing variations, aspects, or embodiments may further each include or incorporate variations of any and all other variations, aspects, or embodiments of this disclosure.

[0545] Example 1: Binding of recombinant human Trim7 protein to RACO1 and MSK1

[0546] While not wishing to be bound by theory, it is believed that MSK1 directly phosphorylates triple motif protein 7 (Trim7). Also, while not wishing to be bound by theory, it is believed that Trim7 can ubiquitinate proteins such as RACO1, mitochondrial antiviral signaling protein (MAVS), and STING, thereby impairing the host's immune interferon responsiveness.

[0547] The binding of Trim7 protein to RACO1 and MSK1 was investigated using an assay based on the Meso Scale Discovery (MSD) platform. Briefly, recombinant human Trim7 protein was coated onto a plate. Increased amounts of RACO1, MSK1, or CD47 protein were added to the plate to capture the plate-bound recombinant Trim7 protein. The RACO1 or MSK1 protein captured by the plate-bound Trim7 protein was detected using anti-human RACO1 or anti-human MSK1 antibodies and SULFO-TAG-conjugated secondary antibodies. Figure 1A As shown, the RACO1 protein binds to the plate-bound recombinant Trim7 protein in a dose-dependent manner. In contrast, the CD47 protein only shows a background signal. Figure 1A Similarly, such as Figure 1B As shown, the MSK1 protein binds to the plate-bound recombinant Trim7 protein in a dose-dependent manner. In contrast, the CD47 protein only shows a background signal. Figure 1B ).

[0548] These results In particular This indicates that the Trim7 protein disclosed in this paper specifically binds to RACO1 and MSK1 proteins.

[0549] Example 2: Binding of recombinant human Trim7 protein to enterovirus 71 2BC protein

[0550] The binding of Trim7 protein to enterovirus 71 2B / C and 2C proteins was investigated using an assay based on the Meso Scale Discovery (MSD) platform. For this experiment, recombinant human RACO1 and MSK1 proteins were used as positive controls, and recombinant human CD47 protein was used as a negative control. Briefly, recombinant human RACO1, MSK1, CD47, enterovirus 71 2B, or enterovirus 71 2BC protein were coated onto a plate. An increased amount of recombinant human Trim7 protein was added to the plate to capture the plate-bound RACO1, MSK1, CD47, enterovirus 71 2B, or enterovirus 71 2BC protein. The Trim7 protein captured by the plate-bound RACO1, MSK1, CD47, enterovirus 71 2B, or enterovirus 71 2BC protein was detected using an anti-human Trim7 antibody and a SULFO-TAG-conjugated secondary antibody. Figure 2 As shown, Trim7 can bind to plate-bound enterovirus 71 2B / C proteins in a dose-dependent manner. As expected, Trim7 can bind to plate-bound RACO1 and MSK1 proteins, but not CD47 protein. Figure 2 Trim7 bound to enterovirus 71 2B / C protein at roughly the same level as it bound to MSK1 and RACO1. In contrast, Trim7 did not bind significantly to the 2B portion of the viral protein. Figure 2 ).

[0551] These results In particular This indicates that the Trim7 protein disclosed in this paper specifically binds to the enterovirus 71 2B / C protein.

[0552] Example 3: Enterovirus 71 2BC protein disrupts the binding of recombinant human Trim7 protein to RACO1 and MSK1

[0553] The effect of enterovirus 71 2B / C protein on the binding of Trim7 protein to recombinant human RACO1 or MSK1 protein was investigated using an assay based on the Meso Scale Discovery (MSD) platform. Briefly, recombinant human Trim7 protein was coated onto a plate. Increased amounts of enterovirus 71 2B / C protein were added to the plate to allow capture by the plate-bound recombinant Trim7 protein. Recombinant human MSK1 protein was added to plates with or without 5 μg / ml enterovirus 71 2B / C protein. Binding was then detected using anti-MSK1 antibody and SULFO-TAG conjugated secondary antibody. Figure 3A As shown, Trim7 can be detected using MSK1 protein / anti-MSK1 antibody. Interestingly, when detected in the presence of 5 μg / ml enterovirus 71 2B / C protein, the signal intensity decreased ( Figure 3A These results In particularThis indicates that the enterovirus 71 2BC protein disrupts the binding of recombinant human Trim7 protein to MSK1.

[0554] In another experiment of this type, recombinant human Trim7 protein was coated onto a culture plate. Increased amounts of enterovirus 712B / C protein were added to the plate to allow capture by the plate-bound recombinant Trim7 protein. Recombinant human RACO1 protein was added to plates with or without 5 μg / ml enterovirus 712B / C protein. Binding was then detected using anti-RACO1 antibody and a SULFO-TAG conjugated secondary antibody. Figure 3B As shown, Trim7 can be detected using RACO1 protein / anti-RACO1 antibody. Interestingly, when detected in the presence of 5 μg / ml enterovirus 71 2B / C protein, the signal intensity decreased. Figure 3B These results In particular This indicates that the enterovirus 71 2BC protein disrupts the binding of recombinant human Trim7 protein to RACO1.

[0555] Example 4: Identification of Trim7 inhibitors based on molecular modeling

[0556] The crystal structure of Trim7 has been resolved. (Muñoz Sosa) et al. , Crystal structure and mutational analysis of the human Trim7 B30.2 domain provide insights into the themolecular basis of its binding to glycogenin-1, J Biol Chem 2021;296:100772. The crystal structure shows malonic acid bound to the pocket. The crystal structure of Trim7 bound to the CVB_2C (319-329) peptide (SVGTTLEALFQ) has also been resolved. Liang et al. , Structural insights into the viral proteins binding by Trim7 reveal a general C-terminal glutamine recognition mechanism, bioRxiv 2022.03.24.485560. Figure 4 (Top left figure) shows a schematic diagram of the CVB3 C2 protein, showing the location of the CVB_2C(319-329) peptide. Figure 4(Lower left figure) shows the crystal structure of CVB_2C protein, the CVB_2C (319-329) peptide, and the crystal structure of Trim7 protein and CVB_2C (319-329) peptide complex. Figure 4 (Right figure) illustrates the interaction of various amino acids between the CVB_2C (319-329) peptide and the Trim7 protein. The crystal structure shows an observed glutamine-specific interaction with the CVB3_2C peptide, which inserts into a positively charged groove in the Trim7 PRY-SPRY domain.

[0557] Based on the available crystal structures, homology models were developed for Trim7 with CVB3_2C peptide (TTLEALFQ), GNI peptide (RKLDTYLQ), or the shortened peptide (Ac-ALFQ). These homology models revealed the interaction between the C-terminal glutamine carboxyl group of the CVB3_2C peptide and the Trim7 protein. Figure 5 Additional hydrophobic interactions were also observed with Phe or Leu at the penultimate amino acid position. Figure 5 Based on these interactions, conformationally restricted rigid small compounds containing carboxyl groups and certain aromatic moieties were identified, which dock well with the molecules, including compounds of formula (I).

[0558] Figure 5 A schematic diagram of a molecular simulation-based method for identifying Trim7 inhibitors (including compounds of Formula 1) is shown. Figure 6 Various docking compounds are shown. Underlined compounds have docking scores better than -7, indicating that their affinity constants may be <100 nM. Figure 7 Representative compounds and their docking scores are shown. Based on this model, compound 1001 can bind to Trim7 ( Figure 8A This bond is stabilized through hydrophobic stacking interactions, etc. Figure 8B ).

[0559] These results In particular This indicates that the compound of formula (I) may disrupt the binding of recombinant human Trim7 protein to MSK1. Therefore, the compound of formula (I) is an inhibitor of Trim7 and can be used in the methods disclosed herein.

