Trim7 inhibitors and uses thereof

Abstract

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

Description

[0001] TRIM7 INHIBITORS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 520,547, filed on August 18, 2023, U.S. Provisional Patent Application No. 63 / 561,068, filed on March 4, 2024, and U.S.

[0004] Provisional Patent Application No. 63 / 631 ,135, filed on April 8, 2024, the contents of all of which are hereby incorporated by reference in their entireties.

[0005] FIELD OF THE DISCLOSURE

[0006] The present disclosure relates to, inter alia, compositions and methods, including compounds including Trim? inhibitors that find use in the treatment of disease, such as therapies for cancer, including cancers that are resistant to anti-checkpoint agents, infectious diseases and inflammatory diseases.

[0007] SEQUENCE LISTING

[0008] The instant application contains a sequence listing, which has been submitted in XML format via EFS-Web. The contents of the XML copy named “SHK-083PC_116981-5083-WO_Sequence_Listing”, which was created on August 15, 2024, and is 4,096 bytes in size, the contents of which are incorporated herein by reference in their entirety.

[0009] BACKGROUND

[0010] Drug resistance remains one of the biggest challenges in cancer therapy. Drug resistance is found across all types of cancer and all modes of treatment, including molecularly targeted therapy, immunotherapy, and chemotherapy. In some patients, initiation of efficacious therapy is delayed by the inability to predict responses. Moreover, it is also common that a patient with advanced cancer receives a drug that helps shrink their tumors, but then the cancer develops resistance to the drug. Unfortunately, few effective therapeutic options are available for some patients having cancers that are resistant to the anti-checkpoint therapies. Therefore, methods for developing new therapies for patients suffering from drug resistant cancer are required for improving outcomes in cancer patients.

[0011] SUMMARY

[0012] Accordingly, the present disclosure provides, in part, compositions and methods for treating cancer, including, without limitations, cancers that are resistant to anti-checkpoint agents. Also provided are methods for treating infectious diseases and infectious diseases and inflammatory diseases. Also provided are methods for selecting patients for cancer treatment, and methods for cancer treatment, based on, for instance, based on gene expression profiles of Trim7, which is dysregulated in anti-checkpoint resistant cancers. In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring; with the proviso that the compound of formula (I) is not a compound of any one of formulas 1001, 1003-1006, 1008, 1009, 1011, 1012, and 1014: In embodiments, the compound is a compound of formula (I) wherein Z is -NR3-. In embodiments, the compound is a compound of formula (I) wherein Z is –(CR3)2-. In embodiments, the compound is a compound of formula (I) wherein R10is -OH. In embodiments, the compound is a compound of formula (I) wherein R10is . In embodiments, the compound is a compound of formula (I) wherein Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2-, is selected from -CH2-, -C(Me)2-, , wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen. In embodiments, the compound is a compound of formula (I) wherein X is a bond. In embodiments, the compound is a compound of formula (I) wherein X is -CR1b-. In embodiments, the compound is a compound of formula (I) wherein R2is selected from H, -OH,-CH3, In embodiments, the compound is a compound of formula (I) wherein R2is absent and Y is -CRA-. In embodiments, the compound is a compound of formula (I) wherein R2is absent, Y is -CRA-, and RAis -CH3. In embodiments, the compound is a compound of formula (I) wherein R3is selected from H, , wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”, at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1, optionally A is selected from and n2is 1. In embodiments, the compound is a compound of formula (I) wherein each occurrence of R5’and R5”is H. In embodiments, the compound is a compound of formula (I) wherein n2is 1, R5’is H, and R5”is unsubstituted alkyl. In embodiments, the compound is a compound of formula (I) wherein R5”is -CH3. In embodiments, the compound is a compound of formula (I) wherein A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selected from In embodiments, the compound is a compound of formula (I) wherein is selected / 150159006.2 from H, . In embodiments, the compound is a compound of formula (I) wherein A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -OH, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I, optionally wherein A is wherein R8aand R8bare selected from H, alkyl, alkoxy, -OH, -CX3, and halogen, optionally R8aand R8bare selected from H, -CH3, -CF3, -OCH3, -OH, F, and Cl. In embodiments, the compound is a compound of formula (I) wherein A is selected from optionally wherein A is In embodi3 ments, the compound is a compound of formula (I) wherein R is selected from optionally wherein R3is selected from In some embodiments, the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof: In some embodiments, the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof:

[0013] wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the compound of formula (14) is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof: In some embodiments, the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof: In some embodiments, the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof: wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof: In some embodiments, the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof: wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, - S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof:

[0014] In some embodiments, the compound is a compound of any one of formula (14), (17)-(20), or (100)-(121) wherein R4bis selected from optionally wherein R4bis selected from In some embodiments, the compound is a compound of any one of formula (14), (17)-(20), or (100)-(121) wherein R4dis selected from H, wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1. In some embodiments, the compound of formula (I) is a compound of any one of formula 1002, 1007, 1010, 1013, 1015-1150, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient: wherein in formula (I):X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) wherein the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof: In some embodiments, the pharmaceutical composition comprises a compound of formula (I) which is a compound of formula (14), or a pharmaceutically acceptable salt thereof: wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the pharmaceutical composition comprises a compound of formula (14) which is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof:

[0015] In some embodiments, the pharmaceutical composition comprises a compound of formula (14) which is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the pharmaceutical composition comprises a compound of formula (17) which is a compound of formula (115) or a pharmaceutically acceptable salt thereof: In some embodiments, the pharmaceutical composition comprises a compound of formula (I) which is a compound of formula (18), or a pharmaceutically acceptable salt thereof: wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the pharmaceutical composition comprises a compound of formula (18) which is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof: In some embodiments, the pharmaceutical composition comprises a compound of formula (I) which is a compound of formula (20), or a pharmaceutically acceptable salt thereof:

[0016] wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In some embodiments, the pharmaceutical composition comprises a compound of formula (17) which is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof:

[0017] In some embodiments, the pharmaceutical composition comprises a compound of any one of formula (14), (17)-(20), or (100)-(121) wherein R4dis selected from H, and wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) which is a compound of any one of formula 1001-1150, 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 formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149 or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method for treating a cancer, an infectious disease, an inflammatory disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition comprising a compound of any one of formula (I), (10)-(23), or (100)-(121). In some embodiments, the cancer is resistant to an anti-checkpoint agent. In some embodiments, the anti- checkpoint agent is an antibody. In some embodiments, the antibody is selected from an anti-PD-1, anti-PD- L1, anti-PD-L2, and anti-CTLA antibody. In some embodiments, the cancer is selected from a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin’s and non-Hodgkin’s lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin’s lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom’s Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs’ syndrome. In some embodiments, the cancer is a hematologic cancer selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia, or a combination thereof. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is caused by a virus selected from papilloma virus, 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, a 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 embodiments, the inflammatory disease is an autoimmune disease or condition, selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture’s syndrome, Wegener’s granulomatosis, autoimmune epilepsy, Rasmussen’s encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addisohn’s disease, Hashimoto’s thyroiditis, Fibromyalgia, Menier’s syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren’s syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter’s syndrome, Grave’s disease, and other autoimmune disease. In another aspect, the present disclosure provides a method for treating an anti-checkpoint agent-resistant cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition comprising a compound of any one of formula (I), (10)-(23), or (100)-(121). In another aspect, the present disclosure provides a method of determining a cancer treatment for a patient, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition comprising a compound of any one of formula (I), (10)-(23), or (100)-(121) if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. In another aspect, the present disclosure provides a method for selecting a patient for a cancer treatment, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition comprising a compound of any one of formula (I), (10)-(23), or (100)-(121) if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. In another aspect, the present disclosure provides a method of treating cancer, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) administering the cancer therapy comprising the pharmaceutical comprising a compound of any one of formula (I), (10)-(23), or (100)-(121) if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally administering a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. In some embodiments, the biological sample used in the above methods is a fresh tissue sample, 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 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), needle biopsy (e.g., fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound-assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy. In some embodiments, the biological sample used in the above methods comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell- containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom. In some embodiments, the biological sample used in the above methods comprises at least one tumor cell. In some embodiments, the evaluating in the above methods is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof. In some embodiments, the evaluating in the above methods is performed by contacting the sample with an agent that specifically binds to Trim7. In some embodiments, the agent that specifically binds to one or proteins comprises an antibody, antibody-like molecule or binding a fragment thereof. In some embodiments, the evaluating in the above methods is performed by contacting the sample with an agent that specifically binds to one or more of nucleic acids of Trim7. In some embodiments, the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe. Any aspect or embodiment disclosed herein can be combined with any other aspect or embodiment as disclosed herein. BRIEF DESCRIPTION OF THE FIGURES The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1A and FIG.1B show the binding of recombinant human (rh) Trim7 to RACO1 and MSK1 in vitro as measured using a Meso Scale Discovery (MSD) platform-based assay. FIG.1A shows the binding to human Trim7 by RACO1 in comparison with CD47, which was used as a negative control. FIG.1B shows the binding to human Trim7 by MSK1 in comparison with CD47, which was used as a negative control. FIG.2 shows the binding of recombinant human (rh) Trim7 to enterovirus 712B or enterovirus 712BC proteins in vitro as measured using a Meso Scale Discovery (MSD) platform-based assay. Recombinant human RACO1 and MSK1 proteins were used as positive controls and recombinant human CD47 protein was used as a negative control. FIG.3A and FIG.3B show that the enterovirus 712BC protein inhibits the binding of recombinant human (rh) Trim7 to MSK1 (FIG.3A) and RACO1 (FIG.3B) in vitro as measured using a Meso Scale Discovery (MSD) platform-based assay. FIG.4 shows the crystal structure of Trim7 bound to the CVB_2C (319-329) peptide (SVGTTLEALFQ), which is the C-terminal fragment of the Coxsackievirus B3 (CVB3)_2C protein. Left top panel shows a schematic representation of the CVB3 C2 protein, showing the location of the CVB_2C (319-329) peptide. Left bottom panel shows crystal structure of CVB_2C protein, showing the CVB_2C (319-329) peptide, and a crystal structure of the Trim7 protein complexed with the CVB_2C (319-329) peptide. Right panel shows the interactions of the CVB_2C (319-329) peptide with various amino acids of Trim7 protein. FIG.5 shows a schematic representation of the molecular simulation-based method used for identification of Trim7 inhibitors, including compound of formula 1. FIG.6A and FIG.6B show various docked compounds. The underlined compounds have a docking score better than -7, indicative of likely affinity constant of <100nM. FIG.7 shows representative compounds along with their docking scores. FIG.8A and FIG.8B show docking of compound 1009. FIG.8A shows compound 1009 in the context of space filling model of Trim7 in the background. FIG.8B shows the binding of compound 1009 to Trim7. FIG.9A and FIG.9B show docking of compound 1014. FIG.9A shows compound 1014 in the context of space filling model of Trim7 in the background. FIG.9B shows the binding of compound 1014 to Trim7. FIG.10A, FIG.10B, and FIG.10C show the elucidation of the Trim7 crystal structure that that partially informed the Trim7 SMIs of the present disclosure. FIG.11 provides data confirming TRIM7 interactions with RACO-1, STING, MAVS, and CVB3_2C (WT but not mutant). FIG.12 is a scheme showing an exemplary workflow for screening and prioritizing candidates. FIG.13 depicts the screening of the certain lead SMI candidates. Binding affinity of certain lead SMI candidates to immobilized TRIM7 protein was assessed using binding affinity (using biolayer interferometry, BLI). FIG. 14A and FIG. 14B depict data from cell-based activity assays demonstrating that TRIM7 over- expression in cells along with over-expression of certain targets, results in that target’s degradation / stabilization. FIG.14A demonstrates that the over expression of TRIM7 (+T7) in 293T cell lines with either CVB3, MAVS, or STING; results in their degradation. FIG.14B is an assay showing that TRIM7 over- expression combined with RACO-1 over-expression in a cell line, results in RACO-1 stabilization, and the addition of compound 1034 blocks TRIM7 stabilization of RACO1, resulting in its degradation. FIGS.15A-15C are activity assays demonstrating that TRIM7 expression in cell-based and cell-free assays results in target degradation / stabilization. FIG.15A is a cell-based assay in HEK293 cells demonstrating that the over expression of TRIM7 (+) with either CVB3, MAVS, or STING results in their degradation. FIG.15B is a cell-free target ubiquitination assay demonstrating that the presence of a TRIM7 SMI (compound 1036) disrupts target degradation / stabilization. FIG.15C demonstrates that RACO-1 over-expressed on its own, resulting in self-ubiquitination and degradation. When TRIM7 is co-expressed with RACO1, RACO1 is stabilized. TRIM7 SMIs, such as compound 1036, have varying activities in blocking TRIM7 stabilization of RACO1, resulting in its degradation. FIG.16 is a cell-free activity assay studying TRIM7 mediated target ubiquitination of CVB3. Compound 1034 blocks TRIM7 ubiquitination of CVB3 resulting in lower ubiquitination signal within a gel. FIG.17 provides data with compound 1036 demonstrating that TRIM7 SMI inhibition in a CT26 ICB-Acquired Resistance (AR) cell line reduces the number of viable tumor cells. FIGS.18A-18C demonstrate that CT26 ICB-acquired resistance (AR) tumor cells are sensitive to TRIM7. inhibition, wherein TRIM7 inhibition in CT26 / AR tumor cells returns the transcriptional profile of AR- dysregulated genes back towards WT CT26. FIG.18A is a heat map depicting 1,181 genes that are compensated (return toward WT) following TRIM7 inhibition with a TRIM7 SMI (compound 1036). FIG.18B is a heat map depicting that many of the compensated genes following inhibition with compound 1036 are associated with TRIM7 pathways (e.g., Ras, MAVS, STING, and Raco1 / AP1). FIG.18C provides some example genes in these TRIM7 pathways that demonstrate a return toward WT expression following TRIM7 inhibition with compound 1036. FIG.19 demonstrates that ICB acquired resistance induces transcriptional hyperactivation of genes associated with IFN alpha / gamma responsiveness, NFKB and JAK / STAT signaling. The inhibition of TRIM7 with a TRIM7 SMI, such as compound 1036, dampens the expression of these associated pathways. FIG.20A, FIG.20B, FIG.20C, FIG.20D, and FIG.20E provide data demonstrating that the inhibition of TRIM7 results in KRAS mutant tumor cell death and this activity increases in combination with KRAS inhibition and the anti-PD1 antibody Keytruda. In FIG.20B, the bars of the left bar graph indicate (from left to right) Vehicle (DMSO), BI2865, TRIM7 siRNA, and Combination; the bars of the right bar graph indicate (from left to right) Vehicle (DMSO) + T cells, BI2865 + T cells, TRIM7 siRNA + T cells, and Combination + T cells. In FIG.20C, the bars of the left bar graph indicate (from left to right) Vehicle (DMSO), BI2865, compound 1036, and Combination. In FIG.20D, the bars of the bar graph indicate (from left to right) Vehicle (DMSO), MRTX1133, compound 1036, and Combination. In FIG.20E, the bars of the bar graph indicate (from left to right) A549 + T cells, +Keytruda, +compound 1036, and +compound 1036 + Keytruda. FIG.21 demonstrates that CT26 / AR cells are sensitive to both TRIM7 and KRAS inhibition and their combination (for example, using compound 1036 as a TRIM7 SMI (TRIM7i-1 and TRIM7i in FIG.21)) results in further proliferative inhibition. Although not wishing to be limited by theory, TRIM7 inhibition may obviate the need to inhibit up-stream KRAS signaling and / or result in additive anti-proliferative activity in combination with existing KRAS pathway inhibitors. FIGS.22A-22B demonstrate that TRIM7 inhibition prevents proliferation of human KRAS mutant tumors and this activity is enhanced in the presence of KRAS inhibition. FIG.22A demonstrates that TRIM7 inhibition using TRIM7 SMI compound 1036 in GP2D colorectal carcinoma cells reverses the expression of genes in the Ras, MAVS, STING, and Raco-1 / AP1 pathways, consistent with the results from CT26 / AR treatment with compound 1036 as a TRIM7 inhibitor. In FIG.22A, the bars of the bar graph indicate (from left to right) Vehicle (DMSO), MRTX1133, TRIM7i-1, and Combination. FIG.22B demonstrates that TRIM7 inhibition using TRIM7 SMI compound 1036 in A549 lung cancer cells reverses the expression of genes in the Ras, MAVS, STING, and Raco-1 / AP1 pathways, consistent with the results from CT26 / AR treatment with compound 1036 as a TRIM7 inhibitor. In FIG.22B, the bars of the bar graph indicate (from left to right) Vehicle (DMSO), BI2865, TRIM7i-1, and Combination. FIGS.23A-23C are in vivo studies in mice demonstrating that TRIM7 inhibition with a TRIM7 SMI, such as compound 1036, controls the growth of CT26 / AR tumors and re-sensitizes them to PD1 blockade through normalization of tumor-intrinsic transcriptional regulation and increased effector T cell infiltration. FIG.23A demonstrates the anti-tumor efficacy of TRIM7 SMI compound 1036 in a mouse CT26 / AR model. FIG 23B is a TIL analysis by flow cytometry. In FIG.23B, the bars of the bar graphs indicate (from left to right) Vehicle, anti-PD1, TRIM7 SMI, and Combination. FIG.23C is a transcriptional analysis of isolated tumors treated with vehicle or TRIM7 SMI compound 1036. DETAILED DESCRIPTION Disclosed herein are Trim7 inhibitors that are useful, inter alia, for the treatment of disease, such as therapies for cancer, including cancers that are resistant to anti-checkpoint agents, infectious diseases and autoimmunity. Drug resistance, either existing before treatment (intrinsic or primary resistance) or developed after therapy (acquired resistance), is responsible for many relapses of cancer, one of the major causes of death. Therefore, better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment. It was reported that anti-PD-1 resistant tumors exhibit a paradoxical dysregulation of some IFNγ-induced genes, with Trim7 being a driver gene involved in the paradoxical dysregulation, and anti-PD-1 resistance. See International Application No. PCT / US2021 / 061834, which is incorporated herein by reference in its entirety. Accordingly, disclosed herein are Trim7 inhibitors that are useful, inter alia, for the treatment of cancers that are resistant to anti-checkpoint agents. Since Trim7 is involved in diverse processes such as tumor growth, innate immunity and pathogenesis of viral infection, the Trim7 inhibitors disclosed herein find use in the treatment of cancer, infectious diseases and autoimmunity. Trim7 Tripartite motif (TRIM) proteins are a group of E3 ubiquitin ligases that are involved in different cellular functions. Many TRIM proteins are induced by type I and type II interferons (IFN-I or IFN-II) or pathogen stimulations, 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 in response to interferons. PLoS One 2009;4(3):e4894. The consensus 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, which confers substrate specificity via protein-protein interactions. The C-terminal domains include PRY and / or SPRY domains (B30.2). Tripartite Motif Containing 7 (Trim7) is known to have roles in tumor cell proliferation, glycogen metabolism, innate immunity (e.g., via IFN induction), virus pathogenesis. Giraldo et al., Envelope protein ubiquitination drives entry and pathogenesis of Zika virus. Nature 2020.10.1038 / s41586-020-2457-8; Montori-Grau et al., GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle. Metabolism. 2018;83:177–187; Lu et al., E3 ubiquitin ligase tripartite motif 7 positively regulates the TLR4-mediated immune response via its E3 ligase domain in macrophages. Mol Immunol. 2019;109:126-133. Without 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 K63-linked polyubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Chakraborty et al., The E3 ubiquitin ligase Trim7 mediates c-Jun / AP-1 activation by Ras signalling. Nat Commun. 2015;6:6782. Trim7 has also been described to negatively regulate responses to DNA viruses by targeting STING for degradation. Yang et al., RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation. PLoS Pathog.2020;16(3):e1008387. Trim7 was identified as one of the genes that was identified as dysregulated in model of acquired resistance for an anti-PD-1 antibody. See International Application No. PCT / US2021 / 061834, which is incorporated herein by reference in its entirety. Trim7 Inhibitors As used herein, the term “alkyl” denotes branched or unbranched hydrocarbon chains, having about 1 to 10 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, 2-methylpentyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl pentyl, octyl, 2,2,4-trimethylpentyl, and the like. “Substituted alkyl” includes an alkyl group unsubstituted or substituted with one or more functional groups which are attached commonly to such chains, such as, hydroxy, halogen, mercapto or thio, cyano, alkylthio, carboxy, nitro, alkoxy, or unsubstituted or substituted, alkyl, amino, alkenyl, carboxamido, carbalkoxy, alkynyl, heterocyclyl, aryl, heteroaryl, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl, phenethyl, benzyl, and the like. The term “halogen” or “halo” as used herein alone or as part of another group refers to chloro, bromo, fluoro, or iodo. The term “alkoxy” refers to alkyl-O-, in which alkyl is as defined above. The term “alkylthio” refers to alkyl-S-, in which alkyl is as defined above. The term “alkylamino” refers to –NR’R”, in which R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein. The term “alkylcarbonyl” refers to –C(=O)-alkyl, in which alkyl is as defined above. The term “carboxy” refers to the moiety –C(=O)OH. The term “carbalkoxy” refers to the moiety –C(=O)-O-alkyl, in which alkyl is as defined above. The term “carboxamido” refers to the moiety –C(=O)-NR’R”, in which R’ and R”, each may independently represent H, alkyl, or aryl, all as defined herein. The term “alkylsulfonyl” refers to the moiety –S(=O)2-alkyl, in which alkyl is as defined above. The term “arylsulfonyl” refers to the moiety –S(=O)2-aryl, in which aryl is as defined herein. For example, arylsulfonyl may be –S(=O)2-phenyl. The term “arylsulfonyloxy” refers to the moiety –OS(=O)2-alkyl, wherein alkyl is as defined above. The term “amino(monoalkylamino-, dialkylamino-)sulfinyl” refers to the moiety –S(=O)NR’R”, in which R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein. The term “amino(monoalkylamino-, dialkylamino-)sulfonyl” refers to the moiety –S(=O)2NR’R”, in which R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein. The term “alkylsulfonylamino” refers to the moiety –NHS(=O)2-alkyl, in which alkyl is as previously defined. The term “hydroxysulfonyloxy” refers to the moiety –OS(=O)2OH. The term “alkoxysulfonyloxy” refers to the moiety –OS(=O)2O-alkyl, in which alkyl is as defined above. The term “alkylsulfonyloxy” refers to the moiety –OS(=O)2-alkyl, in which alkyl is as previously defined. The term “hydroxysulfonyl” refers to the moiety –S(=O)2OH. The term “alkoxysulfonyl” refers to the moiety –S(=O)2O-alkyl, wherein alkyl is as previously defined. The term “alkylsulfonylalkyl” refers to the moiety –alkyl-S(=O)2-alkyl, wherein each alkyl may be as previously defined. The term “amino(monoalkylamino-, dialkylamino-)sulfonylakyl” refers to the moiety –alkyl-S(=O)2-NR’R”, wherein alkyl is as previously defined, and R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein. The term “amino(monoalkylamino-, dialkylamino-)sulfinylalkyl” refer to the moieties –alkyl-S(=O)-NR’R”, wherein alkyl is as previously defined, and R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein. Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or more double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl. “Substituted cycloalkyl” includes a cycloalkyl group optionally substituted with 1 or more substituents such as halogen, alkyl, substituted alkyl, alkoxy, hydroxy, aryl, substituted aryl, aryloxy, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or any of the substituents included in the definition of “substituted alkyl.” Unless otherwise indicated, the term “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal 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-tetradecatrienyl, and the like. “Substituted alkenyl” includes an alkenyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.” Unless otherwise indicated, the term “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3- nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like. “Substituted alkynyl” includes an alkynyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.” Unless otherwise indicated, the term “aryl” or “Ar” as employed herein alone or as part of another group refers to monocyclic, bicyclic, and / or polycyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring, such as aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings or substituted forms thereof. “Substituted aryl” includes an aryl group optionally substituted with one or more functional groups, such as halo, alkyl, haloalkyl (e.g., trifluoromethyl), alkoxy, haloalkoxy (e.g., difluoromethoxy), alkenyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are optionally substituted alkyl, aryl or any of the other substituents recited herein), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylaminocarbonyl, arylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, or arylsulfonaminocarbonyl and / or any of the alkyl substituents recited herein. The term “arylalkyl” refers to –alkyl-aryl, in which alkyl and aryl are as defined above. Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- to 7-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring (e.g. benzothiophene, indole, quinoline, thiazole, isooxazole, benzothiazole, benzimidizole, isoquinoline, pyridine, pyrimidine, benzopyrone, oxazole, thiazole, pyrazine), and includes possible N-oxides. “Substituted heteroaryl” includes a heteroaryl group optionally substituted with 1 to 4 substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.” Substituted heteroaryl also includes fused heteroaryl groups which include, for example, quinoline, isoquinoline, indole, isoindole, carbazole, acridine, benzopyrene, benzopyrone, benzimidazole, benzofuran, isobenzofuran, phenanthroline, purine, and the like. Moreover, the terms “heterocyclo,” “heterocycle,” “heterocyclyl,” or “heterocyclic ring,” as used herein, refer to an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, benzothiophene, chromone, benzopyrene, benzopyrone, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, and oxadiazolyl. The term “heteroarylalkyl” refers to –alkyl-heteroaryl, in which alkyl and heteroaryl are as defined above. As used herein, the terms “optionally substituted” or “substituted” may indicate that a chemical moiety referred to, for example, alkyl, aryl, and heteroaryl, may be unsubstituted or substituted with one or more groups including, without limitation, 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, carboxy, nitro, carbalkoxy, substituted carbalkoxy, carboxamido, substituted carboxamido, alkylamino, substituted alkyl amino, monoalkylaminosulfinyl, substituted, monoalkylaminosulfinyl, dialkylaminosulfinyl, substituted dialkylaminosulfinyl, monoalkylaminosulfonyl, substituted monoalkylaminosulfonyl, dialkylaminosulfonyl, substituted dialkylaminosulfonyl, 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, and the like. The chemical moieties of formula (I), formula (10)-(23), formula (100)- (121), formula 1001-1150, or a pharmaceutically acceptable salt thereof, above, that may be optionally substituted include alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, aryl, heterocycle, and heteroaryl, as described herein. For example, optionally substituted alkyl may include both propyl and 2-chloro-propyl. Additionally, “optionally substituted” is also inclusive of embodiments where the named substituent or substituents have multiple substituents rather than simply a single substituent. For example, optionally substituted aryl may include both phenyl and 3-ethyl-5-methyl-6-bromo-phenyl. The compounds of the disclosure may be administered as salts, which are also within the scope of this disclosure. Pharmaceutically acceptable (i.e., non-toxic, physiologically compatible) salts are preferred. If the compounds of the disclosure have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkane carboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or paratoluene-sulfonic acid. Corresponding acid addition salts can also be formed having plural basic centers, if desired. In some embodiments, the pharmaceutically acceptable salt is selected from valproic acid, maleic acid, tartaric acid, oxalic acid, pamoic acid, phosphonic acid, benzoic acid, citric acid, salicylic acid, succinic acid, methanesulfonic acid, malic acid, and p-toluenesulfonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from valproic acid, maleic acid, tartaric acid, oxalic acid, and pamoic acid. The compounds of the disclosure having at least one acid group (e.g., 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, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or trihydroxy lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts may also be formed. For example, certain salts of the compounds described herein which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate. Moreover, certain salts of the compounds described herein which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines. All stereoisomers of the compounds of the disclosure, either in a mixture or in pure or substantially pure form, are considered to be within the scope of this disclosure. The compounds of the disclosure may have asymmetric centers at any of the carbon atoms including any one of the substituents. Consequently, compounds of the disclosure may exist in enantiomeric or diastereomeric forms or in mixtures thereof. Furthermore, where a stereocenter existing in a compound of the disclosure is represented as a racemate, it is understood that the stereocenter may encompass the racemic mixture of R and S isomers, the S isomers, and the R isomers. The processes for preparation of such compounds can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods including, chromatographic, chiral HPLC, fractional crystallization, or distillation. Some compounds of the present disclosure have groups including alkenyls, iminyls, and the like, which may exist as entgegen (E) or zusammen (Z) conformations, in which case all geometric forms thereof, both E and Z, cis and trans, and mixtures thereof, are within the scope of the present disclosure. Accordingly, when such geometric isomeric products are prepared, they can be separated by conventional methods for example, chromatographic, HPLC, distillation or crystallization. Accordingly, in one aspect, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C](NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring; optionally with the proviso that the compound of formula (I) is not a compound of any one of formulas 1001, 1003-1006, 1008, 1009, 1011, 1012, and 1014: In embodiments, the compound of formula (I) is a compound of any one of formulas 1001-1150. In embodiments, Z is -NR3-. In embodiments, Z is –(CR3)2-. In one embodiment, R10is -OH. In one embodiment, R10is In embodiments, Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2- is selected from -CH2-, - C(Me)2-, wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen. In embodiments, n1is 1 or 2. In embodiments, X is a bond. In embodiments, X is -CR1b-. In embodiments, R2is selected from H, -OH, -CH3, In embodiments, R2is absent and Y is -CRA-. In embodiments, R2is absent, Y is -CRA-, and RAis -CH3. In embodiments, R3is selected from H, wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”, at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1. In embodiments, each occurrence of R5’and R5”is H. In another embodiment, n2is 1, R5’is H, and R5”is unsubstituted alkyl. In embodiments, the unsubstituted alkyl is unsubstituted C1-C5 alkyl. In embodiments, the unsubstituted alkyl is unsubstituted -CH3. In embodiments, n2is 1, R5’is H, and R5”is -CH3. In embodiments, A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selected from In embodiments, R3is selected from H, In embodiments, A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I. In embodiments, A is8a wherein R and R8bare selected from H, alkyl, alkoxy, -OH -CX3, and halogen, optionally wherein R8aand R8bare selected from H, -CH3, -CF3, -OCH3, -OH, F, and Cl. In embodiments, A is selected from In embodiments, R3is selected from In embodiments, R3is selected from In embodiments, the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of formula (10), or a pharmaceutically acceptable salt thereof. formula (11), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (12), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (13), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (15), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (16), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (21), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (22), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (23), or a pharmaceutically acceptable salt thereof. In embodiments, R1ais H. In embodiments, R1bis selected from H, C1-C6alkyl, , and -CH2-CH2-. In embodiments, R1bis joined to the ring to which it is bound to form an unsubstituted or substituted cycloalkyl. In embodiments, the unsubstituted or substituted cycloalkyl is a C3-C7cycloalkyl. In embodiments, R1aand R1bare joined to form an optionally substituted aryl ring. In embodiments, the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof: wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In embodiments, the compound of formula (14) is a compound of formula (100) formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (14) is a compound of formula (100), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (101), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (103), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (104), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (105), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (106), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (107), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (108), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (109), or a pharmaceutically acceptable salt thereof. In embodiments, RAat each occurrence is independently selected from H and unsubstituted or substituted C1-C6alkyl. In embodiments, both RAare joined to form an unsubstituted or substituted cycloalkyl. In embodiments, both RAare joined to form an unsubstituted or substituted C3-C7cycloalkyl. In embodiments, both RAare joined to form an unsubstituted C3-C7cycloalkyl. In embodiments, both RAare joined to form a C3-C7cycloalkyl fused to an optionally substituted aryl ring. In embodiments, both RAare joined to form a C3- C7cycloalkyl fused to an unsubstituted substituted aryl ring. In embodiments, the compound of formula (14) is a compound of formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (14) is a compound of formula (102), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (110), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (111), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (112), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (113), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (114), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (102), formula (110), formula (111), or a pharmaceutically acceptable salt thereof wherein R4ais H, R4dis H, V is -CH2-, m1is 1, n1is 2. In embodiments, one of R4bor R4cis phenyl substituted with one or more -N(Ra)C(O)Ra, -C(O)Ra, or -C(O)N(Ra)2and the other of R4bor R4cis H. In embodiments, one of R4bor R4cis phenyl substituted with one or more - NHC(O)Ra, wherein Rais unsubstituted alkenyl, optionally and the other of R4bor R4cis H. In embodiments, R4bis phenyl substituted with and R4cis H In embodiments, one of R4bor R4cis phenyl substituted with one or more -C(O)Ra, wherein Rais selected from H, unsubstituted alkyl, optionally - CH2CH3, alkenyl, and unsubstituted alkenyl, optionally -CH2=CH2, and the other of R4bor R4cis H. In embodiments, R4bis phenyl substituted with on -C(O)Ra, wherein Rais selected from H, -CH2CH3, and - CH2=CH2, and R4cis H. In embodiments, one of R4bor R4cis phenyl substituted with one or more -- C(O)N(Ra)2, wherein each Rais H, and the other of R4bor R4cis H. In embodiments, R4bis phenyl substituted with --C(O)N(Ra)2, wherein each Rais H, and R4cis H. In embodiments, one of R4bor R4cis pyridinyl substituted with one or more cyano and the other of R4bor R4cis H. In embodiments, R4bis pyridinyl substituted with cyano and R4cis H. In embodiments, R4bis selected from phenyl substituted with phenyl substituted with on -C(O)Ra, whera ein R is selected from H, -CH2CH3, and -CH2=CH2, phenyl substituted with --C(O)N(Ra)2, wherein each Rais H, and pyridinyl substituted with cyano; and wherein R4cis H. In embodiments, R4bis selected from In embodiments, A is phenyl substituted with one or more halogen and CX3, wherein X is selected from F, Cl, Br, and I. In embodiments, when one of R4bor R4cis phenyl substituted with one or more -C(O)H and the other of R4bor R4cis H, A is phenyl substituted with one halogen and one -CX3. In embodiments, when one of R4bor R4cis phenyl substituted with one or more - C(O)Rawherein Rais -CH2=CH2and the other of R4bor R4cis H, A is phenyl substituted with two halogen. In embodiments, A is selected from In embodiments, A is selected from and n2is 1. In embodiments, the compound of formula (I) is a compound of formula (102), formula (110), formula (111), or a pharmaceutically acceptable salt thereof wherein: R4ais H, R4dis H, V is -CH2-, m1is 1, n1is 2, one of R4bor R4cis phenyl substituted with one or more -N(Ra)C(O)Ra, optionally - C(O)Ra, optionally -C(O)H, -C(O)CH2CH3or -C(O)CH2=CH2, or -C(O)N(Ra)2, optionally -C(O)NH2, and the other of R4bor R4cis H, or one of R4bor R4cis pyridinyl substituted with one or more cyano and the other of R4bor R4cis H, and A is phenyl substituted with one or more halogen and CX3, wherein X is selected from F, Cl, Br, and I, with the provisos that: when one of R4bor R4cis phenyl substituted with one or more -C(O)H and the other of R4bor R4cis H, A is phenyl substituted with one halogen and one -CX3, and when one of R4bor R4cis phenyl substituted with one or more -C(O)Rawherein Rais -CH2=CH2and the other of R4bor R4cis H, A is phenyl substituted with two halogen. In one embodiment, the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of formula (17), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (19), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof:

