Heterocycles and their uses

Abstract

The present disclosure provides compounds and pharma- ceutically acceptable salts thereof, as well as methods of use thereof.The compounds and methods have a wide range of applications as therapeutic, diagnostic, and research tools.In particular, the subject compositions and methods are useful for reducing the signaling output of oncogenic proteins.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 159,966, filed March 11, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Many protein tyrosine phosphatases are known to be involved in the regulation of diverse cellular processes and are implicated in a variety of diseases, including metabolic, cardiovascular, neurological, and cancerous disease states. PTPN2 encodes a protein tyrosine phosphatase involved in many intracellular signaling pathways in immune cells. PTPN2 can negatively regulate αβ TCR T cell receptor (TCR) signaling by, for example, dephosphorylating and inactivating Src family kinases, including LCK. Additionally, PTPN2 can antagonize growth factor- or cytokine-mediated signaling required for T cell function, homeostasis, and / or differentiation by dephosphorylating and inactivating JAK family kinases, e.g., JAK-1 and JAK-3, and / or target substrates of JAK family kinases, e.g., STAT-1, STAT-3, and STAT-5.

[0003] Genome-wide association studies have shown that single nucleotide polymorphisms (SNPs) in PTPN2 are associated with the development of several human autoimmune diseases, including, but not limited to, type 1 diabetes, rheumatoid arthritis, Crohn's disease, and celiac disease. For example, the PTPN2 variant rs1893217(C) is associated with a 40% decrease in PTPN2 mRNA expression in CD4+ T cells and the development of type 1 diabetes. Additionally, it has been shown that PTPN2 mRNA expression levels are higher in lung cancer tissue than in normal lung tissue or adjacent normal tissue, and such overexpression promotes lung cancer cell proliferation. Furthermore, two PTPN2 SNPs, rs2847297 and rs2847282, are associated with reduced PTPN2 mRNA expression and lung cancer risk, particularly squamous cell lung cancer risk.

[0004] Cancer is the second leading cause of human death. In 2018, nearly 10 million people died from cancer worldwide, and 17 million new cases were diagnosed. In the United States alone, more than 500,000 people die from cancer each year, and approximately 1.7 million new cases are diagnosed each year (excluding basal and squamous cell carcinomas). The most common causes of cancer death worldwide are lung, liver, stomach, and intestinal cancer, accounting for more than four in 10 of all cancer deaths. Summary of the Invention [Means for solving the problem]

[0005] In view of the above, there is a significant need for alternative compositions and methods for treating diseases associated with PTPN2 activity. The compositions and methods of the present disclosure address these needs and provide additional advantages.

[0006] In one embodiment, there is provided a compound of formula (I-3), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1), C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), or N(R 4 ) and X is N or C(R 5) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14)C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3and R 3a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15, -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9ais combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied, however, Ring A [ka] at least two of which are double bonds).

[0007] In some embodiments, X is C(R 5 )

[0008] In some embodiments, Y is C(R 6 )

[0009] In some embodiments, Z is C(R 7 )

[0010] In some embodiments, J 1 is N and J 2 is C(R 9 )(R 9a )

[0011] In some embodiments, J 1 is C(R 8 ) and J 2 is C(R 9 )(R 9a )

[0012] In some embodiments, J 2 is CH2.

[0013] In some embodiments, J 1is C and J 2 is C(R 9 )

[0014] J 2 9. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0015] In some embodiments, J 3 is N(H).

[0016] In some embodiments, the subject compounds, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (Ia-3), (Ib-3), or (Ic-3): [ka]

[0017] In some embodiments, the subject compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (Ia-3): [ka]

[0018] In some embodiments, W 1 is N and W 2 is C(R 2 ) and W 3 is C(R 3 ) and W 4 is C(R 4 )

[0019] In some embodiments, R 2 is hydrogen and R 3 is hydrogen and R 4 is hydrogen.