[0560] Example 5: Disruption of the binding of recombinant human Trim7 protein to RACO1 and MSK1

[0561] The effect of compound (I) on the binding of Trim7 protein to recombinant human RACO1 or MSK1 protein was investigated using an assay based on the Meso Scale Discovery (MSD) platform. Briefly, recombinant human Trim7 protein was coated onto a plate. An increased amount of compound (I) (e.g., compound 1001) was added to the plate to allow capture by the plate-bound recombinant Trim7 protein. Recombinant human RACO1 and / or MSK1 protein was added to plates with or without compound (I) (e.g., compound 1001). Binding was then detected using a combination of anti-RACO1 antibody and / or anti-MSK1 antibody conjugated with a SULFO-TAG secondary antibody. It was expected that in the absence of compound (I), Trim7 would exhibit binding to RACO1 and / or MSK1 protein (see [link to study]). Figure 1A and Figure 1B Trim7 is expected to exhibit reduced binding to RACO1 and / or MSK1 proteins when detected in the presence of compound (I).

[0562] These results In particular This indicates that the compound of formula (I) disrupts the binding of recombinant human Trim7 protein to RACO1 and / or MSK1 proteins. Therefore, the compound of formula (I) is an inhibitor of Trim7 and can be used in the methods disclosed herein.

[0563] Example 6: IC 50 data

[0564] This embodiment provides ICs of the compounds of this disclosure as determined by TRIM7 fluorescence polarization (FP) binding assay. 50 Value data.

[0565] TRIM7 fluorescence polarization (FP) binding assays were performed on the compounds disclosed herein. The assays were performed using the distal C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3), which had previously been shown to interact with the same TRIM7-PrySpry (324-511) domains (Ru, Y. Proc. Natl. Acad.Sci. USA, 2022, 119(30): e2203218119), incubated with His-TRIM7-PrySpry (324-511) for 22 hours. An unlabeled version of the same peptide (a shorter version of the peptide (LFQ only) or a small molecule inhibitor (SMI)) was added to compete with the fluorescently labeled peptide for binding to the same docking pocket. The loss of fluorescence signal resulting from the competition of the labeled peptide was quantified. The results are shown in the table below, where IC50 is the lowest common molecular weight value (CMW).50 It is expressed as follows: +++ = IC 50 < 15 μM ++ = 15 μM < IC 50 < 100 μM + = IC 50 > 100 μM N / A = Compound has not yet been tested.

[0566] Example 7: Covalent Trim7 inhibitors of the present disclosure

[0567] This embodiment provides relevant IC50 values ​​of the compounds of this disclosure, calculated at 4 hours and 22 hours, as shown by TRIM7 fluorescence polarization (FP) binding assays. 50 Data on the values. While not wishing to be bound by any particular theory, the IC values ​​of compounds 1013 and 1012 are... 50 In comparison, IC measured at 22 hours 50 The improvement indicates that, over time, the compounds covalently bind to Trim7, thereby enhancing their ability to suppress the gene. The table below shows the IC50 values ​​at 22 hours for each compound tested. 50 The value is relative to the IC value over 4 hours. 50 In terms of value (4 hours relative IC) 50 The value is 1).

[0568]

[0569] Example 8: IC 50 data

[0570] The compounds of this disclosure were subjected to TRIM7 fluorescence polarization (FP) binding assays. The assays were performed using the distal C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3), which had previously been shown to interact with the same TRIM7-PrySpry (324-511) domains, incubated with His-TRIM7-PrySpry (324-511) for 1.5 h, 4 h, or 22 h. An unlabeled version of the same peptide (a shorter version of the peptide (LFQ only) or a small molecule inhibitor (SMI)) was added to compete with the fluorescently labeled peptide for binding to the same docking pocket. The loss of fluorescence signal resulting from the labeled peptide being contested was quantified. The results are shown in the table below, where IC50 is the highest concentration of 124 mg / mL. 50 It is expressed as follows: +++ = IC 50 < 15 μM ++ = 15 μM < IC 50 < 100 μM + = IC 50 > 100 μM N / A = Compound has not yet been tested.

[0571] Example 9: Interaction between TRIM7 and the SMI of this disclosure

[0572] TRIM7 is the most described virus in viral biology. It ubiquitinates viral proteins (e.g., CVB3_2BC, EV71, and SARS-CoV2) and targets and degrades them. Figure 9A The crystal structure of the c-terminal PrySpry domain of TRIM7 was recently resolved, identifying a key pocket where viral binding may occur. Figure 9B The crystal structures of TRIM7 and the viral peptide have been resolved, and a key cysteine ​​residue in the binding pocket has been identified, which can be used for covalent binding (…). Figure 9C Importantly, the C-terminal amino acid of viral CVB3_2C has been shown to specifically interact with this pocket, and this amino acid motif is conserved with the native proteins GN1 and RACO-1. ​​This structural knowledge provides some basis for small molecule inhibitors of TRIM7.

[0573] Recombinant proteins were generated to facilitate the development of small molecule inhibitors (SMIs) and to validate their binding / functional activity. The interactions of TRIM7 with RACO-1, STING, MAVS, and CVB3_2C (WT, not mutant) were confirmed. Figure 10 Using these findings, various compounds disclosed herein were screened through a series of binding / activity assays and prioritized for further chemical modification. Figure 11 ).

[0574] Table 1 provides binding data for several compounds disclosed herein with the PrySpry domain. The binding was qualitatively assessed based on whether the correct SMI quality (full scan) was detected after incubation with TRIM7PrySpry and whether the interaction was confirmed at the expected C501 in the binding pocket (peptide map), and a score was assigned. , , or .

[0575] legend: or The results indicate that some binding was detected, but the assay requires further optimization. or The scoring indicator has a high binding confidence level. ND-indicating compounds have not been tested.

[0576] Table 1. Binding data of the compounds disclosed herein with the PrySpry domain.

[0577] Figures 12A to 12B Based on cell activity assays, it was shown that TRIM7 expression in cells leads to target degradation / stabilization. Figure 12A This indicates that overexpression of TRIM7 (+T7) in 293T cell lines expressing CVB3, MAVS, or STING leads to their degradation, consistent with previous studies. Figure 12B This indicates that RACO-1 self-overexpression leads to self-ubiquitination and degradation. RACO1 is stable when TRIM7 is co-expressed with it. TRIM7 SMIs, such as compound 1028, exhibit varying activities in blocking TRIM7 stabilization of RACO1, thus leading to its degradation.

[0578] Example 10: IC50 of the compounds disclosed herein 50 value

[0579] This embodiment provides IC50 of compound 1028 of this disclosure as shown by TRIM7 fluorescence polarization (FP) binding assay. 50 Value data.

[0580] Compound 1028 was subjected to a TRIM7 fluorescence polarization (FP) binding assay. The assay was performed using the distal C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3), which had previously been shown to interact with the same TRIM7-PrySpry (324-511) domain (Ru, Y. et al., Proc. Natl. Acad. Sci. USA, 2022, 119(3): e2203218119), incubated with His-TRIM7-PrySpry (324-511) for 30 min. An unlabeled version of the same peptide (a shorter version of the peptide (LFQ only) or a small molecule inhibitor (SMI)) was added to compete with the fluorescently labeled peptide for binding to the same docking pocket for 1.5 h. The loss of fluorescence signal as the labeled peptide was competitively displaced was quantified. The results are shown in the table below, where IC50 is the lowest common molecular weight value (CMW). 50 It is expressed as follows: Symbol explanation: +++ = IC 50 < 15 μM ++ = 15 μM < IC 50 < 100 μM + = IC 50 > 100 μM

[0581] Example 11: Combination of compound (I) with Kras inhibitor in vivo Antitumor activity

[0582] The efficacy was evaluated by combining the compound of formula (I) with a Kras inhibitor. Briefly, 500,000 mouse colon cancer CT26 cells were inoculated into the posterior abdomen of BALB / c mice. When the average tumor volume reached 80–100 mm... 3 At day 0, mice were randomly assigned to one of four treatment groups. Each group was administered (1) a mediator-only control, (2) a compound of formula (I) alone, (3) a kras inhibitor alone, or (4) a combination of a compound of formula (I) and a kras inhibitor. Administration was performed on days 0, 3, 6, 9, 12, and 15. Tumors were measured daily using electronic calipers and plotted using GraphPad Prism software. Tumor growth in each treatment group was assessed by plotting tumor growth curves for individual mice, mean tumor growth curves for each treatment group, mean tumor size on an exemplary day, and / or Kaplan-Meier plots.