[0018] In embodiments, the compound of formula (18) is a compound of formula (116), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (18) is a compound of formula (117), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (18) is a compound of formula (118), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (20) is a compound of formula (119), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (20) is a compound of formula (120), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (20) is a compound of formula (121), or a pharmaceutically acceptable salt thereof. In embodiments, R4aof any one of formula (14), formula (17), formula (19), or formula (100)-formula (121) is selected from H and halogen. In embodiments, R4ais F. In embodiments, R4bof any one of formula (14), formula (17), formula (19), or formula (100)-formula (121) is a substituent which functions as a non-covalent linker. In another embodiment, R4bis a substituent which functions as a covalent linker. In embodiments, R4bis selected from H, -N(Ra)C(O)Ra, halogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl. In embodiments, R4bis - CH3or -CF3. In embodiments, R4bis4 In embodiments, Rbis selected from halogen, -N(Ra)C(O)Ra, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl, wherein the halogen, -N(Ra)C(O)Ra, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkyl functions as a covalent linker. In embodiments, R4cof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is H. In embodiments, R4bof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is selected from optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted pyrrolyl. In embodiments, R4bis phenyl substituted with one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, -NH2, -N(Ra)C(O)Ra, halogen, cyano, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl. In embodiments, R4bis9a wherein R is selected from -NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, halogen, cyano, -N(Ra)C(O)Ra, wherein Rais selected from H, optionally substituted alkyl, and optionally substituted alkenyl, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl. In embodiments, R4bis , wherein each R9ais independently optionally substituted alkyl. In some embodiments, R4bis , wherein each R9ais independently unsubstituted alkyl, optionally -CH3. In embodiments, R4bis selected from In embodiments, R4bis pyridinyl substituted with one or more halogen or cyano. In embodiments, R4bis selected from I4b n embodiments, R is In embodiments, R4bis selected from phenyl substituted witha phenyl substituted with on -C(O)R, wherein Rais selected from H, -CH2CH3, and -CH2=CH2, phenyl substituted with –C(O)N(Ra)2, wherein each Rais H, and pyridinyl substituted with cyano; and wherein R4cis H. In embodiments, R4bis selected from In embodiments, A is selected from In embodiments, A is selected from and n2is 1. In embodiments, R4dof any one of formula (14), formula (17), formula (19), or formula (100)-formula (121) is H. In embodiments, R4dof any one of formula (14), formula (17), formula (19), or formula (100)-formula (121) is selected from H, wherei5a 5b 5c 5d n R , R , R , R , and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3; n4is an integer from 0 to 4; and n5is an integer from 0 to 4. In embodiments, n3is 0. In embodiments, n3is 1. In embodiments, n4is 2. In embodiments, n5is 1. In embodiments, R5a, R5b, R5d, and R5eare each H. In embodiments, R5cis optionally substituted alkoxy. In embodiments, R5cis -OMe. In embodiments, R5a, R5c, R5d, and R5eare each H. In embodiments, R5bis optionally substituted alkoxy. In embodiments, R5bis -OMe. In embodiments, R4dis selected from H, In embodiments, the compound of formula (I) is a compound of any one of formula 1001-1150, or a pharmaceutically acceptable salt thereof:

[0019] In embodiments, the compound of formula (I) is not a compound of any one of formula 1001, 1003-1006, 1008, 1009, 1011, 1012, 1014, or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094- 1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof:

[0020] In embodiments, the compound of the disclosure (e.g. a compound of any one of formula (I), formula (10)- (23), formula (100)-(121), or formula 1001-1150) is a non-covalent inhibitor of Trim7. In a non-limiting example, a 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 compound of the disclosure (e.g. a compound of any one of formula (I), formula (10)-(23), formula (100)-(121), or formula 1001-1150) is a covalent inhibitor of T rim7. In a non-limiting example, a 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 comprising one or more moiety capable of forming a covalent bond with the Trim7 gene product, including but not limited to alkenes, such as alkenes that are Michael acceptors, as would be understood by one of ordinary skill in the art. Non- limiting examples of alkenes include -C(O)-CH=CH2moieties. Pharmaceutical compositions Aspects of the present disclosure include a pharmaceutical composition comprising the Trim7 inhibitors any of the herein disclosed aspects or embodiments. In one aspect, the present 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: wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring; optionally with the proviso that the compound of formula (I) is not a compound of any one of formulas 1001, 1003-1006, 1008, 1009, 1011, 1012, and 1014: In embodiments, the compound of formula (I) is a compound of any one of formulas 1001-1150. In some embodiments, Z is -NR3-. In some embodiments, Z is –(CR3)2-. In embodiments, R10is -OH. In embodiments, R10is In embodiments, X is a bond. In embodiments, X is -CR1b-. In embodiments, Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2- is selected from -CH2-, - C(Me)2-, wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen. In embodiments, n1is 1 or 2.