[0020] In some embodiments, the subject compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (Ig-3), (Ih-3), or (Ii-3): [ka]

[0021] In some embodiments, the subject compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (Ig-3): [ka]

[0022] In some embodiments, W 1 is C(R 1 ) and W 2 is C(R 2 )

[0023] In some embodiments, R 1 is hydrogen and R 2 is hydrogen.

[0024] In some embodiments, W 3 is C(O) and W 4 is N(R 4 )

[0025] In some embodiments, R 4 is methyl.

[0026] In one embodiment, there is provided a compound of formula (III-3), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W2 is N, N(R 2 ), C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where: W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2ais combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20mis halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied).

[0027] In one embodiment, there is provided a compound of formula (II-3), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, V 1 is a bond or S, V 4 is a bond or S, where V 1 If is a bond, V 4 is S and V 1 If S, then V 4 is a bond, V 2 is N or C(R 2 ) and V 3 is N or C(R 3 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15, -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12)(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12)(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl).

[0028] In some embodiments, R 5 is selected from hydrogen and halogen.

[0029] In some embodiments, R 6 is -OH.

[0030] In some embodiments, R 7 is hydrogen.

[0031] In some embodiments, R 9 is hydrogen and R 9a is hydrogen and R 10 is hydrogen.

[0032] In some embodiments, R 2 -OR 12 and R 12 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, and -CH2-C 2-9 heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, and -CH2-C 2-9 Heterocycloalkyl can have one, two, or three R 20k is optionally replaced by

[0033] In some embodiments, R 20k is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, and -CH2-C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0034] In some embodiments, R 2 teeth, [ka] is selected from.

[0035] In some embodiments, R 2 is -N(R 12 )(R 13 ) and R 13 are independently hydrogen, and R 12 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, and -CH2-C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, and -CH2-C 1-9 Heteroaryl can be one, two, or three R 20k is optionally replaced by

[0036] In some embodiments, R 20k is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22, and -OC(O)R 25 are independently selected from, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, and -CH2-C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0037] In some embodiments, R 2teeth, [ka] is selected from.

[0038] In some embodiments, R 2 is C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b is optionally replaced by

[0039] In some embodiments, R 20b is oxo, -CN, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -N(R 22 )(R 23 ), -C(O)R 25 , -S(O)2R 25 , and -P(O)(R 25 )2, independently selected from 1-6 Alkyl and C 3-6 Cycloalkyl is substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0040] In some embodiments, R 2 teeth, [ka] is selected from.

[0041] In some embodiments, R 2 is C 1-6 Alkyl, C 2-9 Heterocycloalkyl, C 1-9 Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-9 Heterocycloalkyl, and C 1-9 Heteroaryl can be one, two, or three R 20b is optionally replaced by

[0042] In some embodiments, R 2 -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15, -C(O)N(R 12 )(R 13 ) and R 13 is hydrogen, R 12 and R 15 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0043] In some embodiments, R 2 -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R12 )(R 13 ) and R 13 is hydrogen, R 12 and R 15 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0044] In some embodiments, R 2 teeth, [ka] is selected from R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0045] In some embodiments, R 2 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0046] In some embodiments, R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -OR 12 , -SR 12 , and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 2-9 Heterocycloalkyl can have one, two, or three R 20c is optionally replaced by

[0047] In some embodiments, R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OR 12 is selected from, where C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 20c is optionally replaced by

[0048] In one embodiment, there is provided a compound selected from the following, or a pharmaceutically acceptable salt or solvate thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0049] In one aspect, a pharmaceutical composition is provided that includes a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0050] In one aspect, provided is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0051] In one embodiment, there is provided a method for enhancing cellular immunity, comprising: contacting a cell with a compound described herein, thereby enhancing the immunity of the cell; Methods are provided in which the cells comprise (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen.

[0052] In one embodiment, there is provided a method for enhancing cellular immunity, comprising: (a) contacting a cell with a compound described herein; (b) introducing into the cell (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen, thereby enhancing the immunity of the cell.

[0053] In some embodiments, the cell is a lymphoid cell.

[0054] In some embodiments, the method further comprises administering the cells to a subject in need thereof.

[0055] In some embodiments, the method further comprises administering to the subject a compound described herein before, simultaneously with, or after administering the cells.