[0583] Expected results especiallyThis indicates that the combination of compound (I) with a kras inhibitor has greater antitumor activity compared to monotherapy.

[0584] Example 12: Combination of compound (I) with a braf inhibitor in vivo Antitumor activity

[0585] The efficacy was evaluated by combining the compound of formula (I) with a braf inhibitor. Briefly, 500,000 mouse colon cancer CT26 cells were inoculated into the posterior abdomen of BALB / c mice. When the average tumor volume reached 80–100 mm... 3 At day 0, mice were randomly assigned to one of four treatment groups. Each mouse group was administered (1) a mediator-only control, (2) a compound of formula (I) alone, (3) a braf inhibitor alone, or (4) a combination of a compound of formula (I) and a braf inhibitor. Administration was performed on days 0, 3, 6, 9, 12, and 15. Tumors were measured daily using electronic calipers and plotted using GraphPad Prism software. Tumor growth in each treatment group was assessed by plotting tumor growth curves for individual mice, mean tumor growth curves for each treatment group, mean tumor size on an exemplary day, and / or Kaplan-Meier plots.

[0586] Expected results especially This indicates that the combination of compound (I) with a braf inhibitor has greater antitumor activity compared to monotherapy.

[0587] Example 13: Combination of compound (I) with MEK inhibitor in vivo Antitumor activity

[0588] The efficacy was evaluated by combining the compound of formula (I) with a MEK inhibitor. Briefly, 500,000 mouse colon cancer CT26 cells were inoculated into the posterior abdomen of BALB / c mice. When the average tumor volume reached 80–100 mm... 3 At day 0, mice were randomly assigned to one of four treatment groups. Each group was administered (1) a mediator-only control, (2) a compound of formula (I) alone, (3) a MEK inhibitor alone, or (4) a combination of a compound of formula (I) and a MEK inhibitor. Administration was performed on days 0, 3, 6, 9, 12, and 15. Tumors were measured daily using electronic calipers and plotted using GraphPad Prism software. Tumor growth in each treatment group was assessed by plotting tumor growth curves for individual mice, mean tumor growth curves for each treatment group, mean tumor size on an exemplary day, and / or Kaplan-Meier plots.

[0589] Expected results especially This indicates that the combination of compound (I) with a MEK inhibitor has greater antitumor activity compared to monotherapy.

[0590] Example 14: IC50 of the compounds disclosed herein 50 data

[0591] This embodiment provides ICs of the compounds of this disclosure as determined by TRIM7 fluorescence polarization (FP) binding assay. 50 Value data.

[0592] TRIM7 fluorescence polarization (FP) binding assays were performed on the compounds disclosed herein. The assays were performed using the distal C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3), which had previously been shown to interact with the same TRIM7-PrySpry (324-511) domain (Ru, Y. et al., Proc. Natl. Acad. Sci. USA, 2022, 119(3): e2203218119), incubated with His-TRIM7-PrySpry (324-511) for 30 min, 1.5 h, 4 h, or 22 h. An unlabeled version of the same peptide (a shorter version of the peptide (LFQ only) or a small molecule inhibitor (SMI)) was added to compete with the fluorescently labeled peptide for binding to the same docking pocket. The loss of fluorescence signal resulting from the competition of the labeled peptide was quantified. The results are shown in the table below, where IC50 is the lowest common molecular weight ratio (CMR). 50 It is expressed as follows: Symbol explanation: +++ = IC 50 < 15 μM ++ = 15 μM < IC 50 < 100 μM + = IC 50 > 100 μM N / A = Compound has not yet been tested.

[0593] Example 15

[0594] Synthesis of 5-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1010):

[0595] Preparation of 2-(dibenzylcarbamoyl)-5-nitrobenzoic acid and 2-(dibenzylcarbamoyl)-4-nitrobenzoic acid (intermediate-1a) (step 1): 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and bis(benzylamine) (2.0 g, 10.4 mmol, 1.0 eq.) were dissolved in THF (25 ml), and the solution was stirred at room temperature for 18 hours. The solution was concentrated to give a 1:1 mixture (4.0 g, 100% yield) of the desired product as a clear oil. 1 H NMR (400MHz, DMSO-d6) δ ppm 8.63 (d, J=2.4 Hz, 1H), 8.43 – 8.40 (m, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.17 (d, J=3.2 Hz, 1H), 8.04 (J=2.4 Hz, 1H), 7.74 (d, J=8.0 Hz,1H), 7.35 – 7.05 (m, 20H), 4.23 (br s, 2H), 4.18 (br s, 2H). LCMS EI-MS m / z: =391.0[M+H] + .

[0596]

[0597] Preparation of 5-amino-2-(dibenzylcarbamoyl)benzoic acid (intermediate-1b) (step 2): A mixture of 2-(dibenzylcarbamoyl)-5-nitrobenzoic acid and 2-(dibenzylcarbamoyl)-4-nitrobenzoic acid (intermediate-1a) (1.50 g, 3.84 mmol) was dissolved in ethanol (38 ml), and Pd / C (0.3 g, 20 wt%) was added. The suspension was placed under a hydrogen balloon for 24 hours. Insoluble catalyst was removed by diatomaceous earth filtration, and the filtrate was concentrated. The residue was purified by preparative reversed-phase HPLC using water / acetonitrile containing 0.05% TFA to give two products. Based on two-dimensional NMR analysis, the compound with the faster elution rate (0.8 g, 40% yield) was designated as the structure of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm7.65 – 7.25 (m, 8H), 7.20 – 7.15 (m, 3H), 7.10 – 7.05 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.21 (s, 2H), 4.00 – 3.00 (br, 2H). LCMSEI-MS m / z: = 361.2[M+H] + .

[0598]

[0599] Preparation of 5-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1010) (step 3): 5-amino-2-[bis(benzyl)carbamoyl]benzoic acid-trifluoroacetic acid (1 / 1) (100 mg, 0.20 mmol) was dissolved in 1N sodium hydroxide solution (2.0 ml), and acryloyl chloride (0.05 ml, 0.60 mmol, 3.0 eq.) was added. The solution was stirred at room temperature for 3 hours. The reaction was quenched by adding 1N hydrochloric acid, resulting in the precipitation of a white solid. The solid was collected by filtration and then purified by preparative reversed-phase HPLC using water / acetonitrile containing 0.05% TFA to give the title compound (46 mg, 55% yield) as a white powder. 1 ¹H NMR (400 MHz, methanol-d⁴) δ ppm 8.37 (d, J =2.0 Hz, 1H), 7.95 (dd, J =8.4 Hz, 2.0 Hz, 1H), 7.50 – 7.10 (m, 11 Hz), 6.50 – 6.30 (m,2H), 5.80 (dd, J =8.8 Hz, 3.2 Hz, 1H), 4.70 (br s, 2H), 4.26 (s, 2H). LCMS EI-MS m / z: = 415.1[M+H] + .

[0600] Example 16

[0601] Synthesis of 4-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1011):

[0602] Following the procedure described in step 3 of the synthesis of compound 1010, 4-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (intermediate-1c) (80 mg, 0.02 mmol) and acryloyl chloride (0.04 ml, 0.05 mmol) were used to synthesize 4-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1011), yielding the title compound (20 mg, 21% yield). 1 HNMR (400 MHz, methanol– d 4) δ = 8.07 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 2.1, 8.6 Hz, 1H), 7.39 – 7.22 (m, 8H), 7.14 (d, J = 6.6Hz, 2H), 6.43 (d, J = 2.4 Hz, 2H), 5.82 (dd, J = 4.7, 7.1 Hz, 1H), 4.23 (brs, 2H). LCMS EI-MS m / z: = 415.1[M+H] + .