[0021] In embodiments, R2is selected from H, -OH, -CH3, In embodiments, R3is selected from H, wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”, at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1, optionally A is selected from and n is 1. In embodime5’ 5” 2nts, each occurrence of R and R is H. In another embodiment, n2is 1, R5’is H, and R5”is unsubstituted alkyl. In embodiments, n2is 1, R5’is H, and R5””is -CH3. In embodiments, A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selected from In embodiments, R3is selected from H, embodiments, A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I. In embodiments, A is selected from In embodiments, R3is selected from In embodiments, R3is selected from In embodiments, the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of formula (10), or a pharmaceutically acceptable salt thereof. formula (11), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (12), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (13), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (15), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (16), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (21), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (22), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (23), or a pharmaceutically acceptable salt thereof. In embodiments, R1ais H. In embodiments, R1bis selected from H, C1-C6alkyl, and -CH2-CH2-. In embodiments, R1bis joined to the ring to which it is bound to form an unsubstituted or substituted cycloalkyl. In embodiments, the unsubstituted or substituted cycloalkyl is a C3-C7cycloalkyl. In embodiments, R1aand R1bare joined to form an optionally substituted aryl ring. In embodiments, the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof: wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. In embodiments, the compound of formula (14) is a compound of formula (100) formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), formula (109), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (14) is a compound of formula (100), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (101), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (103), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (104), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (105), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (106), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (107), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (108), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (109), or a pharmaceutically acceptable salt thereof. In embodiments, RAat each occurrence is independently selected from H and unsubstituted or substituted C1-C6alkyl. In embodiments, both RAare joined to form an unsubstituted or substituted cycloalkyl. In embodiments, both RAare joined to form an unsubstituted or substituted C3-C7cycloalkyl. In embodiments, both RAare joined to form an unsubstituted C3-C7cycloalkyl. In embodiments, both RAare joined to form a C3-C7cycloalkyl fused to an optionally substituted aryl ring. In embodiments, both RAare joined to form a C3- C7cycloalkyl fused to an unsubstituted aryl ring. In embodiments, the compound of formula (14) is a compound of formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (14) is a compound of formula (102), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (110), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (111), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (112), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (113), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (14) is a compound of formula (114), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (102), formula (110), formula (111), or a pharmaceutically acceptable salt thereof wherein R4ais H, R4dis H, V is -CH2-, m1is 1, n1is 2. In embodiments, one of R4bor R4cis phenyl substituted with one or more -N(Ra)C(O)Ra, -C(O)Ra, or -C(O)N(Ra)2and the other of R4bor R4cis H. In embodiments, one of R4bor R4cis phenyl substituted with one or more - NHC(O)Ra, wherein Rais unsubstituted alkenyl, optionally and the other of R4bor R4cis H. In embodiments, one of R4bor R4cis phenyl substituted with one or more -C(O)Ra, wherein Rais selected from H, unsubstituted alkyl, optionally -CH2CH3, alkenyl, and unsubstituted alkenyl, optionally -CH2=CH2, and the other of R4bor R4cis H. In embodiments, R4bis phenyl substituted with one -C(O)Ra, wherein Rais selected from H, -CH2CH3, and -CH2=CH2, and R4cis H. In embodiments, one of R4bor R4cis phenyl substituted with one or more -C(O)N(Ra)2, wherein each Rais H, and the other of R4bor R4cis H. In embodiments, R4bis phenyl substituted with -C(O)N(Ra)2, wherein each Rais H, and R4cis H. In embodiments, one of R4bor R4cis pyridinyl substituted with one or more cyano and the other of R4bor R4cis H. In embodiments, R4bis pyridinyl substituted with cyano and R4cis H. In embodiments, R4bis selected from phenyl substituted with phenyl substituted with one -C(O)Ra,a wherein R is selected from H, -CH2CH3, and -CH2=CH2, phenyl substituted with -C(O)N(Ra)2, wherein each Rais H, and pyridinyl substituted with cyano; and wherein R4cis H. In embodiments, R4bis selected from In embodiments, A is phenyl substituted with one halogen and one -CX3. In embodiments, when one of R4bor R4cis phenyl substituted with one or more - C(O)Rawherein Rais -CH2=CH2and the other of R4bor R4cis H, A is phenyl substituted with two halogen. In embodiments, A is selected from In embodiments, A is selected from and and n2is 1. In embodiments, the compound of formula (I) is a compound of formula (102), formula (110), formula (111), or a pharmaceutically acceptable salt thereof wherein: R4ais H, R4dis H, V is -CH2-, m1is 1, n1is 2, one of R4bor R4cis phenyl substituted with one or more -N(Ra)C(O)Ra, optionally - C(O)Ra, optionally -C(O)H, -C(O)CH2CH3or -C(O)CH2=CH2, or -C(O)N(Ra)2, optionally -C(O)NH2, and the other of R4bor R4cis H, or one of R4bor R4cis pyridinyl substituted with one or more cyano and the other of R4bor R4cis H, and A is phenyl substituted with one or more halogen and CX3, wherein X is selected from F, Cl, Br, and I, with the provisos that: when one of R4bor R4cis phenyl substituted with one or more -C(O)H and the other of R4bor R4cis H, A is phenyl substituted with one halogen and one -CX3, and when one of R4bor R4cis phenyl substituted with one or more -C(O)Rawherein Rais -CH2=CH2and the other of R4bor R4cis H, A is phenyl substituted with two halogen. In embodiments, the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (I) is a compound of formula (17), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of formula (19), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof: In some embodiments, the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (18) is a compound of formula (116), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (18) is a compound of formula (117), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (18) is a compound of formula (118), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof: In embodiments, the compound of formula (20) is a compound of formula (119), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (20) is a compound of formula (120), or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (20) is a compound of formula (121), or a pharmaceutically acceptable salt thereof. In embodiments, R4aof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is selected from H and halogen. In embodiments, R4ais F. In embodiments, R4bof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is a substituent which functions as a non-covalent linker. In another embodiment, R4bis a substituent which functions as a covalent linker. In embodiments, R4bis selected from H, -N(Ra)C(O)Ra, halogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl. In embodiments, R4bis - CH3or -CF3. In embodiments, R4bis . In embodiments, R4bis selected from halogen, -N(Ra)C(O)Ra, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl, wherein the halogen, -N(Ra)C(O)Ra, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkyl functions as a covalent linker. In embodiments, R4bis selected from optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted pyrrolyl. In embodiments, R4bis phenyl substituted with one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, -NH2, -N(Ra)C(O)Ra, halogen, cyano, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl. In embodiments, R4bis wher9a ein R is selected from -NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, halogen, cyano, -N(Ra)C(O)Ra, wherein Rais selected from H, optionally substituted alkyl, and optionally substituted alkenyl, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl. In embodiments, R4bis wherein each R9ais independently optionally substituted alkyl. In embodiments, R4bis wherein each R9ais independently unsubstituted alkyl, optionally -CH3 . In embodiments, R4bis selected from In embodiments, R4bis pyridinyl substituted with one or more halogen or cyano. In embodiments, R4bis selected from In another embodiment, R4bis In embodiments, R4bis selected from phenyl substituted with phenyl substituted with on -C(O)Ra, wherein Rais selected from H, -CH2CH3, and -CH2=CH2, phenyl substituted with –C(O)N(Ra)2, wherein each Rais H, and pyridinyl substituted with cyano; and wherein R4cis H. In embodiments, R4bis selected from In embodiments, A is selected from and In embodiments, A is selected from and n2is 1. In embodiments, R4cof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is H. In embodiments, R4dof any one of formula (14), formula (17)-formula (19), or formula (100)-formula (121) is selected from H, wherein: R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3; n4is an integer from 0 to 4; and n5is an integer from 0 to 4. In embodiments, n3is 0. In embodiments, n3is 1. In embodiments, n4is 2. In embodiments, n5is 1. In embodiments, R5a, R5b, R5d, and R5eare each H. In embodiments, R5cis optionally substituted alkoxy. In embodiments, R5cis -OMe. In embodiments, R5a, R5c, R5d, and R5eare each H. In embodiments, R5bis optionally substituted alkoxy. In embodiments, R5bis -OMe. In embodiments, R4d

[0022] is selected from H, In embodiments, the compound of formula (I) is a compound of any one of formula 1001-1150, or a pharmaceutically acceptable salt thereof. In embodiments, the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094- 1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition is formulated for parenteral administration. In embodiments, the pharmaceutical composition is formulated for topical, dermal, intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration. In embodiments, the pharmaceutical composition is formulated for topical administration. In embodiments, any of the Trim7 inhibitors disclosed herein (and / or additional agents) are included various formulations. Any Trim7 inhibitor (and / or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In embodiments, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed.1995), incorporated herein by reference. In embodiments, the Trim7 inhibitor disclosed herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety. In embodiments, the compositions disclosed herein are in the form of a pharmaceutically acceptable salt. Further, any Trim7 inhibitor disclosed herein can be administered to a subject as a component of pharmaceutical composition, that comprises a pharmaceutically acceptable carrier or vehicle. Such pharmaceutical compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In embodiments, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent disclosed herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent disclosed herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. The present disclosure includes the disclosed Trim7 inhibitor in various formulations of pharmaceutical composition. Any Trim7 inhibitor disclosed herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. DNA or RNA constructs encoding the protein sequences may also be used. In embodiments, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed.1995), incorporated herein by reference. Where necessary, the pharmaceutical compositions comprising the Trim7 inhibitor can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Pharmaceutical compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0023] The pharmaceutical compositions comprising the Trim? inhibitor of the present disclosure may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately bringing therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art)

[0024] In embodiments, any Trim? inhibitor disclosed herein is formulated in accordance with routine procedures as a pharmaceutical composition adapted for a mode of administration disclosed herein.

[0025] Administration, Dosing, and Treatment Regimens

[0026] In embodiments, any Trim7 inhibitor (and / or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0027] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In embodiments, the administering is effected orally or by parenteral injection. In most instances, administration results in the release of any agent described herein into the bloodstream.

[0028] Any Trim? inhibitor (and / or additional agents) described herein can be administered orally. Such Trim? inhibitors (and / or additional agents) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

[0029] In specific embodiments, it may be desirable to administer locally to the area in need of treatment. In embodiments, for instance in the treatment of cancer, the Trim? inhibitor (and / or additional agents) are administered in the tumor microenvironment (e.g., cells, molecules, extracellular matrix and / or blood vessels that surround and / or feed a tumor cell, inclusive of, for example, tumor vasculature; tumor-infiltrating lymphocytes; fibroblast reticular cells; endothelial progenitor cells (EPC); 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 proximal to a tumor) or lymph node and / or targeted to the tumor microenvironment or lymph node. In various embodiments, for instance in the treatment of cancer, the Trim7 inhibitor (and / or additional agents) are administered intratumorally. Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g., lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art. The dosage of any Trim7 inhibitor (and / or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject’s general health, and the administering physician’s discretion. Any Trim7 inhibitor described herein, can be administered prior to (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 before), concurrently with, or subsequent to (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 after) the administration of an additional agent, to a subject in need thereof. In various embodiments any Trim7 inhibitor and additional agent described herein are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, 1 week apart, 2 weeks apart, 3 weeks apart, or 4 weeks apart. In various embodiments, the current disclosure relates to the co-administration of a Trim7 inhibitor which induces an innate immune response and another Trim7 inhibitor which induces an adaptive immune response. In such embodiments, the Trim7 inhibitor which induces an innate immune response may be administered before, concurrently with, or subsequent to administration of the Trim7 inhibitor which induces an adaptive immune response. For example, the Trim7 inhibitors may be administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, 1 week apart, 2 weeks apart, 3 weeks apart, or 4 weeks apart. In an illustrative embodiment, the Trim7 inhibitor which induces an innate immune response and the Trim7 inhibitor which induces an adaptive response are administered 1 week apart, or administered on alternate weeks (i.e., administration of the Trim7 inhibitor inducing an innate immune response is followed 1 week later with administration of the Trim7 inhibitor which induces an adaptive immune response and so forth). The dosage of any Trim7 inhibitor (and / or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected. For administration of any Trim7 inhibitor (and / or additional agents) described herein by parenteral injection, the dosage may be about 0.1 mg to about 250 mg per day, about 1 mg to about 20 mg per day, or about 3 mg to about 5 mg per day. Generally, when orally or parenterally administered, the dosage of any agent described herein may be about 0.1 mg to about 1500 mg per day, or about 0.5 mg to about 10 mg per day, or about 0.5 mg to about 5 mg per day, or about 200 to about 1,200 mg per day (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 1,000 mg, about 1,100 mg, about 1,200 mg per day). In embodiments, administration of the Trim7 inhibitor (and / or additional agents) described herein is by parenteral injection at a dosage 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 to about 1,200 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 1,000 mg, about 1,100 mg, about 1,200 mg per treatment). In embodiments, a suitable dosage of the Trim7 inhibitor (and / or additional agents) is in a range of about 0.01 mg / kg to about 100 mg / kg of body weight ,or about 0.01 mg / kg to about 10 mg / kg of 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 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, 1.9 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg body weight, inclusive of all values and ranges therebetween. In another embodiment, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989). Any Trim7 inhibitor (and / or additional agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill 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. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. In another embodiment, polymeric materials can be used (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). In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used. Administration of any Trim7 inhibitor (and / or additional agents) described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. The dosage regimen utilizing any Trim7 inhibitor (and / or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the disclosure employed. Any Trim7 inhibitor (and / or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any Trim7 inhibitor (and / or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen. Diseases; Methods of Treatment, and Patient Selections In one aspect, the present disclosure relates to a method for treating a cancer, an infectious disease, an inflammatory disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any of the embodiments disclosed herein. In embodiments, the cancer is selected from a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs’ syndrome.

[0030] In embodiments, the cancer is a hematologic cancer selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia, or a combination thereof.

[0031] In embodiments, the cancer is resistant to an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is an antibody. In embodiments, the anti-checkpoint agent an anti-PD-1, anti-PD-L1 , anti-PD-L2, and / or anti-CTLA antibody. In embodiments, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), Cemiplimab (LIBTAYO), Atezolizumab (TECENTRIQ), Avelumab (BAVENCIO), and Durvalumab (IMFINZI).

[0032] In embodiments, the infectious disease is a viral infection. In embodiments, the viral infection is caused by a virus selected from papilloma virus, 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, a human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV- 2). In embodiments, the inflammatory disease is an autoimmune disease or condition, selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Grave's disease, and other autoimmune disease. In one aspect, the present disclosure relates to a method for treating an anti-checkpoint agent-resistant cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments disclosed herein. In embodiments, the anti-checkpoint agent is an antibody. In embodiments, the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), Cemiplimab (LIBTAYO), Atezolizumab (TECENTRIQ), Avelumab (BAVENCIO), and Durvalumab (IMFINZI). In one aspect, the present disclosure relates to methods of treating viral infections including, without limitation, acute or chronic viral infections, for example, of the respiratory tract, of papilloma virus infections, of herpes simplex virus (HSV) infection, of human immunodeficiency virus (HIV) infection, and of viral infection of internal organs such as infection with hepatitis viruses. In embodiments, the viral infection is caused by a virus of family Flaviviridae. In embodiments, the virus of family Flaviviridae is 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 a virus of family Picornaviridae, e.g., poliovirus, rhinovirus, enterovirus, coxsackievirus. In embodiments, the viral infection is caused by a member of Orthomyxoviridae, e.g., an influenza virus. In embodiments, the viral infection is caused by a member of Retroviridae, e.g., a lentivirus. In embodiments, the viral infection is caused by a member of Paramyxoviridae, e.g., respiratory syncytial virus, a human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, and human metapneumovirus. In embodiments, the viral infection is caused by a member of Bunyaviridae, e.g., hantavirus. In embodiments, the viral infection is caused by a member of Reoviridae, e.g., a rotavirus. In one aspect, the present disclosure relates to methods of treating parasitic infections such as protozoan or helminths infections. In embodiments, the parasitic infection is by a protozoan parasite. In embodiments, the oritiziab parasite is selected from intestinal protozoa, tissue protozoa, or blood protozoa. 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, Plasmodium falciparum, Trichomonas vaginalis, and Histomonas meleagridis. In embodiments, the parasitic infection is by a helminthic parasite such as nematodes (e.g., Adenophorea). In embodiments, the parasite is selected from Secementea (e.g., Trichuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Wuchereria bancrofti, Dracunculus medinensis). In embodiments, the parasite is selected from trematodes (e.g. blood flukes, liver flukes, intestinal flukes, and lung flukes). In embodiments, the parasite is selected from: Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola gigantica, Heterophyes, Paragonimus westermani. In embodiments, the parasite is selected from cestodes (e.g., Taenia solium, Taenia saginata, Hymenolepis nana, Echinococcus granulosus). In one aspect, the present disclosure relates to methods of treating bacterial infections. In embodiments, the bacterial infection is by gram-positive bacteria, gram-negative bacteria, aerobic and / or anaerobic bacteria. In embodiments, the bacteria is selected from, but not limited to, Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms. In embodiments, the bacteria is selected from, but 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, Salmonella enteritidis, Shigella dysenteriae, Shigella 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 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, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, 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 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, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus. In one aspect, the present disclosure relates to methods of treating one or more autoimmune diseases or disorders. In embodiments, the treatment of an autoimmune disease or disorder may involve modulating the immune system with the present Trim7 inhibitors to favor immune inhibition over immune stimulation. Illustrative autoimmune diseases or disorders treatable with the present Trim7 inhibitors include those in which the body’s own antigens become targets for an immune response, such as, for example, rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, ankylosing spondylitis, Sjögren's syndrome, inflammatory bowel diseases (e.g. colitis ulcerosa, Crohn's disease), multiple sclerosis, sarcoidosis, psoriasis, Grave's disease, Hashimoto's thyroiditis, psoriasis, hypersensitivity reactions (e.g., allergies, hay fever, asthma, and acute edema cause Type I hypersensitivity reactions), and vasculitis. Methods of Determining a Cancer Treatment for a Patient; Methods of Selecting a Patient for a Cancer Treatment; and Methods of Treatment In one aspect, the present disclosure relates to a method of determining a cancer treatment for a patient, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any embodiments disclosed herein, if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is selected from an anti-PD-1, anti-PD- L1, anti-PD-L2, and / or anti-CTLA agent. In embodiments, the anti-checkpoint agent is selected from an anti- PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibody. In one aspect, the present disclosure relates to a method for selecting a patient for a cancer treatment, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any embodiments disclosed herein, if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent. In embodiments, the anti-checkpoint agent is selected from an anti-PD-1, anti-PD- L1, anti-PD-L2, and / or anti-CTLA agent. In embodiments, the anti-checkpoint agent is selected from an anti- PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibody. In one aspect, the present disclosure relates to a method of treating cancer, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) administering the cancer therapy comprising the pharmaceutical composition of any embodiments disclosed herein, if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally administering a second cancer therapy comprising an anti- checkpoint agent. In embodiments, the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA agent. In embodiments, the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA antibody. In embodiments, the biological sample is a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen. In embodiments, 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), needle biopsy (e.g., fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound-assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy. In embodiments, the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom. In embodiments, the biological sample comprises at least one tumor cell. In embodiments, the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof. In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to Trim7. In embodiments, the agent that specifically binds to one or proteins comprises an antibody, antibody-like molecule or binding a fragment thereof. In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to one or more of nucleic acids of Trim7. In embodiments, the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe. Combination Therapies and Conjugation In embodiments, the disclosure provides for Trim7 inhibitors and methods that further comprise administering an additional agent to a subject. In embodiments, the disclosure pertains to co-administration and / or co- formulation. Any of the compositions described herein may be co-formulated and / or co-administered. In embodiments, any Trim7 inhibitor described herein acts synergistically when co-administered with another agent and is administered at doses that are lower than the doses commonly employed when such agents are used as monotherapy. In embodiments, inclusive of, without limitation, cancer applications, the present disclosure pertains to chemotherapeutic agents as additional agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara- C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (TYKERB); inhibitors of PKC-α, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, the methods of treatment can further include the use of radiation. In addition, the methods of treatment can further include the use of photodynamic therapy. In embodiments, inclusive of, without limitation, cancer applications, the present additional agent is one or more immune-modulating agents selected from an agent that blocks, reduces and / or inhibits PD-1 and PD- L1 or PD-L2 and / or the binding of PD-1 with PD-L1 or PD-L2 (by way of non-limiting example, one or more of 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)), an agent that increases and / or stimulates CD137 (4-1BB) and / or the binding of CD137 (4-1BB) with one or more of 4-1BB ligand (by way of non-limiting example, urelumab (BMS-663513 and anti-4-1BB antibody), and an agent that blocks, reduces and / or inhibits the activity of CTLA-4 and / or the binding of CTLA-4 with one or more of AP2M1, CD80, CD86, SHP-2, and PPP2R5A and / or the binding of OX40 with OX40L (by way of non-limiting example GBR 830 (GLENMARK), MEDI6469 (MEDIMMUNE)). In embodiments, inclusive of, without limitation, infectious disease applications, the present disclosure pertains to anti-infectives as additional agents. In embodiments, the anti-infective is an anti-viral agent including, but not limited to, Abacavir, Acyclovir, Adefovir, Amprenavir, Atazanavir, Cidofovir, Darunavir, Delavirdine, Didanosine, Docosanol, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Etravirine, Famciclovir, and Foscarnet. In embodiments, the anti-infective is an anti-bacterial agent including, but not limited to, cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole); fluoroquinolone antibiotics (cipro, Levaquin, floxin, tequin, avelox, and norflox); tetracycline antibiotics (tetracycline, minocycline, oxytetracycline, and doxycycline); penicillin antibiotics (amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactam antibiotics (aztreonam); and carbapenem antibiotics (ertapenem, doripenem, imipenem / cilastatin, and meropenem). In embodiments, the anti-infectives include anti-malarial agents (e.g., chloroquine, quinine, mefloquine, primaquine, doxycycline, artemether / lumefantrine, atovaquone / proguanil and sulfadoxine / pyrimethamine), metronidazole, tinidazole, ivermectin, pyrantel pamoate, and albendazole. In embodiments, inclusive, without limitation, of autoimmune applications, the additional agent is an immunosuppressive agent. In embodiments, the immunosuppressive agent is an anti-inflammatory agent such as a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent (NSAID). Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art. Examples of corticosteroids useful in the present disclosure include, without limitation, hydroxyltriamcinolone, alpha- methyl dexamethasone, beta-methyl betamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate. (NSAIDS) that may be used in the present disclosure, include but are not limited to, salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, and indomethacin. In embodiments, the immunosupressive agent may be cytostatics such as alkylating agents, antimetabolites (e.g., azathioprine, methotrexate), cytotoxic antibiotics, antibodies (e.g., basiliximab, daclizumab, and muromonab), anti-immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), inteferons, opioids, TNF binding proteins, mycophenolates, and small biological agents (e.g., fingolimod, myriocin). In embodiments, inclusive, without limitation, the additional agent is a kras inhibitor (e.g. a kras G12C inhibitor). In embodiments, the kras inhibitor is selected from BI2865, MRTX11, sotorasib (AMG510) and adagrasib (MRTX849). In embodiments, inclusive, without limitation, the additional agent is a braf inhibitor. In embodiments, the braf inhibitor is selected from vemurafenib, dabrafenib and encorafenib. In embodiments, inclusive, without limitation, the additional agent is a MEK inhibitor. In embodiments, the MEK inhibitor is selected from binimetinib (MEK162), cobimetinib (XL518), selumetinib, and trametinib (GSK1120212).

[0033] In embodiments, the Trim7 inhibitors (and / or additional agents) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives include composition that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of turicamycin, etc. Additionally, the derivative can contain one or more non- classical amino acids. In still other embodiments, the Trim7 inhibitors (and / or additional agents) described herein further comprise a cytotoxic agent, comprising, in illustrative embodiments, a toxin, a chemotherapeutic agent, a radioisotope, and an agent that causes apoptosis or cell death. Such agents may be conjugated to a composition described herein.

[0034] The Trim7 inhibitors (and / or additional agents) described herein may thus be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0035] Subjects and / or Animals

[0036] In embodiments, the subject and / or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the subject and / or animal is a non-mammal, such, for example, a zebrafish. In embodiments, the subject and / or animal may comprise fluorescently-tagged cells (with e.g. GFP). In embodiments, the subject and / or animal is a transgenic animal comprising a fluorescent cell.