[0056] In some embodiments, prior to administration of a compound described herein, the subject's cells exhibit PTPN2 expression or activity.

[0057] In one embodiment, there is provided a method of immune enhancing in a subject in need thereof, comprising: (a) selecting a subject exhibiting PTPN2 expression or activity; (b) downregulating the expression or activity of PTPN2 by introducing a compound described herein into cells of the subject, thereby enhancing the subject's immunity.

[0058] In one embodiment, there is provided a method of immune enhancing in a subject in need thereof, comprising: administering lymphoid cells to a subject; and administering to the subject a compound described herein, thereby enhancing the subject's immunity.

[0059] In one embodiment, there is provided a method of enhancing anti-tumor or anti-cancer immunity in a subject in need thereof, comprising: (a) contacting lymphoid cells of a subject with a compound described herein, thereby enhancing anti-tumor or anti-cancer immunity in the subject.

[0060] In one embodiment, there is provided a method of treating a tumor or cancer in a subject in need thereof, comprising: (a) contacting lymphoid cells of a subject with a compound described herein, thereby treating a tumor or cancer in the subject.

[0061] In one aspect, provided is a method of treating a tumor or cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein and an additional agent selected from the group consisting of a chemotherapeutic agent and an immunomodulatory agent.

[0062] In one aspect, provided is a method of treating a tumor or cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein in combination with a cell therapy.

[0063] In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), O, C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14)S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14)S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20k optionally replaced by R 12a is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied, however, i) Ring A [ka] at least two of which are double bonds, ii)J 3 If is CH2, R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12a , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by iii) The compound is [ka] isn't it).

[0064] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R 5 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Y is C(R 6 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Z is C(R 7 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is N and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is C(R 8 ) and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 2 is CH. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is C and J 2 is C(R 9 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 2 is C(H). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3 is N(R 10 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3is N(H). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ia): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 at least one of is N).

[0065] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ib): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 at least one of is N).

[0066] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ic): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 at least one of is N).

[0067] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is N and W 2 is C(R 2 ) and W 3 is C(R 3 ) and W 4 is C(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(R1 ) and W 2 is N and W 3 is C(R 3 ) and W 4 is C(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 3 is N and W 4 is C(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 3 is C(R 3 ) and W 4 is N.

[0068] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ig): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O).

[0069] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ih): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R3 ), N(R 4 ), or O).

[0070] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ii): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O).

[0071] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(R 1 ) and W 2 is C(R 2 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 3 is N(R 3 ) and W 4 is C(O). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 3 is C(O) and W 4 is N(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 3 is O and W 4 is C(R 4 )(R 4a )

[0072] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ij): [ka] (In the formula, W 1 , W2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N, or O).

[0073] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ik): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N, or O).

[0074] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Im): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O).

[0075] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(R 1 )(R 1a ) and W 2 is O and W 3 is C(R 3 ) and W 4 is C(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is CO, N(R1) or C(R 1)(R 1a ) and W 2 is CO, N(R2), or C(R 2 )(R 2a ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 )

[0076] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Iv): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 4 ), N, or O).

[0077] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Iw): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 4 ), N, or O).

[0078] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ix): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4At least one of N(R 1 ), N(R 4 ), N, or O).

[0079] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Io): [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 4 is C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is).

[0080] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ioa): [ka]

[0081] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Iob): [ka]

[0082] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ioc): [ka]

[0083] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of formula (Iop): [ka] (In the formula, W 1 is C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 3 is C(R 3 ) and W 4 is C(R 4 ) is).

[0084] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ipa): [ka]

[0085] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of formula (Ipb): [ka]

[0086] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ipc): [ka]

[0087] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of formula (Ipd): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is).

[0088] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Iq): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is).

[0089] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (Ir): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is).

[0090] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 4 is C(O).

[0091] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3), or P(O)(R 3 ) and W 4 is N, N(R 4 ), O, C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where: i)W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, ii) W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C 3-6Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14)S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22)(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied, However, the compound is [ka] isn't it).