[0603] Example 17

[0604] Synthesis of 5-acrylamido-2-(diisobutylcarbamoyl)benzoic acid (compound 1012):

[0605] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(diisobutylcarbamoyl)benzoic acid (compound 1012) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and diisobutylamine (1.3 g, 10.4 mmol, 1.0 eq.) to give the title compound (15 mg, yield 28%). 1 H NMR (400MHz, methanol-) d 4) δ ppm 8.33 (d, J =2.0 Hz, 1H), 7.98 (dd, J =8.2, 2.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 6.50 – 6.40 (m, 4H), 5.81 (dd, J =9.2, 3.2 Hz, 2H), 3.37 (d, J =7.8 Hz, 2H), 2.98 (d, J =7.8 Hz, 2H), 2.25 – 2.15 (m, 1H), 1.85 –1.70 (m, 1H), 1.02 (d, J =6.4 Hz, 6H), 0.77 (d, J =6.4 Hz, 6H). LCMS EI-MS m / z:= 347.1[M+H] + .

[0606] Example 18

[0607] Synthesis of 4-acrylamido-2-(diisobutylcarbamoyl)benzoic acid (compound 1013):

[0608] Following the procedure described in steps 1-3 of the synthesis of compound 1011, 4-acrylamido-2-(diisobutylcarbamoyl)benzoic acid (compound 1013) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and diisobutylamine (1.3 g, 10.4 mmol, 1.0 eq.) to give the title compound (13 mg, 20% yield). 1 H NMR (400MHz, methanol-) d 4) δ ppm 8.03 (d, J =8.4 Hz, 1H), 7.80 – 7.40 (m, 2H), 6.50 – 6.30(m, 2H), 5.81 (dd, J =8.4, 3.2 Hz, 1H), 3.75 (d, J =7.6 Hz, 2H), 3.00 (br, s,2H), 2.25 – 2.20 (m, 1H), 1.95 – 1.85 (m, 1H), 1.03 (d, J =6.4 Hz, 6H), 0.79(d, J =6.4 Hz, 6H). LCMS EI-MS m / z: = 347.1[M+H] +

[0609] Example 19

[0610] Synthesis of 4-bromo-2-(diisobutylcarbamoyl)benzoic acid (compound 1014):

[0611] Following the procedure described in step 1 of the synthesis of compound 1011, 4-bromo-2-(diisobutylcarbamoyl)benzoic acid (compound 1014) was synthesized from 5-bromoisobenzofuran-1,3-dione (1.6 g, 8.3 mmol) and diisobutylamine (1.1 g, 8.3 mmol, 1.0 eq.) to give the title compound (900 mg, yield 47%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.11 (s,1H), 7.62 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 3.75 (d, J =7.6 Hz, 2H), 3.00 (br, s, 2H), 2.25 – 2.20 (m, 1H), 1.95 – 1.85 (m, 1H), 1.03(d, J =6.4 Hz, 6H), 0.79 (d, J =6.4 Hz, 6H). LCMS EI-MS m / z: = 432.1, 434.1[M+H] + .

[0612] Example 20

[0613] Synthesis of 5-amino-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1015):

[0614] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-amino-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1015) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and N-(cyclohexylmethyl)-2-methoxyethyl-1-amine (1.8 g, 10.4 mmol, 1.0 eq.) to give the title compound (160 mg, yield 56%). 1 H NMR (400 MHz, methanol–) d 4) δ = 7.80 (d,J = 8.6 Hz, 1H), 6.67 (dd, J = 2.3, 8.6 Hz, 1H), 6.46 (dd, J 1.99 – 1.80 (m, 2H), 1.76 (br d, J = 12.4 Hz, 1H), 1.71– 1.52 (m, 4H), 1.38 – 1.10 (m, 3H), 1.08 – 1.00 (m, 1H), 0.69 (br t, J =10.6 Hz, 1H). LCMS EI-MS m / z: = 335.2[M+H] + .

[0615] Example 21

[0616] Synthesis of 4-amino-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1016):

[0617] Following the procedure described in steps 1-3 of the synthesis of compound 1011, 4-amino-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1016) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and N-(cyclohexylmethyl)-2-methoxyethyl-1-amine (1.8 g, 10.4 mmol, 1.0 eq.) to give the title compound (150 mg, 29% yield). 1 H NMR (400 MHz, methanol–) d4) δ = 7.50 (s, 1H), 7.15 –7.01 (m, 2H), 3.69 – 3.62 (m, 2H), 3.38 – 3.36 (m, 3H), 3.29 – 3.15 (m, 2H),1.89 – 1.73 (m, 3H), 1.71 – 1.56 (m, 4H), 1.35 – 1.14 (m, 3H), 1.11 – 0.97 (m, 2H), 0.72 – 0.57 (m, 1H). LCMS EI-MS m / z: = 335.2[M+H] + .

[0618] Example 22

[0619] Synthesis of 2-(diisobutylcarbamoyl)-5-ethynylbenzoic acid (compound 1017):

[0620] Intermediate-2a was prepared as described in compound 1014. Intermediate-2b was prepared from intermediate-2a in methanol using thionyl chloride. Intermediate-2c was prepared from intermediate-2b in TMS-acetylene, Pd(PPh3)4, cuprous iodide, and triethylamine. Compound 1017 was prepared from intermediate-2c using an aqueous solution of sodium hydroxide to give the title compound (15 mg, 9% yield). 1 H NMR (400 MHz, methanol–) d 4) δ = 8.10 (s, 1H), 7.71 (dd, J = 1.4, 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 3.70 (s, 1H), 3.43 – 3.32 (m, 2H), 2.95 (br s, 2H), 2.19(quind, J = 6.8, 13.7 Hz, 1H), 1.85 (quind, J = 6.9, 13.7 Hz, 1H), 1.02 (d, J = 6.6 Hz, 6H), 0.77 (d, J = 6.6 Hz, 6H). LCMS EI-MS m / z: = 302.1[M+H] + .

[0621] Example 23

[0622] Synthesis of 4-amino-2-(dibenzylcarbamoyl)benzoic acid (compound 1018):

[0623] Following the procedure described in steps 1-2 of the synthesis of compound 1010, 4-amino-2-(dibenzylcarbamoyl)benzoic acid (compound 1018) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and N,N-dibenzylamine (2.2 g, 10.4 mmol, 1.0 eq.) to give the title compound (100 mg, 30% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.55 – 7.25 (m, 8H), 7.20 – 7.15 (3H), 7.10 – 7.00 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.54 (br 2H), 4.21 (s, 2H), 4.00 – 3.70 (br 1H). LCMSEI-MS m / z: = 361.1[M+H] + .

[0624] Example 24

[0625] Synthesis of 5-amino-2-(dibenzylcarbamoyl)benzoic acid (compound 1019):

[0626] Following the procedure described in steps 1-3 of the synthesis of compound 1011, 5-amino-2-(dibenzylcarbamoyl)benzoic acid (compound 1019) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and N,N-dibenzylamine (2.2 g, 10.4 mmol, 1.0 eq.) to give the title compound (150 mg). 1 H NMR (400 MHz, DMSO-d6)δ ppm 7.75 – 7.50 (m, 8H), 7.25 – 7.20 (3H), 7.10 – 7.00 (m, 1H), 6.52 (d, J =8.0 Hz, 1H), 4.50 (br 2H), 3.95 (s, 2H), 4.00 – 3.70 (br 1H). LCMS EI-MS m / z:= 361.1[M+H] + .

[0627] Example 25

[0628] Synthesis of 5-acrylamido-2-((4-chlorobenzyl)carbamoyl)benzoic acid (compound 1020):

[0629] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-((4-chlorobenzyl)carbamoyl)benzoic acid (compound 1020) was synthesized from 5-nitroisobenzofuran-1,3-dione (0.4 g, 2.1 mmol) and 4-chlorobenzylamine (0.3 g, 2.1 mmol, 1.0 eq.) to give the title compound (12 mg). LCMS EI-MS m / z: =359.1 [M+H] + .