[0037] In embodiments, the subject and / or animal is a human. In embodiments, the human is a pediatric human. In embodiments, the human is an adult human. In embodiments, the human is a geriatric human. In embodiments, the human may be referred to as a patient. In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old. In embodiments, the subject is a non-human animal, and therefore the disclosure pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal. Kits The disclosure provides kits that can simplify the administration of any agent described herein. An illustrative kit of the disclosure comprises any composition described herein in unit dosage form. In embodiments, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In embodiments, the kit comprises a container containing an effective amount of a composition of the disclosure and an effective amount of another composition, such those described herein. The instant disclosure also provides certain embodiments as follows: Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring; with the proviso that the compound of formula (I) is not a compound of any one of formulas 1001, 1003-1006, 1008, 1009, 1011, 1012, and 1014: Embodiment 2. The compound of Embodiment 1, wherein Z is -NR3-. Embodiment 3. The compound of Embodiment 1, wherein Z is –(CR3)2-. Embodiment 4. The compound of any one of Embodiments 1-3, wherein R10is -OH. Embodiment 5. The compound of any one of Embodiments 1-3, wherein R10is . Embodiment 6. The compound of any one of Embodiments 1-5, wherein Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2-, is selected from -CH2-, -C(Me)2-, , wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen. Embodiment 7. The compound of any one of Embodiments 1-6, wherein X is a bond. Embodiment 8. The compound of any one of Embodiments 1-6, wherein X is -CR1b-. Embodiment 9. The compound of any one of Embodiments 1-8, wherein R2is selected from H, -OH,-CH3, , Embodiment 10. The compound of any one of Embodiments 1-5, wherein R2is absent and Y is -CRA-. Embodiment 11. The compound of Embodiment 10, wherein RAis -CH3. Embodiment 12. The compound of any one of Embodiments 1-11, wherein R3is selected from H, , wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”,at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1, optionally A is selected from and n2is 1. Embodiment 13. The compound of Embodiment 12, wherein each occurrence of R5’and R5”is H. Embodiment 14. The compound of Embodiment 12, wherein n2is 1, R5’is H, and R5”is unsubstituted alkyl. Embodiment 15. The compound of Embodiment 14, wherein R5”is -CH3. Embodiment 16. The compound of any one of Embodiments 12-15, wherein A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selected from Embodiment 17. The compound of any one of Embodiments 12-16, wherein R3is selected from H, , Embodiment 18. The compound of any one of Embodiments 12-16, wherein A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -OH, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I, optionally wherein A is wherein R8aand R8bare selected from H, alkyl, alkoxy, - OH, -CX3, and halogen, optionally R8aand R8bare selected from H, -CH3, -CF3, -OCH3, -OH, F, and Cl.

[0038] Embodiment 19. The compound of Embodiment 18, wherein A is selected from , , optionally wherein A is Embodiment 20. The compound of any one of Embodiments 12-16, 18, or 19, wherein R3is selected from o3 ptionally wherein R is selected from Embodiment 21. The compound of any one of Embodiments 1, 2, 4, 6-9, or 12-20, wherein the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof. Embodiment 22. The compound of any one of Embodiments 1-21, wherein R1ais H. Embodiment 23. The compound of any one of Embodiments 1-22, wherein R1bis selected from H, C1-C6alkyl, and -CH2-CH2-. Embodiment 24. The compound of any one of Embodiments 1-21, wherein R1aand R1bare joined to form an optionally substituted aryl ring. Embodiment 25. The compound of Embodiment 24, wherein the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof. Embodiment 26. The compound of Embodiment 24, wherein the compound of formula (14) is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), or a pharmaceutically acceptable salt thereof. Embodiment 27. The compound of Embodiment 25, wherein the compound of formula (14) is a compound of formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof. Embodiment 28. The compound of any one of Embodiments 1-4, 6, 8, or 10-20, wherein the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 29. The compound of Embodiment 28, wherein the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof: Embodiment 30. The compound of any one of Embodiments 1, 3, 4, 6, 8, 9, or 12-20, wherein the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof: wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 31. The compound of Embodiment 30, wherein the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof:

[0039] Embodiment 32. The compound of any one of Embodiments 1, 2, 5, 6, 8, 9, or 12-20, wherein the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof: wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 33. The compound of Embodiment 32, wherein the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof: Embodiment 34. The compound of any one of Embodiments 25-33, wherein R4ais selected from H and halogen, optionally F. Embodiment 35. The compound of any one of Embodiments 25-34, wherein R4bis selected from H, - N(Ra)C(O)Ra, optionally halogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl, optionally -CH3, and -CF3. Embodiment 36. The compound of Embodiment 35, wherein R4bis selected from optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted pyrrolyl. Embodiment 37. The compound of Embodiment 36, wherein R4bis phenyl substituted with one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, -NH2, -N(Ra)C(O)Ra, halogen, cyano, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl, optionally wherein R4bis9a wherein R is selected from -NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, halogen, cyano, -N(Ra)C(O)Ra, wherein Rais selected from H, optionally substituted alkyl, and optionally substituted alkenyl, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl, optionally wherein R4bis , wherein each R9ais independently optionally substituted alkyl. Embodiment 38. The compound of Embodiment 37, wherein R4bis selected from optionally wherein R4bis selected from Embodiment 39. The compound of Embodiment 36, wherein R4bis pyridinyl substituted with one or more halogen or cyano. Embodiment 40. The compound of Embodiment 39, wherein R4bis selected from . Embodiment 41 The compound of Embodiment 36, wherein R4bis . Embodiment 42. The compound of any one of Embodiments 25-41, wherein R4cis H. Embodiment 43. The compound of any one of Embodiments 25-42, wherein R4dis selected from H, wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1. Embodiment 44. The compound of Embodiment 43, wherein R5a, R5b, R5d, and R5eare each H. Embodiment 45. The compound of Embodiment 43 or 44, wherein R5cis optionally substituted alkoxy, optionally -OMe. Embodiment 46. The compound of Embodiment 43, wherein R5a, R5c, R5d, and R5eare each H. Embodiment 47. The compound of Embodiment 43 or 46, wherein R5bis optionally substituted alkoxy, optionally -OMe.

[0040] Embodiment 48. The compound of any one of Embodiments 43-47, wherein R4dis selected from H, optio4d nally wherein R is H. Embodiment 49. The compound of any one of Embodiments 1-48, wherein the compound of formula (I) is a compound of any one of formula 1002, 1007, 1010, 1013, 1015-1150, or a pharmaceutically acceptable salt thereof. Embodiment 50. The compound of any one of Embodiments 1-49, wherein the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124- 1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof. Embodiment 51. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient: wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH and and RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring. Embodiment 52. The pharmaceutical composition of Embodiment 51, wherein Z is -NR3-. Embodiment 53. The pharmaceutical composition of Embodiment 51, wherein Z is –(CR3)2-. Embodiment 54. The pharmaceutical composition of any one of Embodiments 51-53, wherein R10is -OH. Embodiment 55. The pharmaceutical composition of any one of Embodiments 51-53, wherein R10is . Embodiment 56. The pharmaceutical composition of any one of Embodiments 51-55, wherein Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2- is selected from -CH2-, -C(Me)2-, , , wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen. Embodiment 57. The compound of any one of Embodiments 51-56, wherein X is a bond. Embodiment 58. The compound of any one of Embodiments 51-56, wherein X is -CR1b-. Embodiment 59. The pharmaceutical composition of any one of Embodiments 51-56, wherein R2is selected from H, -OH, -CH3, Embodiment 60. The pharmaceutical composition of any one of Embodiments 51-59, wherein R2is absent and Y is -CRA-. Embodiment 61. The pharmaceutical composition of Embodiment 60, wherein RAis -CH3. Embodiment 62. The pharmaceutical composition of any one of Embodiments 51-61, wherein R3is selected from H, wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”, at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1, optionally A is selected from and n2is 1. Embodiment 63. The pharmaceutical composition of Embodiment 62, wherein each occurrence of R5’and R5”is H. Embodiment 64. The pharmaceutical composition of Embodiment 62, wherein n2is 1, R5’is H, and R5”is unsubstituted alkyl. Embodiment 65. The pharmaceutical composition of Embodiment 64, wherein R5”is -CH3. Embodiment 66. The pharmaceutical composition of any one of Embodiments 62-65, wherein A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selected from , and . Embodiment 67. The pharmaceutical composition of any one of Embodiments 62-66, wherein R3is selected from H, . Embodiment 68. The pharmaceutical composition of Embodiment 62-66, wherein A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I, optionally wherein A is wherein R8a 8b and R are selected from H, alkyl, alkoxy, -OH, -CX3, and halogen, optionally R8aand R8bare selected from H, -CH3, -CF3, -OCH3, -OH, F, and Cl. Embodiment 69. The pharmaceutical composition of Embodiment 68, wherein A is selected from and optionally wherein A is Embodiment 70. The pharmaceutical composition of Embodiment 68 or 69, wherein R3is selected from optionally3 wherein R is selected from Embodiment 71. The pharmaceutical composition of any one of Embodiments 51, 52, 54, 56-59, or 62-70, wherein the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), or formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof: Embodiment 72. The pharmaceutical composition of any one of Embodiments 51-71, wherein R1ais H. Embodiment 73. The pharmaceutical composition of any one of Embodiments 51-72, wherein R1bis selected from H, C1-C6alkyl, and -CH2-CH2-. Embodiment 74. The pharmaceutical composition of any one of Embodiments 52-73, wherein R1aand R1bare joined to form an optionally substituted aryl ring. Embodiment 75. The pharmaceutical composition of Embodiment 74, wherein the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof: wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 76. The pharmaceutical composition of Embodiment 75, wherein the compound of formula (14) is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), or a pharmaceutically acceptable salt thereof:

[0041] Embodiment 77. The pharmaceutical composition of Embodiment 76, wherein the compound of formula (14) is a compound of formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof: Embodiment 78. The pharmaceutical composition of any one of Embodiments 51-54, 56, 58, or 60-70, wherein the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof: wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 79. The pharmaceutical composition of Embodiment 78, wherein the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof: Embodiment 80. The pharmaceutical composition of any one of Embodiments 51, 53, 54, 56, 58, 59, or 62- 70, wherein the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof: wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 81. The pharmaceutical composition of Embodiment 80, wherein the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof: Embodiment 82. The pharmaceutical composition of any one of Embodiments 51, 52, 55, 56, 58, 59, or 62- 70, wherein the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof: wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2. Embodiment 83. The pharmaceutical composition of Embodiment 82, wherein the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof: Embodiment 84. The pharmaceutical composition of any one of Embodiments 75-83, wherein R4ais selected from H and halogen, optionally F. Embodiment 85. The pharmaceutical composition of any one of Embodiments 75-84, wherein R4bis selected from H, -N(Ra)C(O)Ra, optionally , halogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkyl, optionally -CH3, and -CF3. Embodiment 86. The pharmaceutical composition of Embodiment 85, wherein R4bis selected from optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted pyrrolyl. Embodiment 87. The pharmaceutical composition of Embodiment 86, wherein R4bis phenyl substituted with one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, -NH2, -N(Ra)C(O)Ra, halogen, cyano, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl, optionally wherein R4bis wherein R9ais selected from -NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, halogen, cyano, -N(Ra)C(O)Ra, wherein Rais selected from H, optionally substituted alkyl, and optionally substituted alkenyl, and -C(O)R7, wherein R7is selected from H, -NH2, optionally substituted alkyl, and optionally substituted alkenyl, optionally wherein R4bis9a wherein each R is independently optionally substituted alkyl. Embodiment 88. The pharmaceutical composition of Embodiment 87, wherein R4bis selected from , optionally wherein R4bis selected from Embodiment 89. The pharmaceutical composition of Embodiment 86, wherein R4bis pyridinyl substituted with one or more halogen or cyano. Embodiment 90. The pharmaceutical composition of Embodiment 89, wherein R4bis selected from Embodiment 91. The pharmaceutical composition of Embodiment 86, wherein R4bis . Embodiment 92. The pharmaceutical composition of any one of Embodiments 75-91, wherein R4cis H. Embodiment 93. The pharmaceutical composition of any one of Embodiments 75-92, wherein R4dis selected from H, wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1. Embodiment 94. The pharmaceutical composition of Embodiment 93, wherein R5a, R5b, R5d, and R5eare each H. Embodiment 95. The pharmaceutical composition of Embodiment 93 or 94, wherein R5cis optionally substituted alkoxy, optionally -OMe. Embodiment 96. The pharmaceutical composition of Embodiment 93, wherein R5a, R5c, R5d, and R5eare each H. Embodiment 97. The pharmaceutical composition of Embodiment 93 or 96, wherein R5bis optionally substituted alkoxy, optionally -OMe. Embodiment 98. The pharmaceutical composition of any one of Embodiments 93-97, wherein R4dis selected from H, Embodiment 99. The pharmaceutical composition of any one of Embodiments 51-98, wherein the compound of formula (I) is a compound of any one of formula 1001-1150, or a pharmaceutically acceptable salt thereof. Embodiment 100. The pharmaceutical composition of any one of Embodiments 51-99, wherein the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof. Embodiment 101. A method for treating a cancer, an infectious disease, an inflammatory disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of Embodiments 51-100. Embodiment 102. The method of Embodiment 101, wherein the cancer is selected from a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin’s and non-Hodgkin’s lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin’s lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom’s Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs’ syndrome. Embodiment 103. The method of Embodiment 101 or 102, wherein the cancer is a hematologic cancer selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia, or a combination thereof. Embodiment 104. The method of any one of Embodiments 101-103, wherein the cancer is resistant to an anti-checkpoint agent. Embodiment 105. The method of Embodiment 104, wherein the anti-checkpoint agent is an antibody, optionally selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA antibody. Embodiment 106. The method of Embodiment 105, wherein the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), Cemiplimab (LIBTAYO), Atezolizumab (TECENTRIQ), Avelumab (BAVENCIO), and Durvalumab (IMFINZI). Embodiment 107. The method of Embodiment 101, wherein the infectious disease is a viral infection. Embodiment 108. The method of Embodiment 107, wherein the viral infection is caused by a virus selected from papilloma virus, 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, a human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2). Embodiment 109. The method of Embodiment 101, wherein the inflammatory disease is an autoimmune disease or condition, selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture’s syndrome, Wegener’s granulomatosis, autoimmune epilepsy, Rasmussen’s encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addisohn’s disease, Hashimoto’s thyroiditis, Fibromyalgia, Menier’s syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren’s syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter’s syndrome, Grave’s disease, and other autoimmune disease. Embodiment 110. A method for treating an anti-checkpoint agent-resistant cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of Embodiments 51-100. Embodiment 111. The method of Embodiment 110, wherein the anti-checkpoint agent is an antibody, optionally selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA antibody. Embodiment 112. The method of Embodiment 111, wherein the antibody is selected from nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559, MPDL328OA (ROCHE), Cemiplimab (LIBTAYO), Atezolizumab (TECENTRIQ), Avelumab (BAVENCIO), and Durvalumab (IMFINZI). Embodiment 113. A method of determining a cancer treatment for a patient, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any one of Embodiments 51-100 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. Embodiment 114. A method for selecting a patient for a cancer treatment, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any one of Embodiments 51-100 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. Embodiment 115. A method of treating cancer, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) administering the cancer therapy comprising the pharmaceutical composition of any one of Embodiments 51-100 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally administering a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody. Embodiment 116. The method of any one of Embodiments 113-115, wherein the biological sample is a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen. Embodiment 117. The method of any one of Embodiments 113-116, 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), needle biopsy (e.g., fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound-assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy. Embodiment 118. The method of any one of Embodiments 113-117, wherein the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom. Embodiment 119. The method of any one of Embodiments 113-118, wherein the biological sample comprises at least one tumor cell. Embodiment 120. The method of any one of Embodiments 113-119, wherein the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof.

[0042] Embodiment 121 . The method of any one of Embodiments 113-120, wherein the evaluating is performed by contacting the sample with an agent that specifically binds to Trim7.

[0043] Embodiment 122. The method of Embodiment 121 , wherein the agent that specifically binds to one or proteins comprises an antibody, antibody-like molecule or binding a fragment thereof.

[0044] Embodiment 123. The method of any one of Embodiments 113-122, wherein the evaluating is performed by contacting the sample with an agent that specifically binds to one or more of nucleic acids of Trim7.

[0045] Embodiment 124. The method of Embodiment 123, wherein the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

[0046] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0047] The disclosure will be further described in the following examples, which do not limit the scope of the disclosure described in the claims. EXAMPLES