[0092] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R 5 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Y is C(R 6 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Z is C(R 7 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is N and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is C(R 8 ) and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 2 is CH. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is C and J 2 is C(R 9 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J2 is C(H). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3 is N(R 10 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3 is N(H).

[0093] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIa): [ka]

[0094] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIb): [ka]

[0095] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIc): [ka]

[0096] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is C(O). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 2 is N(R 2 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 3 and W 4 is connected by a double bond. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 2is C(O). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is N(R 1 ) and W 3 and W 4 is connected by a double bond. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 3 is C(O). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 2 is N(R 2 ) and W 1 is C(R 1 )(R 1a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 4 is N(R 4 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 4 is C(R 4 )(R 4a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 4 is N(R 4 ) and W 1 and W 2 is connected by a double bond. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 4 is C(O). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 1 is O. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 2 is C(R 2 )(R 2a ) and W 3 is C(R 3 )(R 3a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, W 2 is C(R 2 ) and W 3is C(R 3 )

[0097] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIId): [ka]

[0098] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIe): [ka]

[0099] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIf): [ka]

[0100] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIg): [ka]

[0101] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIh): [ka]

[0102] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIi): [ka]

[0103] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIj): [ka]

[0104] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIk): [ka]

[0105] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIl): [ka]

[0106] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIm): [ka]

[0107] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIn): [ka]

[0108] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIo): [ka]

[0109] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIp): [ka]

[0110] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIq): [ka]

[0111] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIr): [ka]

[0112] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIs): [ka]

[0113] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIt): [ka]

[0114] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIIu): [ka]

[0115] In one embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, V 1 is a bond or S, V 4 is a bond or S, where V 1 If is a bond, V 4 is S and V 1 If S, then V 4 is a bond, V 2 is N or C(R 2 ) and V 3 is N or C(R 3 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally replaced by R3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13)-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is halogen, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl).

[0116] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R 5 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Y is C(R 6 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, Z is C(R 7 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is N and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1 is C(R 8 ) and J 2 is C(R 9 )(R 9a In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 2 is CH. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 1is C and J 2 is C(R 9 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 2 is C(H). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3 is N(R 10 In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, J 3 is N(H). In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, V 1 is a bond and V 4 is S. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, V 1 is S and V 4 is a bond.

[0117] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIa): [ka]

[0118] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIb): [ka]

[0119] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIc): [ka]

[0120] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IId): [ka]

[0121] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIe): [ka]

[0122] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure of Formula (IIf): [ka]

[0123] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 5 is hydrogen, halogen, and one, two, or three R 20e C optionally replaced with 1-6 alkyl.

[0124] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 5 is selected from hydrogen and halogen.

[0125] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 6 is hydrogen, halogen, -OR 12a , and 1, 2, or 3 R 20f C optionally replaced with 1-6 alkyl.

[0126] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 6 is -OH.

[0127] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 7 is hydrogen, halogen, and one, two, or three R 20g C optionally replaced with 1-6 alkyl.

[0128] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 7 is hydrogen.

[0129] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 9 is hydrogen.

[0130] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 9a is hydrogen.

[0131] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 10 is hydrogen.

[0132] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 is hydrogen, halogen, C 1-6 Alkyl, C 2-9 Heterocycloalkyl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -S(O)N(R 12 )(R13 )-, where C 1-6 Alkyl, C 2-9 Heterocycloalkyl, and C 1-9 Heteroaryl can be one, two, or three R 20b is optionally replaced by

[0133] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 is C 1-6 Alkyl, C 2-9 Heterocycloalkyl, C 1-9 Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-9 Heterocycloalkyl, and C 1-9 Heteroaryl can be one, two, or three R 20b is optionally replaced by

[0134] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ) and R 13 is hydrogen, R 12 and R 15 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0135] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ) and R 13 is hydrogen, R 12 and R 15 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0136] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 teeth, [ka] is selected from R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0137] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 2 is, independently, [ka] and R 26 is halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 are independently selected from

[0138] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -OR 12 , -SR 12 , and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 2-9 Heterocycloalkyl can have one, two, or three R 20c In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OR 12 is selected from, where C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 20c is optionally replaced by

[0139] In one embodiment, there is provided a compound selected from the following, or a pharmaceutically acceptable salt or solvate thereof: [ka] [ka]

[0140] In one aspect, a pharmaceutical composition is provided that includes a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0141] In one aspect, provided is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (including embodiments thereof), or a pharmaceutically acceptable salt or solvate thereof.