[0630] Example 26

[0631] Synthesis of 5-acrylamido-2-(benzyl(4-methylbenzyl)carbamoyl)benzoic acid (compound 1021):

[0632] The synthesis of 5-acrylamido-2-(benzyl(4-methylbenzyl)carbamoyl)benzoic acid (compound 1021) was carried out from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and N-benzyl-1-(p-tolyl)methylamine (2.2 g, 10.4 mmol, 1.0 eq.) to give the title compound (18 mg). 1 H NMR (400 MHz, methanol–) d 4) δ = 8.37 (s, 1H), 7.95 (t, J = 7.0 Hz, 1H), 7.41– 7.21 (m, 6H), 7.17 – 7.08 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.47 – 6.35(m, 2H), 5.80 (dd, J = 2.2, 8.8 Hz, 1H), 4.22 (br d, J = 12.3 Hz, 2H), 2.32(d, J = 11.1 Hz, 3H). LCMS EI-MS m / z: = 429.1[M+H] +.

[0633] Example 27

[0634] Synthesis of 5-acrylamido-2-(benzyl(4-methylbenzyl)carbamoyl)benzoic acid (compound 1023):

[0635] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(benzyl(4-methylbenzyl)carbamoyl)benzoic acid (compound 1023) was synthesized from 5-nitroisobenzofuran-1,3-dione (320 mg, 1.6 mmol) and bis[(p-chlorophenyl)methyl]amine (440 g, 1.6 mmol, 1.0 eq.) to give the title compound (10 mg, 19% yield). 1 H NMR (400 MHz, DMSO- d 6) δ ppm 13.45 (br s, 1H), 10.44 (s, 1H), 8.28(d, J =2.4 Hz, 1H), 7.90 (d, J =2.4 Hz, 1H), 7.51 – 7.35 (m, 7H), 7.25 – 7.15(m, 2H), 6.45 – 6.40 (m, 1H), 6.37 – 6.30 (m, 1H), 5.80 – 5.75 (m, 1H), 4.60(br s, 2H), 4.19 (s, 2H). LCMS EI-MS m / z: = 484.1[M+H] + .

[0636] Example 28

[0637] Synthesis of 5-acrylamido-2-(bis(3-fluoro-4-(trifluoromethyl)benzyl)carbamoyl)benzoic acid (compound 1024):

[0638] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(bis(3-fluoro-4-(trifluoromethyl)benzyl)carbamoyl)benzoic acid (compound 1024) was synthesized from 5-nitroisobenzofuran-1,3-dione (170 mg, 0.9 mmol) and bis(3-fluoro-4-(trifluoromethyl)benzyl)amine (320 g, 0.9 mmol, 1.0 eq.) to give the title compound (10 mg, 17% yield). 1 H NMR (400 MHz, DMSO- d 6) δ ppm 13.60 (br s, 1H),10.46 (s, 1H), 8.31 (d, J =2.0 Hz, 1H), 7.94 – 7.92 (m, 1H), 7.80 – 7.20 (m,7H), 6.51 – 6.43 (m, 1H), 6.34 – 6.26 (m, 1H), 5.85 – 5.80 (m, 1H), 4.75 (brs, 2H), 4.42 (s, 2H). LCMS EI-MS m / z: = 587.0[M+H] + .

[0639] Example 29

[0640] Synthesis of 5-acrylamido-2-(bis(4-methoxybenzyl)carbamoyl)benzoic acid (compound 1025):

[0641] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(bis(4-methoxybenzyl)carbamoyl)benzoic acid (compound 1025) was synthesized from 5-nitroisobenzofuran-1,3-dione (350 mg, 1.8 mmol) and bis(4-methoxybenzyl)amine (466 mg, 1.8 mmol, 1.0 eq.) to give the title compound (30 mg, 11% yield). 1 H NMR (400 MHz, DMSO- d 6) δ ppm 13.45 (br s, 1H), 10.44 (s, 1H), 8.27 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.40 – 6.90 (m, 9H), 6.50 – 6.30 (m, 2H), 5.82 – 5.80 (m, 1H), 4.50 (br s, 2H), 4.07 (s, 2H), 3.75 (s, 3H), 3.74 (s,3H). LCMS EI-MS m / z: = 475.2[M+H] + .

[0642] Example 30

[0643] Synthesis of 5-acrylamido-2-(benzyl(4-fluorobenzyl)carbamoyl)benzoic acid (compound 1027):

[0644] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(benzyl(4-fluorobenzyl)carbamoyl)benzoic acid (compound 1027) was synthesized from 5-nitroisobenzofuran-1,3-dione (180 mg, 0.9 mmol) and (benzyl)[(p-fluorophenyl)methyl]amine (200 mg, 0.9 mmol, 1.0 eq.) to give the title compound (40 mg, 9% yield). 1 H NMR (400 MHz, DMSO- d 6)δ ppm 13.44 (br s, 1H), 10.44 (d, J =2.1Hz, 1H), 8.28 (s, 1H), 7.88 - 7.96 (m, 1H), 7.25 - 7.43 (m, 6H), 7.09 - 7.22(m, 4H), 6.40 (dd, J =10.1, 1.8 Hz, 1H) 6.25 - 6.34 (m, 1H) 5.80 (br d, J =10.1 Hz, 1H), 4.52 (s, 2H), 4.19 (s, 2H). LCMS EI-MS m / z: = 433.1[M+H] + .

[0645] Example 31

[0646] Synthesis of 5-acrylamido-2-(benzyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1028):

[0647] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(benzyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1028) was synthesized from 5-nitroisobenzofuran-1,3-dione (1.5 g, 7.8 mmol) and benzyl[(oxecyclohexane-4-yl)methyl]amine (1.6 g, 7.8 mmol, 1.0 eq.) to give the title compound (10 mg, 15% yield). 1 H NMR (400 MHz, methanol–) d 4) δ ppm 8.41 – 8.37 (m,2H), 7.91 (dd, J = 2.1, 8.4 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.41 – 7.27(m, 9H), 7.23 (d, J = 7.1 Hz, 3H), 6.49 – 6.37 (m, 4H), 5.82 (dd, J = 3.1,8.5 Hz, 2H), 4.43 (s, 3H), 3.95 (br dd, J = 3.0, 11.4 Hz, 3H), 3.51 – 3.35(m, 5H), 3.31 – 3.12 (m, 3H), 2.68 (s, 1H), 1.78 (br d, J = 11.1 Hz, 4H). LCMSEI-MS m / z: = 423.1[M+H] + .

[0648] Example 32

[0649] Synthesis of 5-acrylamido-2-((3-fluoro-4-(trifluoromethyl)benzyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1029):

[0650] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-((3-fluoro-4-(trifluoromethyl)phenyl]methyl}[(oxacyclohexane-4-yl)methyl]amine (1.0 g, 3.4 mmol, 1.0 eq.) was used to synthesize 5-acrylamido-2-((3-fluoro-4-(trifluoromethyl)benzyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1029) to give the title compound (35 mg, 17% yield). 1 H NMR (400 MHz, DMSO- d 6) δ ppm 13.4 (br s, 1H), 10.43 (d, J =28 Hz, 1H), 8.31 (d, J =2.0 Hz, 1H), 8.10 – 7.20 (m, 5H), 6.50 – 6.20 (m, 2H), 5.80 – 5.75(m, 1H), 4.82 (br s, 1H), 4.45 (s, 1H), 3.30 – 3.00 (m, 4H), 2.10 – 1.80 (m,1H), 1.80 – 1.70 (m, 1H), 1.50 – 1.40 (m, 1H), 1.20 – 1.10 (m, 2H), 0.90 –0.80 (m, 2H). LCMS EI-MS m / z: = 509.1[M+H] + .

[0651] Example 33

[0652] Synthesis of 5-acrylamido-2-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1030):

[0653] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)benzoic acid (compound 1030) was synthesized from 5-nitroisobenzofuran-1,3-dione (1.5 g, 7.8 mmol) and [(p-methoxyphenyl)methyl][(tetrahydro-2H-pyran-4-yl)methyl]amine (1.8 g, 7.8 mmol, 1.0 eq.) to give the title compound (35 mg). LCMS EI-MS m / z: = 453.1 [M+H] + .