[0048] The examples herein are provided to illustrate advantages and benefits of the present disclosure and to further assist a person of ordinary skill in the art with preparing or using the Trim7 inhibitors of the present disclosure. The examples herein are also presented in order to more fully illustrate the preferred aspects of the present disclosure. The examples should in no way be construed as limiting the scope of the present disclosure, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present disclosure described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects or embodiments of the present disclosure. Example 1: Binding of Recombinant Human Trim7 Protein to RACO1 and MSK1 Without wishing to be bound by theory, it is believed that MSK1 directly phosphorylates the tripartite motif containing 7 (Trim7). It is believed, without wishing to be bound by theory, that Trim7 can ubiquitinylate proteins such as RACO1, Mitochondrial Anti-Viral Signaling Protein (MAVS) and STING, which in turn impairs host immune interferon responsiveness. The binding of Trim7 protein to RACO1 and MSK1 was studied using a Meso Scale Discovery (MSD) platform-based assay. Briefly, recombinant human Trim7 protein was coated on a plate. Increasing amounts of RACO1, MSK1, or CD47 proteins were added to the plate for capture by the plate-bound recombinant Trim7 protein. The RACO1 or MSK1 proteins captured by the plate-bound Trim7 protein was detected using an anti-human RACO1 o anti-human MSK1 antibodies and a SULFO-TAG conjugated secondary antibody. As shown in FIG.1A, RACO1 protein bound to the plate-bound recombinant Trim7 protein in a dose- dependent manner. In comparison, the CD47 protein showed only background signal (FIG.1A). Similarly, as shown in FIG.1B, MSK1 protein bound to the plate-bound recombinant Trim7 protein in a dose-dependent manner. In comparison, the CD47 protein showed only background signal (FIG.1B). These results demonstrate, inter alia, that the Trim7 protein disclosed herein specifically binds to RACO1, MSK1 proteins. Example 2: Binding of Recombinant Human Trim7 Protein to Enterovirus 712BC Protein The binding of Trim7 protein to enterovirus 712B / C and 2C proteins was studied using a Meso Scale Discovery (MSD) platform-based assay. 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 712B or enterovirus 712BC proteins were coated on a plate. Increasing amounts of recombinant human Trim7 protein was added to the plate for capture by the plate-bound RACO1, MSK1, CD47, enterovirus 712B or enterovirus 712BC proteins. The Trim7 protein captured by the plate-bound RACO1, MSK1, CD47, enterovirus 712B or enterovirus 712BC proteins was detected using an anti-human Trim7 antibody and a SULFO-TAG conjugated secondary antibody. As shown in FIG.2, Trim7 was able to bind the plate-bound enterovirus 712B / C protein in a dose- dependent manner. As expected, Trim7 was able to bind the plate-bound RACO1 and MSK1 proteins, but not CD47 protein (FIG.2). The extent of binding of Trim7 to enterovirus 712B / C protein approximated the levels of binding to MSK1 and RACO1. In comparison, Trim7 did not noticeably bind to the 2B portion of the viral protein (FIG.2). These results demonstrate, inter alia, that the Trim7 protein disclosed herein specifically binds to enterovirus 712B / C protein. Example 3: Enterovirus 712BC Protein Disrupts the Binding of Recombinant Human Trim7 Protein to RACO1 and MSK1 The effect of enterovirus 712B / C protein on the binding of Trim7 protein to recombinant human RACO1 or MSK1 proteins was studied using an a Meso Scale Discovery (MSD) platform-based assay. Briefly, recombinant human Trim7 protein was coated on a plate. Increasing amounts of enterovirus 712B / C protein was added to the plate for capture by the plate-bound recombinant Trim7 protein. Recombinant human MSK1 protein was added to the plate with or without 5 μg / ml enterovirus 712B / C protein. The binding was then detected using anti-MSK1 antibody and a SULFO-TAG conjugated secondary antibody. As shown in FIG. 3A, Trim7 could be detected with MSK1 protein / anti-MSK1 antibody. Interestingly, the amount of signal reduced when the detection was performed in the presence of 5 μg / ml enterovirus 712B / C protein (FIG.3A). These results demonstrate, inter alia, that enterovirus 712BC protein disrupts the binding of recombinant human Trim7 protein to MSK1. In another such experiment, recombinant human Trim7 protein was coated on a plate. Increasing amounts of enterovirus 712B / C protein was added to the plate for capture by the plate-bound recombinant Trim7 protein. Recombinant human RACO1 protein was added to the plate with or without 5 μg / ml enterovirus 71 2B / C protein. The binding was then detected using anti-RACO1 antibody and a SULFO-TAG conjugated secondary antibody. As shown in FIG.3B, Trim7 could be detected with RACO1 protein / anti-RACO1 antibody. Interestingly, the amount of signal reduced when the detection was performed in the presence of 5 μg / ml enterovirus 712B / C protein (FIG.3B). These results demonstrate, inter alia, that enterovirus 712BC protein disrupts the binding of recombinant human Trim7 protein to RACO1. Example 4: Identification of Trim7 Inhibitors Based on Molecular Modeling The crystal structure of Trim7 has been solved. Muñoz Sosa, et al., Crystal structure and mutational analysis of the human Trim7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1, J Biol Chem 2021;296:100772. The crystal structure has malonic acid bound to a pocket. The crystal structure of Trim7 bound to the CVB_2C (319-329) peptide (SVGTTLEALFQ) has also been solved. 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. FIG.4 (left top panel) shows a schematic representation of the CVB3 C2 protein, showing the location of the CVB_2C (319-329) peptide. FIG.4 (left bottom panel) shows crystal structure of CVB_2C protein, showing the CVB_2C (319-329) peptide, and a crystal structure of the Trim7 protein complexed with the CVB_2C (319-329) peptide. FIG.4 (right panel) shows the interactions of the CVB_2C (319-329) peptidewith various amino acids of Trim7 protein. This crystal structure shows that glutamine-specific interaction is observed with the CVB3_2C peptide, which is inserted into a positively charged groove of the Trim7 PRY-SPRY domain. A homology models of Trim7 with CVB3_2C peptide (TTLEALFQ), GNI peptide (RKLDTYLQ) or a shortened peptide (Ac-ALFQ) were developed based on available crystal structures. Homology models revealed interaction of carboxy-group of the C-terminal glutamine of CVB3_2C peptide with Trim7 protein (FIG.5). Additional hydrophobic interactions with Phe or Leu at second-last amino acid were also observed (FIG.5). Based on these interactions, conformationally restrained, rigid small compounds containing carboxy group and certain aromatic moieties that dock well in the molecule were identified, which included the compounds of formula (I). FIG.5 shows a schematic representation of the molecular simulation-based method used for identification of Trim7 inhibitors, including compound of formula 1. FIG.6A and FIG.6B show various docked compounds. The underlined compounds have a docking score better than -7, indicative of likely affinity constant of <100nM. Representative compounds along with their docking scores are shown in FIG.7. Based on this model, compound 1009 can bind to Trim7 (FIG.8A). This binding is stabilized by hydrophobic stacking interactions, among others (FIG.8B). Modelling studies also showed the binding of compound 1014 (FIG. 9A), which is also stabilized by hydrophobic stacking interactions, among others (FIG.9B). These results demonstrate, inter alia, that the compounds of formula (I) are likely to disrupt the binding of recombinant human Trim7 protein to MSK1. Accordingly, the compounds of formula (I) are inhibitors of Trim7, which are useful in the methods disclosed herein. Example 5: Disruption of the Binding of Recombinant Human Trim7 Protein to RACO1 and MSK1 The effect of compounds of formula (I) on the binding of Trim7 protein to recombinant human RACO1 or MSK1 proteins is studied using an a Meso Scale Discovery (MSD) platform-based assay. Briefly, recombinant human Trim7 protein is coated on a plate. Increasing amounts of compounds of formula (I) (e.g., compound 1009 and 1014) are added to the plate for capture by the plate-bound recombinant Trim7 protein. Recombinant human RACO1 and / or MSK1 protein is added to the plate with or without compounds of formula (I) (e.g., compound 1009 and 1014). The binding is then detected using anti-RACO1 antibody and / or anti- and / or MSK1 antibody in combination with a SULFO-TAG conjugated secondary antibody. It is expected that Trim7 will exhibit binding to RACO1 and / or MSK1 protein in the absence of compounds of formula (I) (See FIG.1A and FIG.1B). It is anticipated that Trim7 will exhibit reduced binding to RACO1 and / or MSK1 protein when the detection is performed in the presence compounds of formula (I). These results will demonstrate, inter alia, that compounds of formula (I) disrupt the binding of recombinant human Trim7 protein to RACO1 and / or MSK1 protein. Accordingly, the compounds of formula (I) are inhibitors of Trim7, which are useful in the methods disclosed herein. Example 6: IC50data of compounds of the disclosure This Example provides data showing IC50values of compounds of the disclosure from a TRIM7 fluorescence polarization (FP) binding assay. A TRIM7 fluorescence polarization (FP) binding assay was performed on compounds of the disclosure. The assay was performed using the far C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3) previously shown to interact with the same TRIM7-PrySpry(324-511) domain (Ru, Y. et al., Proc. Natl. Acad. Sci. U.S.A., 2022, 119(3): e2203218119), which was incubated for 22 hours with His-TRIM7-PrySpry(324-511). An unlabeled version of the same peptide, a shorter version of that peptide (LFQ only), or the small molecule inhibitors (SMIs) were added to compete with the binding of the fluorescently labeled peptide to the same docking pocket. The loss of fluorescent signal as the labeled peptide is competed off was quantified. The results are shown in the table below, where the IC50is indicated as follows: Key: +++ = IC50< 15 µM ++ = 15 µM < IC50< 100 µM + = IC50> 100 µM N / A = Compound not yet tested Example 7: IC50data of compounds of the disclosure A TRIM7 fluorescence polarization (FP) binding assay was performed on compounds of the disclosure. The assay was performed using the far C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3) previously shown to interact with the same TRIM7-PrySpry(324-511) domain, which was incubated for 22 hours with His-TRIM7-PrySpry(324-511). An unlabeled version of the same peptide, a shorter version of that peptide (LFQ only), or the small molecule inhibitors (SMIs) were added to compete with the binding of the fluorescently labeled peptide to the same docking pocket. The loss of fluorescent signal as the labeled peptide is competed off was quantified. The results are shown in the table below, where the IC50is indicated as follows: Key: +++ = IC50< 15 µM ++ = 15 µM < IC50< 100 µM + = IC50> 100 µM N / A = Compound not yet tested Example 8: TRIM7 interaction with SMIs of the disclosure TRIM7 is most described in viral biology, where it ubiquitinates viral proteins (e.g., CVB3_2BC, EV71, and SARS-CoV2) and targets them for degradation (FIG.10A). The crystal structure of the c-term PrySpry domain of TRIM7 was recently solved, identifying the key pocket where viral binding could occur (FIG.10B). The crystal structure of TRIM7 with viral peptide was solved and identified a key cysteine in the binding pocket that could be exploited for covalent binding (FIG.10C). Importantly, the c-term amino acids of viral CVB3_2C were shown to specifically interact in this pocket, and this amino acid motif is conserved with the native proteins GN1 and RACO-1. These structural learnings partially informed the small molecule inhibition of TRIM7. Recombinant proteins were generated to facilitate small molecule inhibitor (SMI) development and to verify binding / functional activity. TRIM7 interactions with RACO-1, STING, MAVS, and CVB3_2C (WT but not mutant) were confirmed (FIG.11). Using these findings, various compounds of the disclosure have been developed, screened through a series of binding / activity assays, and prioritized for further chemical modification (FIG.12). Binding affinity of immobilized TRIM7 protein to certain TRIM7 SMIs was determined using (using Biolayer Interferometry, BLI) (FIG.13). The data demonstrates compounds 1077, 1123, and 1124 outperform native interactions of TRIM7 and CVB3 enterovirus. The BLI target affinity assessment indicates that the SMI binding affinities to TRIM7 are in the pM to nM range (FIG.13). Table 1 provides binding data for several compounds of the disclosure to the PrySpry domain. Binding was assessed qualitatively, with a score of *, **, ***, or **** based on whether the correct SMI mass was detected following incubation with TRIM7_PrySpry (Full Scan), and whether an interaction was confirmed at the intended C501 in the binding pocket (peptide mapping). Legend: Scores of * or ** indicate some binding was detected however assay requires further optimization. Scores of *** or **** indicate high confidence binding. ND indicates that the compound has not been tested. Table 1. Binding data to the PrySpry domain for compounds of the disclosure FIGS.14A-14B are cell-based activity assays demonstrating that TRIM7 expression in cells results in target degradation / stabilization. FIG.14A demonstrates that the over expression of TRIM7 (+T7) in 293T cell lines with either CVB3, MAVS, or STING; results in their degradation, consistent with previous studies. FIG.14B demonstrates that RACO-1 over-expressed on its own, resulting in self-ubiquitination and degradation. When TRIM7 is co-expressed with RACO1, RACO1 is stabilized. TRIM7 SMIs, such as compound 1034, have varying activities in blocking TRIM7 stabilization of RACO1, resulting in its degradation. FIGS.15A-15C are activity assays demonstrating that TRIM7 expression in cell-based and cell-free assays results in target degradation / stabilization. FIG.15A is a cell-based assay in HEK293 cells demonstrating that the over expression of TRIM7 (+) with either CVB3, MAVS, or STING results in their degradation and the over expression of TRIM7 (+) with RACO-1 results in its stabilization. FIG. 15B is a cell-free target ubiquitination assay demonstrating that the presence of a TRIM7 SMI (compound 1036) disrupts target ubiquitination. FIG.15C demonstrates that RACO-1 over-expressed on its own, resulting in self-ubiquitination and degradation. When TRIM7 is co-expressed with RACO1, RACO1 is stabilized. TRIM7 SMIs, such as compound 1036, have varying activities in blocking TRIM7 stabilization of RACO1, resulting in its degradation. FIG.16 is a cell-free activity assay demonstrating TRIM7 mediated target ubiquitination of CVB3. For this assay, it was expected that TRIM7 incubation with target viral protein CVB3 should facilitate TRIM7-mediated poly-ubiquitination. Ubiquitination on an individual CVB3 protein level will vary, resulting in an increase in banding and ‘smearing’ in a gel. While not wishing to be bound by any particular theory, the ubiquitination should be reversed in the presence of a specific TRIM7 SMI. The results confirm that compound 1034 reduces TRIM7-mediated ubiquitination of CVB3_2C in a dose dependent manner. FIG.17 demonstrates that TRIM7 SMI inhibition in an CT26 immune checkpoint blockade (ICB) acquired resistance (AR) cell line using compound 1036 reduces tumor cell viability in a dose dependent manner. FIGS.18A-18C demonstrate that CT26 ICB-acquired resistance (AR) tumor cells are sensitive to TRIM7 inhibition, wherein TRIM7 inhibition in CT26 / AR tumor cells returns the transcriptional profile of AR- dysregulated genes back towards WT CT26. FIG.18A is a heat map depicting 1,181 genes that are compensated (return toward WT) following TRIM7 inhibition with a TRIM7 SMI (compound 1036). FIG.18B is a heat map depicting that many of the compensated genes following inhibition with compound 1036 are associated with TRIM7 pathways (e.g., Ras, MAVS, STING, and Raco1 / AP1). FIG.18C provides some example genes in these TRIM7 pathways that demonstrate a return toward WT expression following TRIM7 inhibition with compound 1036. FIG.19 demonstrates that ICB acquired resistance induces transcriptional hyperactivation of genes associated with IFN alpha / gamma responsiveness, NFKB and JAK / STAT signaling. The inhibition of TRIM7 with a TRIM7 SMI, such as compound 1036, dampens the expression of these associated pathways FIGS.20A-20E demonstrate that the inhibition of TRIM7 results in KRAS mutant tumor cell death and the activity is increased in the presence of KRAS inhibition and the anti-PD1 antibody Keytruda. FIG.20A depicts two human cancer cell lines (A549 and GP2D) that express TRIM7 protein. The detection of Histone H3 is used as a protein loading control. FIG.20B depicts that a knock down of TRIM7 using siRNA reduces tumor viability and increases T cell mediated killing of tumor cells, and this activity is enhanced in the presence of KRAS inhibition. FIGS. 20C and 20D demonstrate that TRIM7 small molecule inhibition (using compound 1036) also reduces tumor cell viability alone and in combination with KRAS inhibition. FIG. 20E demonstrates that TRIM7 inhibition combined with KRAS inhibition induced tumor cell apoptosis in the presence of activated T cells and this activity was significantly improved in combination with Keytruda.

[0049] FIG. 21 demonstrates that CT26 / AR cells are sensitive to both TRIM7 and KRAS inhibition and their combination (for example, using compound 1036 as a TRIM7 SMI (TRIM7i-1 and TRIM7i in FIG. 21)) results in further proliferative inhibition. Although not wishing to be limited by theory, TRIM7 inhibition may obviate the need to inhibit up-stream KRAS signaling and / or result in additive anti-proliferative activity in combination with existing KRAS pathway inhibitors.

[0050] FIGS. 22A-22B demonstrate that TRIM7 inhibition prevents proliferation of human KRAS mutant tumors and this activity is enhanced in the presence of KRAS inhibition. FIG. 22A demonstrates that TRIM7 inhibition using TRIM7 SMI compound 1036 in GP2D colorectal carcinoma cells reverses the expression of genes in the Ras, MAVS, STING, and Raco-1 / AP1 pathways, consistent with the results from CT26 / AR treatment with compound 1036 as a TRIM7 inhibitor. FIG. 22B demonstrates that TRIM7 inhibition using TRIM7 SMI compound 1036 in A549 lung cancer cells reverses the expression of genes in the Ras, MAVS, STING, and Raco-1 / AP1 pathways, consistent with the results from CT26 / AR treatment with compound 1036 as a TRIM7 inhibitor.

[0051] FIGS. 23A-23C are in vivo studies in mice demonstrating that TRIM7 inhibition with a TRIM7 SMI, such as compound 1036, controls the growth of CT26 / AR tumors and re-sensitizes them to PD1 blockade through normalization of tumor-intrinsic transcriptional regulation and increased effector T cell infiltration. FIG. 23A demonstrates the anti-tumor efficacy of TRIM7 SMI compound 1036 in a mouse CT26 / AR model. FIG 23B is a TIL analysis by flow cytometry. FIG. 23C is a transcriptional analysis of isolated tumors treated with vehicle or TRIM7 SMI compound 1036.

[0052] In summary various compounds of the disclosure have been synthesized and prioritized through a series of binding / activity assays. The specific binding was confirmed specific binding through BLI, fluorescent polarization, and mass spec analysis. The functional activity was validated through the disruption of target ubiquitination and stabilization. TRIM7 inhibition in CT26 / AR was found to result in decreased proliferation and increased apoptosis. The TRIM7 SMIs were also found to disrupt proliferation of TRIM7-expressing KRAS mutant human cancer cell lines and the activity of TRIM7 SMI is improved in combination with KRAS inhibition. Taken together, these results demonstrate that TRIM7 may be a driver of ICB acquired resistance and its inhibition alone or in combination with KRAS pathway inhibition, may be a therapeutic approach to treat ICB resistance and restore patient sensitivity to immune checkpoint therapy. Example 9: IC50values of compounds of the disclosure This Example provides data showing IC50values of compounds of the disclosure from a TRIM7 fluorescence polarization (FP) binding assay. A TRIM7 fluorescence polarization (FP) binding assay was performed on compounds of the disclosure. The assay was performed using the far C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3) previously shown to interact with the same TRIM7-PrySpry(324-511) domain (Ru, Y. et al., Proc. Natl. Acad. Sci. U.S.A., 2022, 119(3): e2203218119), which was incubated for 30 minutes with His-TRIM7-PrySpry(324-511). An unlabeled version of the same peptide, a shorter version of that peptide (LFQ only), or the small molecule inhibitors (SMIs) were added to compete with the binding of the fluorescently labeled peptide to the same docking pocket for 1.5 hours. The loss of fluorescent signal as the labeled peptide is competed off was quantified. The results are shown in the table below, where the IC50 is indicated as follows: Key: +++ = IC50< 15 µM ++ = 15 µM < IC50< 100 µM + = IC50> 100 µM Example 10: In vivo anti-tumor activity of a compound of formula (I) in Combination with a kras Inhibitor The efficacy of a compound of formula (I) is evaluated in combination with a kras inhibitor. Briefly, BALB / C mice are inoculated with 500,000 murine colon carcinoma CT26 cells on the rear flank. When average tumor volume reached 80-100 mm3(indicating day 0), mice, the mice are randomly distributed in four following treatment groups. The groups of mice are administered (1) vehicle only control, (2) a compound of formula (I) alone, (3) kras inhibitor alone, or (4) a combination of a compound of formula (I) and a kras inhibitor. The administration is performed on days on days 0, 3, 6, 9, 12, and 15. Tumors are measured with electronic calipers on every day and plotted using the GraphPad Prism software. The tumor growth for each treatment group is assessed by plotting tumor growth curves of individual mice, average tumor growth curves for treatment groups, average tumor sizes on an illustrative day, and / or Kaplan-Meier plots. The results are expected to demonstrate, inter alia, that the combination of a compound of formula (I) and a kras inhibitor has greater anti-tumor activity compared to either single treatment. Example 11: In vivo anti-tumor activity of a compound of formula (I) in Combination with a braf Inhibitor The efficacy of a compound of formula (I) is evaluated in combination with a braf inhibitor. Briefly, BALB / C mice are inoculated with 500,000 murine colon carcinoma CT26 cells on the rear flank. When average tumor volume reached 80-100 mm3(indicating day 0), mice, the mice are randomly distributed in four following treatment groups. The groups of mice are administered (1) vehicle only control, (2) a compound of formula (I) alone, (3) braf inhibitor alone, or (4) a combination of a compound of formula (I) and a braf inhibitor. The administration is performed on days on days 0, 3, 6, 9, 12, and 15. Tumors are measured with electronic calipers on every day and plotted using the GraphPad Prism software. The tumor growth for each treatment group is assessed by plotting tumor growth curves of individual mice, average tumor growth curves for treatment groups, average tumor sizes on an illustrative day, and / or Kaplan-Meier plots. The results are expected to demonstrate, inter alia, that the combination of a compound of formula (I) and a braf inhibitor has greater anti-tumor activity compared to either single treatment. Example 12: In vivo anti-tumor activity of a compound of formula (I) in Combination with a MEK Inhibitor The efficacy of a compound of formula (I) is evaluated in combination with a MEK inhibitor. Briefly, BALB / C mice are inoculated with 500,000 murine colon carcinoma CT26 cells on the rear flank. When average tumor volume reached 80-100 mm3(indicating day 0), mice, the mice are randomly distributed in four following treatment groups. The groups of mice are administered (1) vehicle only control, (2) a compound of formula (I) alone, (3) MEK inhibitor alone, or (4) a combination of a compound of formula (I) and a MEK inhibitor. The administration is performed on days on days 0, 3, 6, 9, 12, and 15. Tumors are measured with electronic calipers on every day and plotted using the GraphPad Prism software. The tumor growth for each treatment group is assessed by plotting tumor growth curves of individual mice, average tumor growth curves for treatment groups, average tumor sizes on an illustrative day, and / or Kaplan-Meier plots. The results are expected to demonstrate, inter alia, that the combination of a compound of formula (I) and a MEK inhibitor has greater anti-tumor activity compared to either single treatment. Example 13: IC50 data of compounds of the disclosure This Example provides data showing IC50values of compounds of the disclosure from a TRIM7 fluorescence polarization (FP) binding assay. A TRIM7 fluorescence polarization (FP) binding assay was performed on compounds of the disclosure. The assay was performed using the far C-terminal 9 amino acids (GATLEALFQ (SEQ ID NO: 1)) of a fluorescently labeled viral peptide (CVB3) previously shown to interact with the same TRIM7-PrySpry(324-511) domain (Ru, Y. et al., Proc. Natl. Acad. Sci. U.S.A., 2022, 119(3): e2203218119), which was incubated for 22 hours with His-TRIM7-PrySpry(324-511). An unlabeled version of the same peptide, a shorter version of that peptide (LFQ only), or the small molecule inhibitors (SMIs) were added to compete with the binding of the fluorescently labeled peptide to the same docking pocket. The loss of fluorescent signal as the labeled peptide is competed off was quantified. The results are shown in the table below, where the IC50is indicated as follows: Key: +++ = IC50< 15 µM ++ = 15 µM < IC50< 100 µM + = IC50> 100 µM N / A = Compound not yet tested Example 14 Synthesis of 6'-(2-acrylamidophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1094):