[0654] Example 34

[0655] Synthesis of 5-acrylamido-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1031):

[0656] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-((cyclohexylmethyl)(2-methoxyethyl)carbamoyl)benzoic acid (compound 1031) was synthesized from 5-nitroisobenzofuran-1,3-dione (1.5 g, 7.8 mmol) and (cyclohexylmethyl)(2-methoxyethyl)amine (1.3 g, 7.8 mmol, 1.0 eq.) to give the title compound (35 mg). 1 H NMR (400 MHz, methanol–) d 4) δ = 8.33 (dd, J = 1.6, 8.3 Hz, 1H), 7.97 (t, J = 6.7 Hz, 1H), 7.27 (t, J = 8.9 Hz, 1H), 6.49 – 6.36 (m, 2H), 5.81(dd, J= 1.9, 9.1 Hz, 1H), 3.77 – 3.60 (m, 2H), 3.44 – 3.36 (m, 3H), 3.35– 3.29 (m, 3H), 3.23 (s, 1H), 3.14 – 2.92 (m, 1H), 1.96 – 1.82 (m, 1H), 1.81– 1.56 (m, 5H), 1.34 – 1.14 (m, 2H), 1.12 – 0.98 (m, 1H), 0.73 – 0.58 (m, 1H). LCMS EI-MS m / z: = 389.1[M+H] + .

[0657] Example 35

[0658] Synthesis of 5-acrylamido-2-(benzyl(4-methoxybenzyl)carbamoyl)benzoic acid (compound 1032):

[0659] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(benzyl(4-methoxybenzyl)carbamoyl)benzoic acid (compound 1032) was synthesized from 5-nitroisobenzofuran-1,3-dione (1.5 g, 7.8 mmol) and N-benzyl-1-(4-methoxyphenyl)methylamine (1.8 g, 7.8 mmol, 1.0 eq.) to give the title compound (4 mg, 6% yield). 1 H NMR (400 MHz, methanol–) d 4) δ = 8.43 – 8.30 (m, 1H), 8.02 – 7.85(m, 1H), 7.44 – 7.20 (m, 7H), 7.18 – 7.08 (m, 1H), 7.07 – 6.96 (m, 1H), 6.92– 6.75 (m, 2H), 6.49 – 6.32 (m, 2H), 5.85 – 5.70 (m, 1H), 4.28 – 4.12 (m,3H), 3.86 – 3.66 (m, 4H), 3.34 (s, 4H). LCMS EI-MS m / z: = 445.1[M+H] + .

[0660] Example 36

[0661] Synthesis of 5-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1033):

[0662] Following the procedure described in steps 1-3 of the synthesis of compound 1010, 5-acrylamido-2-(dibenzylcarbamoyl)benzoic acid (compound 1033) was synthesized from 5-nitroisobenzofuran-1,3-dione (2.0 g, 10.4 mmol) and dibenzylamine (2.0 g, 10.4 mmol, 1.0 eq.) to give the title compound (6 mg). 1 H NMR (400 MHz, methanol–) d 4)δ = 8.30 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 2.1, 8.3 Hz, 1H), 7.38 – 7.23 (m,9H), 7.12 (d, J = 6.8 Hz, 2H), 4.84 – 4.57 (m, 2H), 4.24 (s, 2H), 3.37 – 3.32(m, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H). LCMS EI-MS m / z: =429.1[M+H] + .

[0663] Example 37

[0664] Synthesis of 2-(5-acrylamido-2-(benzyl(methyl)carbamoyl)phenyl)acetic acid (compound 1034):

[0665] Synthesis of ethyl 2-(2-(benzyl(methyl)carbamoyl)-5-bromophenyl)acetate (intermediate-3b): A solution of 4-bromo-2-(2-ethoxy-2-oxoethyl)benzoic acid (1.8 g, 6.1 mmol) in dichloromethane (30 ml) was reacted with oxalyl chloride (0.7 ml, 8.0 mmol, 1.3 eq.) in the presence of DMF (0.2 ml). After 3 hours, the solution was concentrated to give the corresponding acyl chloride (1.8 g). A solution of this acyl chloride (0.75 g, 2.6 mmol) was reacted with N-methylbenzylamine (0.36 ml, 2.8 mmol, 1.1 eq.) and diisopropylethylamine (0.58 ml, 3.3 mmol, 1.3 eq.) to give the title compound (910 mg, 95% yield). LCMS EI-MS m / z: = 391.1, 393.1[M+H] + .

[0666] Synthesis of 2-(5-amino-2-(benzyl(methyl)carbamoyl)phenyl)acetic acid (intermediate-3c): A solution of ethyl 2-(2-(benzyl(methyl)carbamoyl)-5-bromophenyl)acetate (910 mg, 2.3 mmol) and lithium hydroxide (223 mg, 9.3 mmol, 4.0 eq.) in THF (2 ml) and water (4 ml) was stirred for 6 hours. The solution was then quenched by adding 1N HCl and extracted into dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the corresponding acid (750 mg, 89% yield). A solution of this acid (300 mg, 0.83 mmol), copper oxide (60 mg, 0.4 mmol, 0.5 eq.), and ammonium hydroxide (0.07 mL, 1.7 mmol, 2.0 eq.) was dissolved in NMP (6 mL) and heated at 80 °C for 16 hours. After cooling, the solution was added to ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and then concentrated. The residue was purified using a dichloromethane / methanol gradient on a Combiflash to give the title product (50 mg, 25% yield). LCMS EI-MS m / z: = 299.0 [M+H] + .

[0667]

[0668] Synthesis of 2-(5-acrylamido-2-(benzyl(methyl)carbamoyl)phenyl)acetic acid (compound 1034): 2-(5-amino-2-(benzyl(methyl)carbamoyl)phenyl)acetic acid (intermediate-3c) (40 mg, 0.17 mmol) was dissolved in 2 N NaOH solution (1 ml), and acryloyl chloride (0.05 ml, 0.4 mmol, 2.5 eq.) was added. After stirring for 3 hours, the solution was quenched by adding 1 N HCl solution. The solution was then extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated. The residue was purified using a dichloromethane / methanol gradient on a Combiflash to give the title product (10 mg, 17% yield) as a white powder. 1 H NMR (400 MHz, methanol–) d 4) δ = 7.75 – 7.60(m, 2H), 7.40 – 7.26 (m, 5H), 7.20 (br d, J = 7.5 Hz, 1H), 6.47 – 6.33 (m,2H), 5.81 – 5.75 (m, 1H), 4.83 – 4.69 (m, 2H), 4.45 (br s, 1H), 3.72 (br s,2H), 3.01 (s, 1H), 2.83 (s, 2H), 1.94 (s, 1H). LCMS EI-MS m / z: = 353.1[M+H] + .

[0669] Example 38

[0670] Synthesis of methyl 4-(benzyl(methyl)carbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate (compound 1035):

[0671] Synthesis of methyl 2-(4-(benzyl(methyl)carbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)acetate (intermediate-3d): A solution of methyl 2-(2-(benzyl(methyl)carbamoyl)-5-bromophenyl)acetate (intermediate-3b) (140 mg, 0.37 mmol), (2-(trifluoromethyl)phenyl)boronic acid (78 mg, 0.41 mmol, 1.1 eq.) and sodium carbonate (79 mg, 0.75 mmol, 2.0 eq.) in 1,4-dioxane (2 ml) and water (2 ml) was degassed with nitrogen. 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride dichloromethane complex (15 mg, 0.02 mmol, 0.05 eq.) was added, and the solution was degassed with nitrogen, followed by heating to 80 °C for the next 16 hours. After cooling, the solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified using a dichloromethane / methanol gradient on a Combiflash to give the title product (56 mg, 33% yield). LCMS EI-MS m / z: = 442.1 [M+H] + .

[0672]

[0673] Synthesis of 2-(4-(benzyl(methyl)carbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)acetic acid (compound 1035): A solution of methyl 4-(benzyl(methyl)carbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate (56 mg, 0.013 mmol) and lithium hydroxide (12 mg, 0.51 mmol, 4.0 eq.) in THF (2 mL) and water (2 mL) was heated to 50 °C for 2 hours. After cooling, the solution was acidified with aqueous HCl and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and then concentrated. The residue was purified using a dichloromethane / methanol gradient on a Combiflash to give the title product (28 mg, 56% yield) as a white powder. LCMS EI-MS m / z: =428.1 [M+H] + .

[0674] Example 39

[0675] Synthesis of 2-(5-acrylamido-2-(dibenzylcarbamoyl)phenyl)acetic acid (compound 1036):

[0676] Following the procedure described in steps 7-9 of the synthesis of compound 1034, 2-(5-acrylamido-2-(dibenzylcarbamoyl)phenyl)acetic acid (compound 1036) was synthesized from 4-bromo-2-(2-ethoxy-2-oxoethyl)benzoic acid (1.7 g, 5.8 mmol) and dibenzylamine (1.1 g, 5.4 mmol) to give the title product (6 mg, 11% yield) as a white powder. 1 H NMR (400 MHz, methanol–) d 4) δ = 7.69 – 7.65 (m, 1H), 7.64 – 7.59 (m, 1H), 7.38 –7.27 (m, 9H), 7.16 (br d, J = 7.4 Hz, 2H), 6.42 – 6.35 (m, 2H), 5.87 – 5.67 (m, 1H), 4.49 – 4.27 (m, 2H). LCMS EI-MS m / z: = 429.2[M+H] + .

[0677] Example 40

[0678] Synthesis of 2-(4-(dibenzylcarbamoyl)-2'-formyl-[1,1'-biphenyl]-3-yl)acetic acid (compound 1037):

[0679] Following the procedure described for the synthesis of compound 1035, 2-(4-(dibenzylcarbamoyl)-2'-formyl-[1,1'-biphenyl]-3-yl)acetic acid (compound 1037) was synthesized from intermediate -3a and dibenzylamine in step 7, and then from 4-formylphenylboronic acid in step 10, to give the title product (5 mg, 5% yield) as a white powder. 1 H NMR (400 MHz, methanol–) d 4) δ = 9.92 (d, J = 6.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.70 (t, J =7.5 Hz, 2H), 7.57 – 7.44 (m, 5H), 7.42 – 7.27 (m, 12H), 7.18 (br d, J= 7.3Hz, 3H), 4.42 (br s, 2H), 3.78 (br s, 2H). LCMS EI-MS m / z: = 464.1[M+H] + .

[0680] Example 41

[0681] Synthesis of 2-(4-(methylcarbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)acetic acid (compound 1038):

[0682] Following the procedure described for the synthesis of compound 1035, 2-(4-(methylcarbamoyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)acetic acid (compound 1038) was synthesized from intermediate-3a and methylamine in step 7, and then from 2-trifluoromethylphenylboronic acid in step 10, to give the title product (6 mg, 9% yield) as a white powder. 1 H NMR (400 M...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: Formula (I) In equation (I): A is selected from , , , , , and ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a 、 -S(O) t OR a 、 -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; t is 1 or 2; The condition is that the compound of formula (I) is not a compound of any of formulas 1001, 1003, 1004, and 1006-1009: 。 2. The compound of claim 1, wherein R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, optionally halogenated, unsubstituted or substituted alkyl and / or unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, halogenated, -C(O)R a -C(O)N(R) a )2、-N(R a )2、-N(R a )C(O)R a and -S(O) t R a .

3. The compound of claim 1 or 2, wherein L is a bond or comprises one or more linking groups, said linking group being selected from unsubstituted or substituted -C1- 10 Alkyl-, -O-C1- 10 Alkyl-, -C1- 10 alkenyl-, -O-C1- 10 alkenyl-, -C1- 10 cycloalkenyl-, -O-C1- 10 cycloalkenyl-, -C1- 10 alkynyl-, -O-C1- 10 alkynyl-, -C1- 10 Aryl-, -O-Cl- 10 -, -aryl-, -cycloalkyl-, -heterocyclic-, -O-, -S-, -SS-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -N(R b )-、-C(O)N(R b )-、-N(R b )C(O)-、-OC(O)N(R b )-、-N(R b )C(O)O-、-SC(O)N(R b )-、-N(R b )C(O)S-、-N(R b )C(O)N(R b )-、-N(R b )C(NR b )N(R b )-、-N(R b S(O) w -、-S(O) w N(R b )-、-S(O) w O-、-OS(O) w -、-OS(O) w O-、-O(O)P(OR b )O-、(O)P(O-)3、-O(S)P(OR b )O- and (S)P(O-)3, where w is 1 or 2, and R b Independently, it is hydrogen, optionally substituted alkyl, or optionally substituted aryl; optionally, L is a bond and / or -C(O)- and / or -C(H)(CH2). p C(O)NH2 and / or Where p is an integer from 1 to 5, and optionally p is 2; optionally L is... The alkyl group is either substituted or unsubstituted. or .

4. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (10): Equation (10) In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

5. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (20) or (21): In equations (20) and (21): n3 is an integer from 0 to 5.

6. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (30) or (31): In equations (30) and (31): p is an integer from 0 to 5.

7. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (32): Equation (32) In equation (32): q is an integer from 1 to 3.

8. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (40): Equation (40) In equation (40): n4 is an integer from 0 to 5.

9. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (50): Equation (50) In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

10. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (60): Equation (60) In equation (60): n6 is an integer between 0 and 5.

11. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (70): Equation (70) In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

12. The compound of claim 11, wherein the compound of formula (70) is a compound of formula (700) or (701): Equation (700) Equation (701).

13. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (80) or formula (81): Equation (80) In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5; Equation (81) In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

14. The compound of claim 13, wherein the compound of formula (80) is a compound of formula (800) or formula (801), or the compound of formula (81) is a compound of formula (802) or formula (803): Equation (800) Equation (801) Equation (802) Equation (803).

15. The compound according to any one of claims 11-14, wherein R 5b and / or R 5c Each group is independently selected from unsubstituted or substituted alkynyl groups, optionally substituted alkynyl groups, substituted aryl groups, substituted heteroaryl groups, halogenated groups, optionally Br, -N(R) groups. a 2. Optional -NH2 and -N(R) a )C(O)R a Optional , , or Optional of R 5b Selected from , , , , , , , , , , , , , , and Optional of R 5c Selected from , , , , , , , , , and .

16. The compound according to any one of claims 11-15, wherein R 11a and R 11b Each is an unsubstituted alkyl group, or R 11a and R 11b Each independently is , or R 11a Selected from H and unsubstituted alkyl groups and R 11b yes , or R 11a It is H and R 11b Y is an unsubstituted alkyl group, wherein Y is selected from unsubstituted or substituted alkyl groups, optionally unsubstituted or substituted C1-C5 alkyl groups, unsubstituted or substituted aryl groups, optionally unsubstituted or substituted phenyl groups, unsubstituted or substituted cycloalkyl groups, optionally unsubstituted or substituted C3-C7 cycloalkyl groups, and unsubstituted or substituted alkoxy groups, optionally unsubstituted or substituted C1-C5 alkoxy groups; and n7 is an integer from 1 to 3, optionally n7 is 1 or 2, optionally wherein R 11a and R 11b Each independently selected , , , , , , , , , , and Optional of R 11a and R 11b Each independently selected , , , , , , , , and .

17. The compound of claim 16, wherein R 11a Selected from H and -CH3 and R 11b Selected from , , , , , , , , , , , and Optional of R 11a Selected from H and -CH3 and R 11b Selected from , , and Optional of R 11a Selected from H and -CH3 and R 11b Selected from , , , and Optional of R 11a It is H and R 11b It is -CH3 or R in it. 11a and R 11b Each is -CH3.

18. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (82): Equation (82) In equation (82): R 11a R 11b 、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.

19. The compound of claim 18, wherein the compound of formula (82) is a compound of formula (804) or (805): Equation (804) Equation (805).

20. The compound according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (90): Equation (90) In equation (90): n is an integer from 1 to 5.

21. The compound of claim 20, wherein the compound of formula (90) is a compound of formula (900), formula (901), or formula (902): Formula (900) Formula (901) Formula (902).

22. The compound of claim 20 or 21, wherein R 11a It is H or a substituted alkyl group, optional. Optional .

23. The compound according to any one of claims 20-22, wherein R 10 It is -C(O)R a Optional of R a Selected from unsubstituted alkenyl, substituted alkyl, substituted aryl, and substituted heterocyclic groups, or R 10 It is -S(O) t R a Optionally, where t is 2 and R a It is a substituted aryl group, wherein R is optionally substituted. 10 Selected from: , , , , , , , , , and .