[0053] Preparation of 6'-bromo-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Int-5a): 4-Bromo-2-(carboxymethyl)benzoic acid (0.6 g, 2.3 mmol) was taken in toluene (15 ml) with cyclopentanone (0.2 mL, 2.3 mmol, 1.0 eq.). {[3-fluoro-4-(trifluoromethyl)phenyl]methyl}amine (0.45 g, 2.3 mmol, 1.0 eq.) was added and the suspension was heated to reflux. The flask was attached to a Dean-Stark trap to collect the water. The solution was heated for 18 hrs. After cooling, the solution was concentrated and purified on Combiflash using dichloromethane / methanol gradient to afford the product as a pale – yellow oil (0.8 g, 69% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.0 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.55 – 7.45 (m, 2H), 7.27 – 7.30 (, 1H), 7.25 – 7.20 (m 1H), 5.30 (d, J=16.0 Hz, 1H), 4.25 (d, J=16.0 Hz, 1H), 3.70 (s, 1H), 2.15 – 2.00 (m, 1H), 1.95 – 1.65 (m, 5H), 1.65 – 1.50 (m, 2H). LCMS EI-MS m / z: = 500.1[M+H]+. Preparation of 6'-(2-aminophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Int-5b): 6'-Bromo-2'-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-1'-oxo-2'H,4'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Int-1a) (225 mg, 0.45 mmol) was taken in 1,4-dioxane / water (2 ml, 1 ml). o-(dihydroxyboryl)aniline (68 mg, 0.49 mmol, 1.1 eq.) and sodium carbonate (95 mg, 0.9 mmol, 2.0 eq.) were added and then nitrogen as bubbled for 10 mins.1,1'-Bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol, 0.05 eq.) was then added and the solution was heated to 80 C for 13 hrs. After cooling, the reaction was quenched by adding 1 N HCl solution (pH ~ 6-7) and then filtered through celite. The filtrate extracted into dichloromethane / isopropanol (4 times). The combined organic layer was filtered through magnesium sulfate and the filtrate was concentrated. The residue was purified on Combiflash using dichloromethane / methanol gradient to afford the title compound as a white solid (120 mg, 53% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.19 (d, J=8.0 Hz, 1H), 7.55 – 7.15 (m, 7H), 6.90 – 6.75 (m, 2H), 5.29 (d, J=16.0 Hz, 1H), 5.10 (br s, 1H), 4.32 (d, J=16.0 Hz, 1H), 3.76 (s, 1H), 2.00 – 1.85 (m, 2H), 1.85 – 1.70 (m, 4H), 1.70 – 1.50 (m, 2H). LCMS ESI-MS m / z: = 513.2[M+H]+. Preparation of 6'-(2-acrylamidophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1094): 6'-(o-aminophenyl)-2'-{[3-fluoro-4- (trifluoromethyl)phenyl]methyl}-1'-oxo-2'H,4'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (275 mg, 0.15 mmol) was taken in THF (1 m) and a solution of 2 N NaOH (1 ml) was added to it. Acryloyl chloride (0.2 ml) was then added, and the solution was stirred for the next 1 hrs. LCMS showed that the reaction was completed. The solution was quenched by adding 1 N HCl and then extracted into dichloromethane. The organic layer was filtered through magnesium sulfate and the filtrate was concentrated. The residue was purified on Combiflash using dichloromethane / methanol gradient to give the product. It was then re-purified on reverse phase HPLC using to afford the title compound (65 mg, 21% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (br s, 1H), 9.60 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 7.34 - 7.59 (m, 8H), 6.31 (dd, J=17.0, 10.1 Hz, 1H), 6.14 (dd, J=17.1 , 1.8 Hz, 1H), 5.65 (dd, J=10.1, 1.7 Hz, 1H), 5.20 (br d, J=17.1 Hz, 1H), 4.39 (br d, J=17.1 Hz, 1H), 3.80 (s, 1H), 1.92 (br dd, J=13.3, 6.5 Hz, 1H) 1.52 - 1.79 (m, 7H). LCMS EI-MS m / z: = 567.2[M+H]+. Example 15 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(o-tolyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1032): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(o-tolyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1032) was synthesized using 2-methylphenylboronic acid in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (11 mg, 9% yield).1H NMR (400 MHz, METHANOL-d4)δ ppm 8.07 (d, J=8.0 Hz, 1H), 7.75 – 7.10 (m, 9H), 5.32 (d, J=16.8 Hz, 1H), 4.44 (d, J=16.4 Hz, 1H), 3.92 (s, 1H), 2.27 (s, 3H), 2.20 – 2.00 (m, 1H), 2.00 – 1.60 (m, 7H). LCMS EI-MS m / z: = 512.2[M+H]+. Example 16 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1033): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1033) was synthesized using 2- trifluoromethyl phenylboronic acid in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (5 mg, 9% yield). LCMS EI-MS m / z: = 556.1[M+H]+. Example 17 Synthesis of 2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclobutane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1035): 2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclobutane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1035) was synthesized using homophthalic anhydride (450 mg, 2.8 mmol), cyclobutanone (0.2 g, 2.8 mmol, 1.0 eq.), and 3,4-dichlorobenzylamine (0.38 ml, 2.8 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (104 mg, 9% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 12.82 (br s, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.35 - 7.60 (m, 5H) 5.05 (d, J=16.5 Hz, 1H), 4.76 (d, J=16.5 Hz, 1H), 4.27 (s, 1H), 2.81 - 2.56 (m, 2H), 2.56 - 2.53 (m, 1H), 2.29 - 2.15 (m, 1H), 1.91 - 1.77 (m, 2H), 1.77 - 1.62 (m, 1H). LCMS EI-MS m / z: = 390.2[M+H]+. Example 18 Synthesis of 6'-(2-cyanophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1036): 6'-(2-cyanophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1036) was synthesized using 2-cyanophenylboronic acid in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (8 mg, 8% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.07 (d, J=8.0 Hz, 1H), 7.75 – 7.10 (m, 9H), 5.32 (d, J=16.8 Hz, 1H), 4.44 (d, J=16.4 Hz, 1H), 3.92 (s, 1H), 2.27 (s, 3H), 2.20 – 2.00 (m, 1H), 2.00 – 1.60 (m, 7H). LCMS EI-MS m / z: = 523.2[M+H]+. Example 19 Synthesis of 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-6-(2-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid (Compound 1037): 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-6-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid (Compound 1037) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (800 mg, 3.1 mmol), acetone (1.36 ml, 18.5 mmol, 3.1 eq.), 3,4-dichlorobenzylamine (540 mg, 3.1 mmol, 1.0 eq.) in Step 17 and 2- trifluoromethyl phenylboronic acid (75 mg, 0.4 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (12 mg, 7% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.22 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.62 – 7.20 (m, 9H), 5.12 (d, J=8.0 Hz, 1H), 4.46 (d, J=8.0 Hz, 1H), 3.70 (s, 1H), 1.44 (s, 3H), 1.28 (s, 3H). LCMS EI-MS m / z: = 522.0[M+H]+. Example 20 Synthesis of 6'-(2-chloropyridin-3-yl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1038): 6'-(2-chloropyridin-3-yl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Compound 1038) was synthesized using (2-chloropyridin-3-yl)boronic acid (37 mg, 0.24 mmol) in Step 18 following the procedure described for compound 1094 to afford the title product as white powder (11 mg, 9% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.43 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H), 7.65 – 7.35 (m, 6H), 5.32 (d, J=8.6 Hz, 1H), 4.44 (d, J=8.6 Hz, 1H), 3.96 (s, 1H), 2.10 – 2.00 (m, 1H), 2.00 – 1.50 (m, 7H). LCMS EI-MS m / z: = 533.1[M+H]+. Example 21 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(1H-pyrrol-2-yl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1039): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(1H-pyrrol-2-yl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1039) was synthesized using {1-[(tert-butoxy)carbonyl]-1H-pyrrol-2- yl}boronic acid (38 mg, 0.18 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (7 mg, 8% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 11.00 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.60 – 7.40 (m, 5H), 6.88 (s, 1H), 6.67 (s, 1H), 6.21 (t, J=2.8 Hz, 1H), 5.30 (d, J=16.0 Hz, 1H), 4.39 (d, J=16.0 Hz, 1H), 3.84 (s, 1H), 2.10 – 2.00 (m, 1H), 1.95 – 1.50 (m, 7H). LCMS EI-MS m / z: = 487.2[M+H]+. Example 22 Synthesis of 6'-fluoro-2'-(furan-2-ylmethyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1041): 6'-fluoro-2'-(furan-2-ylmethyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1041) was synthesized using 4-fluoro-2-(carboxymethyl)benzoic acid (400 mg, 2.0 mmol), cyclopentanone (170 mg, 2.0 mmol, 1.0 eq.), furan-2-ylmethanamine (195 mg, 2.0 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (24 mg, 4% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.02 (dd, J=8.8, 5.6 Hz, 1H), 7.39 (s, 1H), 7.20 – 7.05 (m, 2H), 6.35 – 6.30 (m, 2H), 4.85 (d, J=16.4 Hz, 1H), 4.68 (d, J=16.4 Hz, 1H), 3.82 (s, 1H), 2.50 – 2.40 (m, 1H), 2.10 – 2.00 (m, 1H), 1.90 – 1.80 (m, 2H), 1.80 – 1.70 (m, 1H), 1.70 – 1.55 (m, 2H), 1.55 – 1.42 (m, 1H). LCMS EI-MS m / z: = 344.0[M+H]+. Example 23 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1042): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1042) was synthesized using homophthalic anhydride (480 mg, 3.0 mmol), cyclopentanone (0.25 g, 3.0 mmol, 1.0 eq.), and 3-fluoro-4-trifluoromethylbenzyl amine (0570 mg, 3.0 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (6 mg, 1% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.02 (d, J=7.5 Hz, 1H) 7.63 - 7.53 (m, 2H) 7.51 - 7.37 (m, 4H) 5.29 (d, J=17.0 Hz, 1H) 4.40 (d, J=17.0 Hz, 1H) 3.86 (s, 1H) 2.14 – 1.94 (m, 1H) 1.91 - 1.73 (m, 5H) 1.71 - 1.60 (m, 2H). LCMS EI-MS m / z: = 422.1[M+H]+. Example 24 Synthesis of 2'-benzyl-6'-fluoro-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1043): 2'-benzyl-6'-fluoro-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1043) was synthesized using 4-fluoro-2-(carboxymethyl)benzoic acid (250 mg, 1.3 mmol), cyclopentanone (106 mg, 1.3 mmol, 1.0 eq.), benzylamine (135 mg, 1.3 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (19 mg, 4% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.06 (dd, J=8.8, 5.6 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.30 – 7.25 (m, 2H), 7.25 – 7.10 (m, 3H), 5.13 (d, J= 16.0 Hz, 1H), 4.68 (d, J=16.0 Hz, 1H), 3.82 (s, 1H), 2.20 – 2.10 (m, 1H), 1.92 – 1.72 (m, 4H), 1.70 – 1.55 (m, 3H). LCMS EI-MS m / z: = 354.1[M+H]+. Example 25 Synthesis of 2'-(furan-2-ylmethyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1044): 2'-(furan-2-ylmethyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Example 1044) was synthesized using 2-(carboxymethyl)benzoic acid (860 mg, 4.8 mmol), cyclopentanone (0.4 g, 4.8 mmol, 1.0 eq.), and 1-(furan-2-yl)methanamine (460 mg, 4.8 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (35 mg, 2% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.98 (d, J=7.4 Hz, 1H), 7.55 - 7.33 (m, 4H), 6.37 (d, J=3.1 Hz, 1H), 6.33 (dd, J=3.1, 1.9 Hz, 1H), 4.85 - 4.82 (m, 1H), 4.78 - 4.63 (m, 1H), 3.79 (s, 1H), 2.47 (dt, J=14.0, 7.8 Hz, 1H), 2.02 (dt, J=14.0, 6.7 Hz, 1H), 1.95 - 1.80 (m, 2H), 1.77 - 1.53 (m, 3H), 1.52 - 1.44 (m, 1H). LCMS EI-MS m / z: = 326.1[M+H]+. Example 26 Synthesis of 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1047): 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1047) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (1.0 g, 5.1 mmol), cyclopentanone (0.43 g, 5.1 mmol, 1.0 eq.), and 3,4-dichlorobenzylamine (0.90 g, 5.1 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (550 mg, 25% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 - 12.60 (br 1H), 7.82 (d, J=7.9 Hz, 1H), 7.74 - 7.63 (m, 1H) 7.54 (d, J=8.2 Hz, 1H) 7.36 (dd, J=8.2, 1.6 Hz, 1H) 7.27 (d, J=7.9 Hz, 1H) 7.21 (s, 1H) 5.09 (br d, J=16.9 Hz, 1H) 4.26 (br d, J=16.9 Hz, 1H) 3.76 (s, 1H), , 2.37 (s, 3H), 1.83 - 1.60 (m, 5H) 1.54 (br d, J=6.2 Hz, 2H). LCMS EI- MS m / z: = 418.1[M+H]+. Example 27 Synthesis of 2'-benzyl-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1048): 2'-benzyl-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1048) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (370 mg, 2.3 mmol), 2,3-dihydro-1H-inden-1-one (300 mg, 2.3 mmol, 1.0 eq.), and benzylamine (243 mg, 2.3 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (16 mg, 2% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 - 8.06 (m, 1H), 7.57 - 7.32 (m, 2H), 7.25 - 7.08 (m, 8H), 6.99 - 6.86 (m, 1H), 6.55 (br d, J=7.6 Hz, 1H), 4.88 (br d, J=16.3 Hz, 1H,) 4.10 (s, 1H), 3.95 (br d, J=16.4 Hz, 1H), 2.85 - 2.65 (m, 2H), 2.41 - 2.25 (m, 1H), 2.21 - 2.05 (m, 1H). LCMS EI-MS m / z: = 384.1[M+H]+. Example 28 Synthesis of 2'-(4-chlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclobutane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1049): 2'-(4-chlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclobutane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1049) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (925 mg, 5.7 mmol), cyclobutanone (400 mg, 5.7 mmol, 1.0 eq.), and 4-chlorobenzylamine (810 mg, 5.7 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (20 mg, 1% yield) as a white powder.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.98 (d, J=7.4 Hz, 1H), 7.55 – 7.25 (m, 7H), 5.23 (s, 1H), 4.23 (s, 1H), 4.15 (s, 1H), 2.75 – 2.70 (m, 1H), 2.45 – 2.35 (m, 1H), 2.15 – 2.00 (m, 1H), 1.85 – 1.60 (m, 3H). LCMS EI-MS m / z: = 356.1[M+H]+. Example 29 Synthesis of 2'-(4-chlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1050): 2'-(4-chlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1050) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 4-chlorobenzylamine (220 g, 1.5 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product (15 mg, 3% yield) as a white powder.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.89 (d, J=4.0 Hz 1H), 7.40 – 7.10 (m, 10 H), 5.15 (d, J=16.4 Hz, 1H), 4.38 (d, J=16.4 Hz, 1H), 3.74 (s, 2H), 3.35 – 3.30 (m, 1H), 2.41 (s, 3H), 2.35 – 2.40 (m, 2H), 2.10 – 2.00 (m, 2H), 1.90 – 1.55 (m, 12 H). LCMS EI-MS m / z: = 384.2[M+H]+. Example 30 Synthesis of 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1051): 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1051) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6 e.0q.), 3,4-dichlorobenzylamine (163 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (7 mg, 2% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.09 (d, J=8.0 Hz, 1H), 7.50 – 7.35 (m, 3H), 7.45 – 7.10 (m, 4H), 5.03 (d, J=16.0 Hz, 1H), 4.34 (d, J=16.0 Hz, 1H), 3.58 (s, 1H), 1.33 (s, 3H), 1.16 (s, 3H). LCMS EI-MS m / z: = 378.0[M+H]+. Example 31 Synthesis of 2'-(4-fluoro-3-(trifluoromethyl)benzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1052): 2'-(4-fluoro-3-(trifluoromethyl)benzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1052) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and (4-fluoro-3-(trifluoromethyl)benzylamine (300 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (9 mg, 1% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.89 (d, J=8.0 Hz 1H), 7.79 (d, J=6.4 Hz, 1H), 7.75 – 7.65 (m, 1H), 7.30 – 7.18 (m, 3H), 5.22 (d, J=16.8 Hz, 1H), 4.37 (d, J=16.8 Hz, 1H), 3.78 (s, 1H), 2.41 (s, 3H), 2.10 – 2.00 (m, 1H), 1.90 – 1.55 (m, 7H). LCMS EI-MS m / z: = 436.1[M+H]+. Example 32 Synthesis of 2-(4-fluorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1053): 2-(4-fluorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1053) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6 e.0q.), 4-fluorobenzylamine (116 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (6 mg, 2% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.25 – 8.20 (m, 1H), 7.55 – 7.45 (m, 2H), 7.30 – 7.25 (m, 3H), 6.93 (t, J=8.8 Hz, 1H), 5.05 (d, J=16.0 Hz, 1H), 4.55 (d, J=16.0 Hz, 1H), 3.65 (s, 1H), 1.43 (s, 3H), 1.21 (s, 3H). LCMS EI-MS m / z: = 328.1[M+H]+. Example 33 Synthesis of 2'-(4-fluorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1054): 2'-(4-fluorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1054) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (580 mg, 3.6 mmol), cyclopentanone (300 mg, 3.6 mmol, 1.0 eq.), 4-fluorobenzylamine (450 mg, 3.6 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (10 mg, 1% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=7.5 Hz, 1H) 7.56 - 7.33 (m, 6H) 7.09 (t, J=8.8 Hz, 3H) 5.06 (br d, J=16.1 Hz, 1H) 4.34 (br d, J=16.6 Hz, 1 H), 3.81 (s, 1H) 1.91 – 1.89 (m , 1H), 1.63 - 1.86 (m, 3H) 1.63 - 1.42 (m, 4H). LCMS EI-MS m / z: = 354.1[M+H]+. Example 34 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1055): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1055) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and (4-fluoro-3-(trifluoromethyl)benzylamine (300 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (18 mg, 3% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.92 (d, J=8.0 Hz 1H), 7.75 (d, J=6.4 Hz, 1H), 7.80 – 7.60 (m, 1H), 7.30 – 7.18 (m, 3H), 5.45 (d, J=16.8 Hz, 1H), 4.45 (d, J=16.8 Hz, 1H), 3.92 (s, 1H), 2.41 (s, 3H), 2.10 – 2.00 (m, 1H), 1.90 – 1.55 (m, 7H). LCMS EI-MS m / z: = 436.1[M+H]+. Example 35 Synthesis of 2-(4-fluoro-3-(trifluoromethyl)benzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid (Compound 1056): 2-(4-fluoro-3-(trifluoromethyl)benzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1056) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6.0 eq.), 4-fluoro,3-trifluoromethylbenzylamine (180 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (5 mg, 2% yield).1H NMR (400 MHz, CHLOROFORM–d) δ ppm 8.08 (br d, J = 7.4 Hz, 1H), 7.47 – 7.34 (m, 3H), 7.24 – 7.09 (m, 3H), 5.17 (br d, J = 16.4 Hz, 1H), 4.34 (br d, J = 16.5 Hz, 1H), 3.61 (s, 1H), 1.32 (s, 3H), 1.18 (s, 3H). LCMS EI-MS m / z: = 396.1[M+H]+. Example 36 Synthesis of 2-(3,4-difluorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1057): 2-(3,4-difluorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1057) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6 e.0q.), 3,4-difluorobenzylamine (130 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (3 mg, 1% yield).1H NMR (400 MHz, CHLOROFORM–d) δ ppm 8.09 (dd, J = 1.4, 7.4 Hz, 1H), 7.47 – 7.29 (m, 2H), 7.27 – 7.09 (m, 2H), 7.04 – 6.86 (m, 2H), 5.02 (br d, J = 15.9 Hz, 1H), 4.36 (br d, J = 16.1 Hz, 1H), 3.67 (s, 1H), 1.42 (s, 3H), 1.15 (s, 3H). LCMS EI-MS m / z: = 346.1[M+H]+. Example 37 Synthesis of 2'-(4-fluoro-3-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1058): 2'-(4-fluoro-3-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1058) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (580 mg, 3.5 mmol), cyclopentanone (300 mg, 3.5 mmol, 1.0 eq.), 4-fluoro,3-trifluoromethylbenzylamine (690 mg, 3.5 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (8 mg, 1% yield).1H NMR (400 MHz, CHLOROFORM–d) δ ppm 8.14 (br d, J = 7.5 Hz, 1H), 7.61 (br d, J = 6.4 Hz, 1H), 7.58 – 7.40 (m, 3H), 7.37 – 7.15 (m, 3H), 7.06 (br t, J = 9.3 Hz, 1H), 5.31 (br d, J = 15.9 Hz, 1H), 4.20 (br d, J = 16.1 Hz, 1H), 2.15 – 1.98 (m, 2H), 1.96 – 1.55 (m, 8H). LCMS EI-MS m / z: = 422.1[M+H]+. Example 38 Synthesis of 2'-(3,4-dichlorophenethyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1059): 2'-(3,4-dichlorophenethyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1059) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 3,4-dichlorophenethylamine (300 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (20 mg, 3% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 7.84 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.19 (s, 1H), 4.09 – 3.95 (m, 1H), 3.74 (s, 1H), 3.08 – 2.78 (m, 2H), 2.40 (s, 4H), 2.13 – 2.02 (m, 1H), 1.99 – 1.82 (m, 2H), 1.80 – 1.67 (m, 2H), 1.66 – 1.49 (m, 2H). LCMS EI-MS m / z: = 433.1[M+H]+. Example 39 Synthesis of 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1060): 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1060) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), 2,3- dihydro-1H-inden-1-one (200 mg, 1.5 mmol, 1.0 eq.), and 3,4-dichlorobenzylamine (270 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (19 mg, 3% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 8.01 (d, J = 7.9 Hz, 1H), 7.39 – 7.11 (m, 6H), 7.08 – 6.95 (m, 2H), 6.68 (d, J = 7.8 Hz, 1H), 5.00 – 4.92 (m, 1H), 4.24 – 4.12 (m, 2H), 3.04 – 2.82 (m, 2H), 2.56 – 2.44 (m, 1H), 2.42 – 2.26 (m, 4H), 2.03 (s, 1H). LCMS EI-MS m / z: = 467.1[M+H]+. Example 40 Synthesis of 3,3-dimethyl-2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1061): 3,3-dimethyl-2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1061) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6.0 eq.), p-tolylmethanamine (110 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (4 mg, 1% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.25- 8.21 (m, 1H), 7.50 – 7.45 (m, 1H), 7.45 – 7.11 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 4.93 (d, J=2.0Hz, 1H), 4.72 (d, J=1.6Hz, 1H), 3.66 (s, 1H), 2.30 (s, 3H), 1.46 (s, 3H), 1.19 (s, 3H). LCMS EI-MS m / z: = 324.1[M+H]+. Example 41 Synthesis of 2'-(3,4-difluorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1062): 2'-(3,4-difluorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1062) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 3,4-difluorobenzylamine (220 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (40 mg, 7% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 7.89 (d, J = 8.0 Hz, 1H), 7.37 (br dd, J = 9.0, 11.1 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.23 – 7.12 (m, 3H), 5.16 (d, J = 16.4 Hz, 1H), 4.32 (d, J = 16.5 Hz, 1H), 3.76 (s, 1H), 3.37 – 3.32 (m, 1H), 2.41 (s, 3H), 2.15 – 1.98 (m, 1H), 1.89 – 1.70 (m, 5H), 1.70 – 1.57 (m, 2H). LCMS EI-MS m / z: = 386.2[M+H]+. Example 42 Synthesis of 2'-(3-chlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1063): 2'-(3-chlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1063) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (580 mg, 3.5 mmol), cyclopentanone (300 mg, 3.5 mmol, 1.0 eq.), 3-chlorobenzylamine (500 mg, 3.5 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (15 mg, 1% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 12.83 (br s, 1H), 7.94 (d, J=7.5 Hz, 1H) 7.57 - 7.53 (m, 1H) 7.51 - 7.23 (m, 6H) 5.10 (br d, J=16.8 Hz, 1H) 4.31 (br d, J=16.8 Hz, 1H) 3.84 (s, 1H) 1.97 (br s, 1H) 1.79 - 1.52 (m, 7H). LCMS EI-MS m / z: = 370.1[M+H]+. Example 43 Synthesis of 2'-(3,4-difluorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1064): 2'-(3,4-difluorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1064) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 3,4-dimethylbenzylamine (210 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (20 mg, 4% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 7.90 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 5.9 Hz, 2H), 7.12 – 6.98 (m, 2H), 5.07 – 4.96 (m, 1H), 4.45 (br d, J = 16.1 Hz, 1H), 3.72 (s, 1H), 3.34 (s, 1H), 2.42 – 2.35 (m, 3H), 2.22 (d, J = 3.1 Hz, 6H), 1.87 – 1.70 (m, 4H), 1.67 – 1.53 (m, 3H). LCMS EI-MS m / z: = 378.2[M+H]+. Example 44 Synthesis of 3,32-(3,4-dimethylbenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1065): 2-(3,4-dimethylbenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1065) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6.0 eq.), 3,4-dimethylbenzylamine (150 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (4 mg, 1% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.22-8.20 (m, 1H), 7.50 – 7.45 (m, 1H), 7.25 – 7.22 (m, 1H), 7.18 – 7.00 (m, 3H), 4.91 (d, J=16.0 Hz, 1H), 4.65 (d, J=16.0Hz, 1H), 3.65 (s, 3H), 2.19 (d, J = 8.0 Hz, 1H), 1.46 (s, 3H), 1.19 (s, 3H). LCMS EI-MS m / z: = 338.2[M+H]+. Example 45 Synthesis of 2-(3-chlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1066): 2-(3-chlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1066) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (150 mg, 0.9 mmol), acetone (0.4 ml, 5.5 mmol, 6.0 eq.), 3-chlorobenzylamine (130 mg, 0.9 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (6 mg, 2% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.20- 8.18 (m, 1H), 7.55 – 7.45 (m, 2H), 7.35 (s, 1H), 7.25 – 7.15 (m, 4H), 5.06 (d, J=16.0 Hz, 1H), 4.55 (d, J=16.0 Hz, 1H), 3.66 (s, 1H), 1.43 (s, 3H), 1.22 (s, 3H). LCMS EI-MS m / z: = 344.1[M+H]+. Example 46 Synthesis of 2'-(3-chlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Compound 1067): 2'-(3-chlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1067) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 3-chlorobenzylamine (220 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (20 mg, 4% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 7.90 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.35 – 7.19 (m, 5H), 5.19 – 4.92 (m, 1H), 4.40 (d, J = 16.5 Hz, 1H), 3.76 (s, 1H), 2.41 (s, 3H), 2.09 (br d, J = 8.5 Hz, 1H), 1.89 – 1.69 (m, 5H), 1.69 – 1.56 (m, 2H). LCMS EI-MS m / z: = 384.2[M+H]+. Example 47 Synthesis of 2-(3,4-dichlorobenzyl)-6-(2-fluorophenyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid (Compound 1068): 2-(3,4-dichlorobenzyl)-6-(2-fluorophenyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1068) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (800 mg, 3.1 mmol), acetone (1.4 ml, 18.5 mmol, 6.0 eq.), 3,4-dichlorobenzylamine (550 mg, 3.1 mmol, 1.0 eq.) in Step 17 and then 2- fluorophenylboronic acid (13 mg, 0.1 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (8 mg, 20% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.55 – 7.42 (m, 3H), 7.39 – 7.31 (m, 2H), 7.25 – 7.11 (m, 3H), 5.14 (d, J=16.0 Hz, 1H), 4.45 (d, J=16.0 Hz, 1H), 3.75 (s, 1H), 1.46 (s, 3H), 1.30 (s, 3H). LCMS EI-MS m / z: = 344.1[M+H]+. LCMS EI-MS m / z: = 472.1[M+H]+. Example 49 Synthesis of 6-bromo-2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1069): 6-bromo-2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1069) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (800 mg, 3.1 mmol), acetone (1.4 ml, 18.5 mmol, 6.0 eq.), 3,4-dichlorobenzylamine (550 mg, 3.1 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (700 mg, 50% yield).1H NMR (400 MHz, CDCl3) δ ppm 7.94 (d, J=16.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.48 – 7.42 (m, 1H), 7.35 – 7.30 (m, 1H), 5.08 (d, J = 16.0Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 3.80 (s, 1H), 1.44 (s, 3H), 1.25 (s, 3H). LCMS EI-MS m / z: = 457.9[M+H]+. Example 50 Synthesis of 2-(3,4-dichlorobenzyl)-6-methyl-1-oxo-1,3',4,4'-tetrahydro-2H,2'H-spiro[isoquinoline-3,1'- naphthalene]-4-carboxylic acid (Compound 1070): 2-(3,4-dichlorobenzyl)-6-methyl-1-oxo-1,3',4,4'-tetrahydro-2H,2'H-spiro[isoquinoline-3,1'-naphthalene]-4- carboxylic acid (Compound 1070) was synthesized using 2-(carboxymethyl)-4-methylbenzoic acid (300 mg, 1.5 mmol), 1,2,3,4-tetrahydronaphthalen-1-one (230 mg, 1.5 mmol, 1.0 eq.), and 3,4-dichlorobenzylamine (270 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (6 mg, 1% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 8.01 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.21 – 7.06 (m, 2H), 6.97 (s, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.25 (s, 1H), 4.02 (d, J = 16.8 Hz, 1H), 3.02 – 2.87 (m, 2H), 2.36 – 2.28 (m, 4H), 2.25 – 1.83 (m, 4H). LCMS EI-MS m / z: = 480.2[M+H]+. Example 51 Synthesis of 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-6-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1071): 2-(3,4-dichlorobenzyl)-3,3-dimethyl-1-oxo-6-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Compound 1071) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (800 mg, 3.1 mmol), acetone (1.4 ml, 18.5 mmol, 6.0 eq.), 3,4-dichlorobenzylamine (550 mg, 3.1 mmol, 1.0 eq.) in Step 17 and then phenylboronic acid (16 mg, 0.13 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (5 mg, 10% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.24 (d, J=8.0 Hz, 1H), 7.70 – 7.65 (m, 3H), 7.60 – 7.40 (m, 5H), 7.55 – 7.35 (m, 3H), 5.14 (d, J=16.0 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 3.73 (s, 1H), 1.44 (s, 3H), 1.28 (s, 3H). LCMS EI-MS m / z: = 454.0[M+H]+. Example 52 Synthesis of 2-(3,4-dichlorobenzyl)-6-methyl-1-oxo-1,3',4,4'-tetrahydro-2H,2'H-spiro[isoquinoline-3,1'- naphthalene]-4-carboxylic acid (Compound 1072): 2-(3,4-dichlorobenzyl)-6-methyl-1-oxo-1,3',4,4'-tetrahydro-2H,2'H-spiro[isoquinoline-3,1'-naphthalene]-4- carboxylic acid (Compound 1072) was synthesized using 2-(2-carboxy-5-methylphenyl)-2-methylpropanedioic acid (390 mg, 1.5 mmol), cyclopentanone (130 mg, 1.5 mmol, 1.0 eq.), and 3,4-dichlorobenzylamine (270 mg, 1.5 mmol) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (21 mg, 3% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm 7.88 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (br d, J = 7.6 Hz, 1H), 7.34 (br s, 1H), 7.25 (br t, J = 7.6 Hz, 2H), 5.23 (br d, J = 16.0 Hz, 1H), 4.26 (br d, J = 15.6 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 1H), 2.13 – 1.92 (m, 2H), 1.84 (br s, 2H), 1.69 (br s, 4H), 1.47 (br d, J = 7.1 Hz, 3H). LCMS EI-MS m / z: = 432.2[M+H]+. Example 53 Synthesis of 2'-(1-(3,4-dichlorophenyl)ethyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1073): Diisopropylethylamine (70 uL, 0.5 mmol) was taken in THF (0.5 ml) and cooled to -78 C. n-Butyllithium (0.33 ml, 1.6 M in hexanes, 2.2 eq.) was then added and stirred for 30 mins. A solution of 2'-[(3,4-dichlorophenyl)methyl]-6'- methyl-1'-oxo-2',4'-dihydro-1'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (0.1 g, 0.24 mmol) in THF (0.5 ml) was added and the solution was stirred at -78 C for 1 hr. Iodomethane (0.02 ml, 0.36 mmol, 1.5 eq.) was then added and the solution was stirred for the next 16 hrs. It was quenched by adding 1 N HCl solution and then extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified on reverse phase prep HPLC to afford the title product as a white powder. (6 mg, 6% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 - 7.90 (m, 2H) 7.48 (dd, J=8.4, 1.9 Hz, 1H) 7.39 (d, J=8.4 Hz, 1H) 7.24 (d, J=8.0 Hz, 1H) 7.20 (s, 1H) 3.77 (s, 1H) 3.34 (br s, 1H) 2.40 (s, 3H) 2.30 - 2.10 (m, 1H) 2.02 – 1.79 (m, 8H) 1.76 (br s, 1H) 1.67 - 1.50 (m, 1H). LCMS EI-MS m / z: = 432.1[M+H]+. Example 54 Synthesis of 6'-bromo-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1074): 6'-bromo-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]- 4'-carboxylic acid (Compound 1074) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (600 mg, 2.3 mmol), cyclopentanone (0.2 ml, 2.3 mmol, 6.0 eq.), 3-fluoro,4-trifluoromethylbenzylamine (450 mg, 2.3 mmol, 1.0 eq.) in Step following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (400 mg, 34% yield).1H NMR (400 MHz, CDCl3) δ ppm 7.91 (d, J=8.0 Hz, 1H), 7.64 -7.60 (m, 3H), 7.45 – 7.30 (m, 2H), 5.27 (d, J=16.0 Hz, 1H), 4.39 (d, J=16.0 Hz, 1H), 3.87 (s, 1H), 2.10 – 2.00 (m, 1H), 2.05 – 1.65 (m, 7H). LCMS EI-MS m / z: = 500.0[M+H]+. Example 55 Synthesis of (R)-2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1075). 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid was resolved on Chiralpak AD column eluting with hexanes / isopropanol (70 / 30) to afford the title product (20 mg, 90% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.89 (d, J=7.9 Hz, 1H) 7.63 (s, 1H) 7.42 (d, J=8.5 Hz, 1H) 7.35 (d, J=7.9 Hz, 1H) 7.28 (d, J=8.1 Hz, 1H) 7.21 (s, 1H) 5.16 (d, J=16.6 Hz, 1H) 4.33 (d, J=16.5 Hz, 1H) 3.77 (s, 1H), 2.42 (s, 3H) 2.08 (s, 1H) 1.91 - 1.71 (m, 5H) 1.71 - 1.54 (m, 2H). LCMS EI-MS m / z: = 418.4[M+H]+. Chiralpak AD (hexanes / isopropanol 70 / 30 Rt = 12.7 mins. Example 56 Synthesis of (S)-2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1076). 2'-(3,4-dichlorobenzyl)-6'-methyl-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid was resolved on Chiralpak AD column eluting with hexanes / isopropanol (70 / 30) to afford the title product (20 mg, 90% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.89 (d, J=7.9 Hz, 1H) 7.63 (s, 1H) 7.42 (d, J=8.4 Hz, 1H) 7.34 (d, J=8.5 Hz, 1H) 7.28 (d, J=7.9 Hz, 1H) 7.21 (s, 1H) 5.16 (d, J=16.6 Hz, 1H) 4.33 (d, J=16.6 Hz, 1H) 3.77 (s, 1H) 2.42 (s, 3H) 2.14 – 1.98 (m, 1H) 1.90 - 1.70 (m, 5H) 1.70 - 1.45 (m, 2H). LCMS EI-MS m / z: = 418.1[M+H]+. Chiralpak AD (hexanes / isopropanol) (70 / 30) Rt = 19.8 mins. Example 57 Synthesis of 6'-(2-acryloylphenyl)-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1078): Preparation of 6'-bromo-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]- 4'-carboxylic acid (Int-6a): 6'-bromo-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid was prepared using 4-bromo-2-(carboxymethyl)benzoic acid (1.3 g, 4.9 mmol), cyclopentanone (0.41 g, 4.9 mmol, 1.0 eq.) and 3,4-dichlorobenzylamine (0.86 g, 4.9 mmol, 1.0 eq.) following the procedure described in the preparation of Int-5a to afford the title compound (300 mg, 13% yield). LCMS EI-MS m / z: = 484.1, 486.1[M+H]+. Preparation of 2'-(3,4-dichlorobenzyl)-6'-(2-formylphenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Int-6b): 2'-(3,4-dichlorobenzyl)-6'-(2-formylphenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid was prepared using Int-6a (120 mg, 0.25 mmol), 2-formylphenylboronic acid (37 mg, 0.25 mmol), 1,1'- Bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol, 0.05 eq.), sodium carbonate (53 mg, 0.5 mmol, 2.0 eq.) in 1,4-dioxane (2 ml) and water (0.5 ml) following the procedure described in the preparation of Int-5b to afford the title compound (120 mg, 95% yield). LCMS EI-MS m / z: = 508.1[M+H]+. Preparation of 2'-(3,4-dichlorobenzyl)-6'-(2-(1-hydroxyallyl)phenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Int-6c): 2'-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-6'-(o-formylphenyl)-1'- oxo-2'H,4'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (100 mg, 0.19 mmol) was taken in THF (3 ml) and cooled in an ice-bath. A solution of vinyl magnesium bromide in ether (0.16 ml, 3 M solution) was added and the solution was stirred for 3 hrs at room temperature. The reaction was quenched by adding 1 N HCl solution and then extracted into ethyl acetate. The organic layer was dried over magnesium sulfate and the filtrate was concentrated to afford the title compound (120 mg, 100% yield). LCMS EI-MS m / z: = 536.1[M+H]+. Preparation of 6'-(2-acryloylphenyl)-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1078): 2'-[(3,4-dichlorophenyl)methyl]-6'-[o-(1-hydroxy-2-propenyl)phenyl]-1'-oxo-2'H,4'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (60 mg, 0.11 mmol) was taken in dichloromethane (3 ml) in an ice-bath under nitrogen and Dess-Martin reagent (65 mg, 0.14 mmol) was added to it. The solution was stirred for the next 18 hrs at room temperature. The solution was diluted with dichloromethane and then washed with sodium thiosulfate solution. The organic layer was dried over magnesium sulfate and the filtrate was concentrated. The residue was purified on Combiflash using dichloromethane / methanol gradient to give the product. It was re-purified on preparative reverse phase HPLC to afford the title compound (38 mg, 32% yield) as a white powder.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.07 (d, J=8.0 Hz, 1H), 7.69 - 7.44 (m, 7H), 7.42 - 7.35 (m, 1H), 7.29 (d, J=1.5 Hz, 1H), 6.29 (dd, J=17.5, 10.4 Hz, 1H), 5.97 (dd, J=17.4, 1.1 Hz, 1H), 5.72 (dd, J=10.5, 1.1 Hz, 1H), 5.21 (d, J=16.5 Hz, 1H), 4.38 (d, J=16.6 Hz, 1H), 3.84 (s, 1H), 2.19 - 2.01 (m, 1H), 1.92 - 1.74 (m, 5H), 1.71 - 1.61 (m, 2H). LCMS EI-MS m / z: = 534.1[M+H]+. Example 58 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-propionylphenyl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1080): 6'-bromo-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]- 4'-carboxylic acid (Compound 1080) was synthesized using 3-fluoro,4-trifluoromethylbenzylamine in Step 20 and ethyl magnesium bromide in Step 22 following the procedure described for the synthesis of Example 1078 to afford the title product as white powder (15 mg, 12% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.09 (br d, J=7.5 Hz, 1H), 7.65 - 7.39 (m, 8H), 7.29 (br s, 1H), 5.31 (br d, J=16.6 Hz, 1H), 4.43 (br d, J=17.0 Hz, 1H), 3.89 (s, 1H), 2.48 (q, J=6.8 Hz, 2H), 2.06 (br d, J=8.2 Hz, 1H), 1.96 - 1.56 (m, 7H), 0.93 (br t, J=7.0 Hz, 3H). LCMS EI-MS m / z: = 554.2[M+H]+. Example 59 Synthesis of 6'-(2-carbamoylphenyl)-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1081): 6'-(2-carbamoylphenyl)-2'-(3,4-dichlorobenzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]- 4'-carboxylic acid (Compound 1081) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (1.3 g, 4.9 mmol), cyclopentanone (0.41 g, 4.9 mmol, 1.0 eq.) and 3,4-dichlorobenzylamine (0.86 g, 4.9 mmol, 1.0 eq.) in Step 17 and then (2-carbamoylphenyl)boronic acid (14 mg, 0.1 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (5 mg, 11% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.04 (d, J=8.0 Hz, 1H), 7.75 – 7.25 (m, 9), 5.19 (d, J=16.4 Hz, 1H), 4.37 (d, J=16.4 Hz, 1H), 3.87 (s, 1H), 2.10 – 2.00 (m, 1H), 1.95 – 1.55 (m, 7H). LCMS EI-MS m / z: = 523.1[M+H]+. Example 60 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-(2-(1-hydroxypropyl)phenyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1082): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-(2-(1-hydroxypropyl)phenyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1082) was synthesized using 3-fluoro,4- trifluoromethylbenzylamine in Step 20 and ethyl magnesium bromide in Step 22 following the procedure described for the synthesis of Int-6c to afford the title product (50 mg, 98% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.07 (d, J=8.0 Hz, 1H), 8.65 – 8.60 (m, 2H), 7.55 – 7.20 (m, 7H), 5.32 (d, J=16.8 Hz, 1H), 4.60 – 4.50 (m, 1H), 4.43 (d, J=16.8 Hz, 1H), 3.90 (d, J=8.4 Hz, 1H), 2.15 – 2.00 (m, 1H), 2.00 – 1.55 (m, 9H), 0.78 – 0.73 (m, 3H). LCMS EI-MS m / z: = 556.2[M+H]+. Example 61 Synthesis of 2'-(cyclohexylmethyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Compound 1083): 2'-(cyclohexylmethyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1083) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (500 mg, 1.9 mmol), cyclopentanone (160 mg, 1.9 mmol, 1.0 eq.), (cyclohexylmethyl)amine (220 mg, 1.9 mmol, 1.0 eq.) in Step 17 and 2-trifluoromethyl phenylboronic acid (25 mg, 0.14 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (8 mg, 15% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.98 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.45 – 7.35 (m, 2H), 7.30 (s, 1H), 3.80 (s, 1H), 3.70 – 3.60 (m, 1H), 3.45 – 3.35 (m, 2H), 2.50 -2.45 (m, 2H), 2.20 – 2.10 (m 1H), 1.90 – 1.55 (m, 7H), 1.15 – 1.05 (m, 2H), 0.55 – 0.35 (m, 4H). LCMS EI-MS m / z: = 486.2[M+H]+. Example 62 Synthesis of 2'-(3,4-dichlorobenzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Compound 1084): 2'-(3,4-dichlorobenzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1084) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (1.3 g, 4.9 mmol), cyclopentanone (0.41 g, 4.9 mmol, 1.0 eq.) and 3,4-dichlorobenzylamine (0.86 g, 4.9 mmol, 1.0 eq.) in Step 17 and then 2-trifluoromethyl phenylboronic acid (18 mg, 0.1 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (25 mg, 50% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.06 (d, J=8.0 Hz, 1H) 7.81 (d, J=7.7 Hz, 1H) 7.71 - 7.64 (m, 2H) 7.64 - 7.56 (m, 1H) 7.33 - 7.48 (m, 5H) 5.21 (d, J=16.5 Hz, 1H) 4.38 (d, J=16.6 Hz, 1H) 3.86 (s, 1H) 2.10 (d, J=7.7 Hz, 1H) 1.99 - 1.76 (m, 5H) 1.75 - 1.58 (m, 2H). LCMS EI-MS m / z: = 548.1[M+H]+. Example 63 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-vinylphenyl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1085): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-vinylphenyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1085) was synthesized using (2-ethenylphenyl)boronic acid (60 mg, 0.4 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (50 mg, 24% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.07 (d, J=8.0 Hz, 1H), 7.75 – 7.25 (m, 9H), 6.68 (dd, J=17.6, 11.2 Hz, 1H), 5.74 (d, 17.6 Hz, 1H), 5.32 (d, J=16.8 Hz, 1H), 4.43 (d, J=16.8 Hz, 1H), 3.91 (s, 1H), 2.20 – 2.00 (m, 1H), 2.00 – 1.50 (m, 7H). LCMS EI-MS m / z: = 524.1[M+H]+. Example 64 Preparation of 2'-(3,4-dichlorobenzyl)-6'-(2-formylphenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1087) 2'-(3,4-dichlorobenzyl)-6'-(2-formylphenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid was prepared using Int-6a (120 mg, 0.25 mmol), 2-formylphenylboronic acid (37 mg, 0.25 mmol), 1,1'- Bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol, 0.05 eq.), sodium carbonate (53 mg, 0.5 mmol, 2.0 eq.) in 1,4-dioxane (2 ml) and water (0.5 ml) following the procedure described in the preparation of Int-5b to afford the title compound (120 mg, 95% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 12.92 (br s, 1H), 9.92 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.84 – 7.76 (m, 1H), 7.75 – 7.70 (m, 1H), 7.68 – 7.50 (m, 6H), 7.41 – 7.40 (m, 1H), 5.10 – 5.05 (m, 1H), 4.40 – 4.35 (m, 1H), 3.98 (s, 1H), 2.00 – 1.90 (m, 1H), 1.80 – 1.50 (m, 7H). LCMS EI-MS m / z: = 508.1[M+H]+. Example 65 Synthesis of 6'-(2,6-dimethylphenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1088): 6'-(2,6-dimethylphenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1088) was synthesized using 2,6-dimethylphenylboronic acid (60 mg, 0.4 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (10 mg, 4% yield).1H NMR (400 MHz, METHANOL–d4) δ ppm = 8.09 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.55 – 7.39 (m, 2H), 7.28 – 7.05 (m, 5H), 5.32 (br d, J =17.0 Hz, 1H), 4.44 (br d, J = 16.9 Hz, 1H), 3.91 (s, 1H), 2.10 – 2.09 (m, 1 H), 2.04 (s, 3H), 2.00 (s, 3H), 1.99 – 1.69 (m, 7H). LCMS EI-MS m / z: = 525.1[M+H]+. Example 66 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-(2-methoxyphenyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1089): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-6'-(2-methoxyphenyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1089) was synthesized using 2-methoxyphenylboronic acid (60 mg, 0.4 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (10 mg, 4% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.02 (d, J=8.0 Hz, 1H), 7.75 – 7.25 (m, 7H), 7.10 – 7.00 (m, 2H), 5.31 (d, J=17.2 Hz, 1H), 4.42 (d, J=17.2 Hz, 1H), 3.89 (s, 1H), 3.83 (s, 3H), 2.10 – 2.00 (m, 1H), 2.00 – 1.55 (m, 7H). LCMS EI-MS m / z: = 528.2[M+H]+. Example 67 Synthesis of 2'-(cyclopropylmethyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Compound 1090): 2'-(cyclopropylmethyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid (Compound 1090) was synthesized using 4-bromo-2-(carboxymethyl)benzoic acid (0.5 g, 1.9 mmol), cyclopentanone (0.16 g, 1.9 mmol, 1.0 eq.) and cyclopropylmethanamine (0.14 g, 1.9 mmol, 1.0 eq.) in Step 17 and then 2-trifluoromethyl phenylboronic acid (60 mg, 0.1 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (8 mg, 7% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.99 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.45 – 7.35 (m, 2H), 7.29 (s, 1H), 3.80 (s, 1H), 3.77 (dd, J=20.8, 8.4 Hz, 1H), 3.08 (dd, J=14.0, 6.0 Hz, 1H), 2.35 – 2.25 (m, 1H), 2.20 – 2.15 (m, 1H), 2.00 – 1.85 (m, 2H), 1.80 – 1.55 (m, 5H), 1.25 – 1.15 (m, 2H), 1.15 – 1.00 (m, 2H). LCMS EI-MS m / z: = 444.1[M+H]+. Example 68 Preparation of 6'-(2-aminophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1091) 6'-Bromo-2'-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-1'-oxo-2'H,4'H-spiro[cyclopentane-1,3'-isoquinoline]-4'- carboxylic acid (Int-1a) (225 mg, 0.45 mmol) was taken in 1,4-dioxane / water (2 ml, 1 ml). o-(dihydroxyboryl)aniline (68 mg, 0.49 mmol, 1.1 eq.) and sodium carbonate (95 mg, 0.9 mmol, 2.0 eq.) were added and then nitrogen as bubbled for 10 mins.1,1'-Bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol, 0.05 eq.) was then added and the solution was heated to 80 C for 13 hrs. After cooling, the reaction was quenched by adding 1 N HCl solution (pH ~ 6-7) and then filtered through celite. The filtrate extracted into dichloromethane / isopropanol (4 times). The combined organic layer was filtered through magnesium sulfate and the filtrate was concentrated. The residue was purified on Combiflash using dichloromethane / methanol gradient to afford the title compound as a white solid (120 mg, 53% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.19 (d, J=8.0 Hz, 1H), 7.55 – 7.15 (m, 7H), 6.90 – 6.75 (m, 2H), 5.29 (d, J=16.0 Hz, 1H), 5.10 (br s, 1H), 4.32 (d, J=16.0 Hz, 1H), 3.76 (s, 1H), 2.00 – 1.85 (m, 2H), 1.85 – 1.70 (m, 4H), 1.70 – 1.50 (m, 2H). LCMS ESI-MS m / z: = 513.2[M+H]+. Example 69 Preparation of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-propionamidophenyl)-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1092) 6'-(2-aminophenyl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane-1,3'- isoquinoline]-4'-carboxylic acid, (Compound 1091) (100 mg, 0.19 mmol) was dissolved in 1 N sodium hydroxide solution (4 ml) and then propionyl chloride (0.05 mL, 0.39 mmol, 2.0 eq.) was added to it. After 2 hours, the solution was acidified by adding 1 M HCl solution. The solution was extracted into dichloromethane and the organic layer was dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified on Combiflash using dichloromethane / methanol gradient to afford the title compound (50 mg, 45% yield) as a white powder.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (d, J=8.0 Hz, 1H), 7.64 – 7.61 (m, 1H), 7.55 – 7.20 (m, 8H), 5.31 (d, J =17.2 Hz, 1H), 4.42 (d, J= 17.2 Hz, 1H), 3.88 (s, 1H), 2.26 – 2.20 (m, 2H), 2.20 – 2.00 (m, 1H), 1.95 – 1.55 (m, 7H), 1.09 (t, J=8.0 Hz, 3H). LCMS EI-MS m / z: = 569.2[M+H]+. Example 70 Synthesis of 2'-(4-methoxybenzyl)-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1093): 2'-(4-methoxybenzyl)-1'-oxo-1',2,3,4'-tetrahydro-2'H-spiro[indene-1,3'-isoquinoline]-4'-carboxylic acid (Compounds 1093) was synthesized using 3,4-dihydro-1H-2-benzopyran-1,3-dione (370 mg, 2.3 mmol), 2,3- dihydro-1H-inden-1-one (300 mg, 2.3 mmol, 1.0 eq.), 4-methoxybenzylamine (310 mg, 2.3 mmol, 1.0 eq.) in Step 17 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (13 mg, 1% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 - 8.07 (m, 1H) 7.56 – 7.35 (m, 2H) 7.31 – 7.11 (m, 3H) 7.05 (br d, J=8.7 Hz, 2H) 7.0 – 6.88 (m, 1H), 6.70 (d, J=8.75 Hz, 2H) 6.58 (br d, J=7.6 Hz, 1H) 4.85 (br d, J=16.13 Hz, 1H) 4.10 (s, 1H) 3.98 – 3.74 (m, 1H) 3.64 (s, 3H), 2.88 – 2.64 (m, 2H), 2.25 – 2.34 (m, 1H) 2.20 – 2.00 (m, 1H). LCMS EI- MS m / z: = 414.0[M+H]+. Example 71 Synthesis of 6'-(2-cyanopyridin-3-yl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H- spiro[cyclopentane-1,3'-isoquinoline]-4'-carboxylic acid (Compound 1095):