24. The compound according to any one of claims 1-3 or 11-23, wherein the compound of formula (I) is a compound of any one of formulas 1002, 1005, 1010-1098, or a pharmaceutically acceptable salt thereof: 。 25. The compound according to any one of claims 1-3 or 11-24, wherein the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof: 。 26. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient: Formula (I) In equation (I): A is selected from , , , , , , ; L is a linking group; R 1a R 1b R 2 R 3 R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 6a R 6b R 6c R 6d R 6e R 7a R 7b R 7c R 7d R 8 R 9 、 R 10 R 11a R 11b and R 11c Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a 、 -S(O) t R a 、 -S(O) t OR a 、 -S(O) t N(R a )2 and PO3(R a )2; R 12 It is H or an unsubstituted alkyl group; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n1 is an integer from 0 to 5; and t is 1 or 2.

27. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (10): Equation (10) In equation (10): R 9a R 9b R 9c R 9d and R 9e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n2 is an integer from 0 to 5; and t is 1 or 2.

28. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (20) or (21): In equations (20) and (21): n3 is an integer from 0 to 5.

29. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (30) or (31): In equations (30) and (31): p is an integer from 0 to 5.

30. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (32): Equation (32) In equation (32): q is an integer from 1 to 3.

31. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (40): Equation (40) In equation (40): n4 is an integer from 0 to 5.

32. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (50): Equation (50) In equation (50): R 10a R 10b R 10c R 10d and R 10e Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heteroarylalkyl. n5 is an integer from 0 to 5; and t is 1 or 2.

33. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (60): Equation (60) In equation (60): n6 is an integer between 0 and 5.

34. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (70): Equation (70) In equation (70): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; optionally, the compound of formula (70) is a compound of formula (700) or (701): Equation (700) Equation (701).

35. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (80) or formula (81): Equation (80) In equation (80): R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic alkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and n8 is an integer from 1 to 5; Equation (81) In equation (81): Alk is a substituted or unsubstituted alkyl group; R 11a and R 11b Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; optionally, said compound of formula (80) is a compound of formula (800) or formula (801), or said compound of formula (81) is a compound of formula (802) or formula (803): Equation (800) Equation (801) Equation (802) Equation (803).

36. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (82): Equation (82) In equation (82): R 11a R 11b 、 R 11c and R 11d Each of the following is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -OC(O)-R a -SC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)SR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a -S(O) t R a -S(O) t OR a -S(O) t N(R a )2 and PO3(R a )2; and R a Each time it appears, it is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted heterocyclic, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; optionally, the compound of formula (82) is a compound of formula (804) or (805): Equation (804) Equation (805).

37. The pharmaceutical composition of claim 26, wherein the compound of formula (I) is a compound of formula (90): Equation (90) In equation (90): n is an integer from 1 to 5, and optionally the compound of formula (90) is a compound of formula (900), formula (901), or formula (902): Formula (900) Formula (901) Formula (902).

38. The pharmaceutical composition of any one of claims 26 or 34-37, wherein the compound of formula (I) is a compound of any one of formulas 1001-1098, or a pharmaceutically acceptable salt thereof: 。 39. The pharmaceutical composition of any one of claims 26 or 34-38, wherein the compound of formula (I) is a compound of any one of formulas 1010, 1011, 1020-1030, 1034, 1036, 1037, 1040, 1043, 1050, 1053-1056, 1058, 1060, 1062, 1064, 1066, 1069, 1070, 1075, 1084, or a pharmaceutically acceptable salt thereof: 。 40. A method for treating a subject in need of cancer, an infectious disease, or an inflammatory disease, the method comprising administering to the subject the pharmaceutical composition of any one of claims 26-39, optionally wherein the cancer is resistant to an anti-checkpoint agent, optionally wherein the anti-checkpoint agent is an antibody, optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA antibodies.

41. The method of claim 40, wherein the cancer is selected from basal cell carcinoma; biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancers); glioblastoma; Liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney cancer or renal cell carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancers; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancers; vulvar cancer; lymphoma, including Hodgkin's and non-Hodgkin's lymphomas, and B-cell lymphomas (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) lymphomas. NHL; Intermediate / follicular NHL; Intermediate diffuse NHL; Advanced immunoblastic NHL; Advanced lymphoblastic NHL; Advanced small non-lytic cell NHL; Massive disease NHL; Mantle cell lymphoma; AIDS-related lymphoma; And Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and other cancers and sarcomas; and post-transplant lymphoproliferative disorders (PTLD), as well as abnormal angiogenesis, edema (such as edema associated with brain tumors) and Megs syndrome associated with scarring nevi.

42. The method of claim 40 or 41, wherein the cancer is a blood cancer selected from the group consisting of: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia, and preleukemia, or combinations thereof.

43. The method of claim 40, wherein the infectious disease is a viral infection, optionally wherein the viral infection is caused by a virus selected from: human papillomavirus, herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis virus, Zika virus, yellow fever virus, West Nile virus, dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, hepatitis C virus, poliovirus, rhinovirus, enterovirus, Coxsackie virus, influenza virus, lentivirus, respiratory syncytial virus, human parainfluenza virus, lubra virus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2).

44. The method of claim 40, wherein the inflammatory disease is an autoimmune disease or disorder selected from multiple sclerosis, diabetes, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpassuia syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholecystitis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allogeneic transplant rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Wright's syndrome, Graves' disease, and other autoimmune diseases.

45. A method for treating a subject with checkpoint-resistant cancer, the method comprising administering to the subject any of claims 26-39 a pharmaceutical composition.

46. ​​A method for determining cancer treatment for a patient, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; as well as (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then a cancer therapy comprising the pharmaceutical composition of any one of claims 26-39 is selected; and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

47. A method for selecting patients for cancer treatment, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; as well as (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then a cancer therapy comprising the pharmaceutical composition of any one of claims 26-39 is selected; and (d) Optionally, a second cancer therapy comprising an anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

48. A method for treating cancer, the method comprising: (a) Obtaining biological samples from subjects; (b) Assess the expression of Trim7 in the biological samples; as well as (c) If Trim7 is upregulated compared to healthy tissue, a previous biological sample obtained from the subject, or another biological sample from a patient known to be sensitive to checkpoint agents, then administer a cancer therapy comprising the pharmaceutical composition of any one of claims 26-39; and (d) Optionally administer a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA agents, wherein the anti-checkpoint agent is optionally selected from anti-PD-1, anti-PD-L1, anti-PD-L2 and / or anti-CTLA antibodies.

49. The method of any one of claims 46-48, wherein the biological sample is a fresh tissue sample, a frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

50. The method of any one of claims 46-48, wherein the biological sample is a biopsy sample, optionally wherein the biopsy sample is selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy, and colonoscopy), puncture biopsy (e.g., fine-needle aspiration biopsy, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computed tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy, and ultrasound-assisted biopsy), skin biopsy (e.g., scraping biopsy, puncture biopsy, and incision biopsy), and surgical biopsy, optionally wherein the biological sample includes selected... The biological sample may be derived from the following bodily fluids: blood, plasma, serum, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing bodily fluids, free nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological secretions, skin swabs, vaginal swabs, oral swabs, nasal swabs, irrigation or lavage fluids such as catheter lavage or bronchoalveolar lavage fluid, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other bodily fluids, secretions and / or excretions, and / or cells extracted therefrom, optionally including at least one tumor cell.

51. The method of any one of claims 46-50, wherein the evaluation is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, Western blotting, intracellular Western blotting, immunofluorescence staining, ELISA, and fluorescence activated cell sorting (FACS) or a combination thereof; or the evaluation is performed by contacting the sample with an agent that specifically binds to Trim7, optionally wherein the agent that specifically binds to one or more proteins comprises an antibody, an antibody-like molecule, or a binding fragment thereof; or the evaluation is performed by contacting the sample with one or more of the nucleic acids that specifically bind to Trim7, optionally wherein the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

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