[0054] 6'-(2-cyanopyridin-3-yl)-2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-1',4'-dihydro-2'H-spiro[cyclopentane- 1,3'-isoquinoline]-4'-carboxylic acid (Compound 1095) was synthesized using 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyridinecarbonitrile (100 mg, 0.5 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (10 mg, 4% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.74 (d, J=4.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.80 – 7.60 (m, 4H), 7.48 (d, 12.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 5.33 (d, J=16.8 Hz, 1H), 4.44 (d, J=16.8 Hz, 1H), 3.99 (s, 1H), 2.10 – 2.00 (m, 1H), 2.00 – 1.65 (m, 7H). LCMS EI-MS m / z: = 524.1[M+H]+. Example 72 Synthesis of 2-benzyl-3-methyl-1-oxo-6-(2-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-4-carboxylic acid (Compound 1097): 2-benzyl-3-methyl-1-oxo-6-(2-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-4-carboxylic acid (Compound 1097) was synthesized using 2-benzyl-6-bromo-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (50 mg, 0.14 mmol) and [o-(trifluoromethyl)phenylboronic acid in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (6 mg, 10% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.42 (d, J=4.0 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.75 – 760 (m, 3H), 7.55 – 7.50 (m, 1H), 7.50 – 7.45 (m, 1H), 7.40 – 7.30 (m, 2H), 7.25 – 7.20 (m, 1H), 7.20 – 7.15 (m, 2H), 5.57 (s, 2H), 2.49 (s, 3H). LCMS EI-MS m / z: = 438.1[M+H]+. Example 73 Synthesis of 3-methyl-1-oxo-2-phenyl-6-(2-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-4-carboxylic acid (Compound 1098): 23-methyl-1-oxo-2-phenyl-6-(2-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-4-carboxylic acid (Compound 1098) was synthesized using 6-bromo-3-methyl-1-oxo-2-phenyl-1,2-dihydroisoquinoline-4-carboxylic acid (106 mg, 0.56 mmol) and [o-(trifluoromethyl)phenylboronic acid in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (9 mg, 4% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.36 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.75 – 7.45 (m, 8H), 7.35 (d, J=8.0 Hz, 2H), 2.15 (s, 3H). LCMS EI-MS m / z: = 424.1[M+H]+. Example 74 Synthesis of 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4,4',5-tetrahydro- 2H,2'H-spiro[furan-3,3'-isoquinoline]-4'-carboxylic acid (Compound 1099): 2'-(3-fluoro-4-(trifluoromethyl)benzyl)-1'-oxo-6'-(2-(trifluoromethyl)phenyl)-1',4,4',5-tetrahydro-2H,2'H- spiro[furan-3,3'-isoquinoline]-4'-carboxylic acid (Compound 1099) was synthesized using 4-bromo-2- (carboxymethyl)benzoic acid (0.3 g, 1.2 mmol), oxolan-3-one (0.1 ml, 1.2 mmol, 1.0 eq.) and 3-fluoro,4- trifluoromethylbenzylamine (0.22 g, 1.2 mmol, 1.0 eq.) in Step 17 and then 2-trifluoromethyl phenylboronic acid (22 mg, 0.1 mmol) in Step 18 following the procedure described for the synthesis of compound 1094 to afford the title product as white powder (6 mg, 9% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.05 (d, J=8.8 Hz, 1H), 7.80 – 7.70 (m, 1H), 7.70 – 7.50 (m, 3H), 7.50 – 7.30 (m, 5H), 5.31 (d, J = 16.4 Hz, 1H), 4.72 (d, J=16.4 Hz, 1H), 4.22 (d, J=12.0 Hz, 1H), 4.13 (s, 1H), 4.05 – 4.00 (m, 1H), 3.75 – 3.70 (m, 2H), 2.35 – 2.30 (m, 1H), 2.05 – 1.95 (m, 1H). LCMS EI-MS m / z: = 56...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl;t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH andand RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring; with the proviso that the compound of formula (I) is not a compound of any one of formulas 1001, 1003-1006, 1008, 1009, 1011, 1012, and 1014:

2. The compound of claim 1, wherein Z is -NR3- or –(CR3)2-.

3. The compound of claim 1 or 2, wherein R10is -OH or.

4. The compound of any one of claims 1-3, wherein Y is selected from a bond, C=O, and -C(RA)2-, wherein -C(RA)2-, is selected from -CH2-, -C(Me)2-,, wherein m1and n1are each independently an integer selected from 1 and 2, V is -O- or -CH2-, and R4’and R4”are each independently halogen.

5. The compound of any one of claims 1-4, wherein X is a bond or -CR1b-.

6. The compound of any one of claims 1-5, wherein R2is selected from H, -OH,-CH3,or R2is absent and Y is -CRA-, optionally wherein RAis -CH3.

7. The compound of any one of claims 1-6, wherein R3is selected from H,, wherein A is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, R5’and R5”,at each occurrence, are independently selected from H and optionally substituted alkyl, and n2is an integer from 0 to 3, optionally 0 or 1, optionally A is selected fromand n2is 1.

8. The compound of claim 7, wherein each occurrence of R5’and R5”is H, or wherein n2is 1, R5’is H, and R5”is unsubstituted alkyl, optionally R5”is -CH3.

9. The compound of claim 7 or 8 wherein A is selected from optionally substituted furanyl, optionally substituted tetrahydrofuryl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted phenyl, and optionally substituted C3-C6cycloalkyl, optionally wherein A is selectedfromoptionally wherein A is phenyl substituted with one or more substituents selected from alkyl, alkoxy, -OH, -CX3, and halogen; wherein each X is independently F, Br, Cl, or I, optionally wherein A is8a 8bwherein R and R are selected from H, alkyl, alkoxy, -OH, -CX3, and halogen, optionally R8aand R8bare selected from H, -CH3, -CF3, -OCH3, -OH, F, and Cl, optionally wherein A is selected fromoptionally wherein A is10. The compound of any one of claims 7-9, wherein R3is selected from H,or wherein R3is selected fromoptionally wherein R3is selected from11. The compound of any one of claims 1-10, wherein the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof:

12. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof:wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2.

13. The compound of claim 12, wherein the compound of formula (14) is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), or formula (109), formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof:

14. The compound of any one of claims 1-13, wherein the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof:wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2, optionally wherein the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof:

15. The compound of any one of claims 1-14, wherein the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof:wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; andt is 1 or 2, optionally wherein the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof:

16. The compound of any one of claims 1-15, wherein the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof:wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 orsubstituted heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2, optionally wherein the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof:

17. The compound of claim 16, wherein R4bis selected fromoptionally4bwherein R is selected from18. The compound of any one of claims 12-17, wherein R4dis selected from H,,wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1.

19. The compound of any one of claims 1 -18, wherein the compound of formula (I) is a compound of any one of formula 1002, 1007, 1010, 1013, 1015-1150, or a pharmaceutically acceptable salt thereof:

20. The compound of any one of claims 1 -19, wherein the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124-1127, 1129, 1132, 1133, 1135, 1141-1149, or a pharmaceutically acceptable salt thereof:

21. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient:wherein in formula (I): X is selected from a bond and -CR1b-; Y is selected from a bond, C=O, -CRA-, and -C(RA)2-, as permitted by valency, wherein when X is a bond, Y is not a bond; Z is selected from -NR3- and -C(R3)2-; R1aand R1bare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted orsubstituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, optionally wherein R1bis joined to the ring to which it is bound to form an optionally substituted cycloalkyl; or R1aand R1bare joined to form an optionally substituted aryl; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R2is present or absent as permitted by valency and when present is selected from H, -OH, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R3is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and optionally substituted cycloalkyl; R10is selected from -OH andand RAis at each occurrence independently selected from H and optionally substituted alkyl, or both RAare joined to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, wherein the cycloalkyl is optionally fused to an optionally substituted aryl ring.

22. The pharmaceutical composition of claim 21, wherein the compound of formula (I) is a compound of formula (10), formula (11), formula (12), formula (13), formula (15), or formula (16), formula (21), formula (22), formula (23), or a pharmaceutically acceptable salt thereof:

23. The pharmaceutical composition of claim 21, wherein the compound of formula (I) is a compound of formula (14), or a pharmaceutically acceptable salt thereof:wherein in formula (14): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2.

24. The pharmaceutical composition of claim 23, wherein the compound of formula (14) is a compound of formula (100), formula (101), formula (103), formula (104), formula (105), formula (106), formula (107), formula (108), formula (109), formula (102), formula (110), formula (111), formula (112), formula (113), or formula (114), or a pharmaceutically acceptable salt thereof:

25. The pharmaceutical composition of claim 21, wherein the compound of formula (I) is a compound of formula (17), formula (19), or a pharmaceutically acceptable salt thereof:wherein: R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl,unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2.

26. The pharmaceutical composition of claim 25, wherein the compound of formula (17) is a compound of formula (115) or a pharmaceutically acceptable salt thereof:

27. The pharmaceutical composition of claim 21, wherein the compound of formula (I) is a compound of formula (18), or a pharmaceutically acceptable salt thereof:wherein in formula (18): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2.

28. The pharmaceutical composition of claim 27, wherein the compound of formula (18) is a compound of formula (116), formula (117), formula (118), or a pharmaceutically acceptable salt thereof:

29. The pharmaceutical composition of claim 21, wherein the compound of formula (I) is a compound of formula (20), or a pharmaceutically acceptable salt thereof:wherein in formula (20): R4a, R4b, R4c, and R4dare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2; Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; and t is 1 or 2.

30. The pharmaceutical composition of claim 29, wherein the compound of formula (20) is a compound of formula (119), formula (120), formula (121), or a pharmaceutically acceptable salt thereof:

31. The pharmaceutical composition of any one of claims 23-30, wherein R4dis selected from H,wherein R5a, R5b, R5c, R5d, and R5eare at each occurrence independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -SC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)SRa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, and PO3(Ra)2, Rais independently selected at each occurrence 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 heterocyclyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl; t is 1 or 2; R6is H or optionally substituted alkyl; n3is an integer from 0 to 3, optionally n3is 0 or 1; n4is an integer from 0 to 4, optionally n4is 2; and n5is an integer from 0 to 4, optionally n5is 1.

32. The pharmaceutical composition of any one of claims 21-31, wherein the compound of formula (I) is a compound of any one of formula 1001-1150, or a pharmaceutically acceptable salt thereof:

33. The pharmaceutical composition of any one of claims 21-32, wherein the compound of formula (I) is a compound of any one of formula 1034, 1078-1080, 1094-1096, 1107-1112, 1115, 1116, 1121, 1122, 1124- 1127, 1129, 1132, 1133, 1135, 1141 -1149, or a pharmaceutically acceptable salt thereof:

34. A method for treating a cancer, an infectious disease, an inflammatory disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 21-33, optionally wherein the cancer is resistant to an anti-checkpoint agent, optionally wherein theanti-checkpoint agent is an antibody, optionally selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and anti- CTLA antibody.

35. The method of claim 34, wherein the cancer is selected from a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin’s and non-Hodgkin’s lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin’s lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom’s Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs’ syndrome.

36. The method of claim 34 or 35, wherein the cancer is a hematologic cancer selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma,Hodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia, or a combination thereof.

37. The method of claim 34, wherein the infectious disease is a viral infection, optionally wherein the viral infection is caused by a virus selected from papilloma virus, 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, a human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, human metapneumovirus, hantavirus, rotavirus, norovirus, and SARS virus (e.g., SARS-CoV-2).

38. The method of claim 34, wherein the inflammatory disease is an autoimmune disease or condition, selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture’s syndrome, Wegener’s granulomatosis, autoimmune epilepsy, Rasmussen’s encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addisohn’s disease, Hashimoto’s thyroiditis, Fibromyalgia, Menier’s syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren’s syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter’s syndrome, Grave’s disease, and other autoimmune disease.

39. A method for treating an anti-checkpoint agent-resistant cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 21-33.

40. A method of determining a cancer treatment for a patient, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any one of claims 21- 33 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and(d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody.

41. A method for selecting a patient for a cancer treatment, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) selecting the cancer therapy comprising the pharmaceutical composition of any one of claims 21- 33 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally selecting a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody.

42. A method of treating cancer, the method comprising: (a) obtaining a biological sample from a subject; (b) evaluating the biological sample for the expression of Trim7; and (c) administering the cancer therapy comprising the pharmaceutical composition of any one of claims 21-33 if the Trim7 is upregulated compared to a compared to a healthy tissue, a prior biological sample obtained from the subject, or another biological sample from patient that is known to be sensitive to an anti-checkpoint agent; and (d) optionally administering a second cancer therapy comprising an anti-checkpoint agent, wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti-PD-L2, and / or anti-CTLA agent, optionally wherein the anti-checkpoint agent is selected from an anti-PD-1, anti-PD-L1, anti- PD-L2, and / or anti-CTLA antibody.

43. The method of any one of claims 40-42, wherein the biological sample is a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

44. The method of any one of claims 40-43, 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), needle biopsy (e.g., fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound-assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy, optionally wherein the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom, optionally wherein the biological sample comprises at least one tumor cell.

45. The method of any one of claims 40-44, wherein the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof, or the evaluating is performed by contacting the sample with an agent that specifically binds to Trim7, optionally wherein the agent that specifically binds to one or proteins comprises an antibody, antibody-like molecule or binding a fragment thereof, or the evaluating is performed by contacting the sample with an agent that specifically binds to one or more of nucleic acids of Trim7, optionally wherein the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

Images