[0142] In one aspect, provided is a method of enhancing the immunity of a cell, comprising: (a) contacting the cell with a compound described herein (including embodiments thereof), thereby enhancing the immunity of the cell, wherein the cell comprises (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen.

[0143] In one aspect, provided is a method of enhancing cellular immunity, comprising: (a) contacting a cell with a compound described herein (including embodiments thereof); and (b) introducing into the cell (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen, thereby enhancing cellular immunity.

[0144] In some embodiments of the methods (including embodiments thereof) described herein, (a) is performed before, simultaneously with, or after (b). In some embodiments, the cells (e.g., lymphoid cells) retain PTPN2 expression or activity before (a). In some embodiments, the subject methods further comprise administering the cells to a subject in need thereof. In some embodiments, the subject methods further comprise administering a compound (including embodiments thereof) described herein to the subject before, simultaneously with, or after administering the cells. In some embodiments, the cells of the subject exhibit PTPN2 expression or activity.

[0145] In one aspect, a method is provided for enhancing immunity in a subject in need thereof, comprising administering lymphoid cells to the subject, thereby enhancing the subject's immunity, wherein the expression or activity of PTPN2 in the lymphoid cells is transiently downregulated.

[0146] In some embodiments of the methods described herein (including embodiments thereof), the methods further include transiently downregulating PTPN2 expression or activity in lymphoid cells. If desired, the transient downregulation is performed once or intermittently, such as two or more times, as desired. In some embodiments, the transient downregulation includes introducing a compound described herein (including embodiments thereof) into the cells of interest. In some embodiments, the first intermittent administration regimen of a compound described herein and the second intermittent administration regimen of the compound are the same or different. In some embodiments, prior to transient downregulation, the lymphoid cells contacted with the subject compounds exhibit PTPN2 expression or activity. In some embodiments of the methods described herein (including embodiments thereof), the lymphoid cells comprise (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen. In some embodiments, the method further includes administering a compound described herein to the subject before, simultaneously with, or after administering the lymphoid cells. In some embodiments, the subject exhibits PTPN2 expression or activity. In one aspect, a method of enhancing immunity in a subject in need thereof is provided, the method comprising: (a) selecting a subject exhibiting PTPN2 expression or activity; and (b) downregulating PTPN2 expression or activity in the subject's cells, thereby enhancing the subject's immunity. In some embodiments of the methods described herein, step (b) is performed in vivo or ex vivo. In some embodiments of the methods described herein, downregulating comprises introducing a compound described herein into the cells. If desired, downregulating comprises transiently downregulating PTPN2 expression or activity. In some embodiments, the transient downregulation is performed once, or two, three, or more times.In some embodiments, the first intermittent dosing regimen of the compound described herein is the same as the second intermittent dosing regimen utilizing the compound disclosed herein. In some embodiments, the first intermittent dosing regimen of the compound described herein is different from the second intermittent dosing regimen. In performing any of the aforementioned methods, the subject's cells to be treated may be lymphoid cells comprising (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, each of the TFP and CAR exhibiting specific binding to an antigen. In some embodiments, the subject's cells do not exhibit a mutation in (i) a first gene encoding PTPN2 or (ii) a second gene operably linked to PTPN2, wherein the mutation inhibits PTPN2 expression and / or activity. In some embodiments, the methods described herein further include selecting a subject exhibiting PTPN2 expression or activity. If desired, the selecting step includes performing a nucleic acid assay to detect the mutation using at least a portion of the genome or transcriptome of the subject's cells. In some embodiments, selecting comprises performing a protein assay that detects functionally active or functionally inactive PTPN2.

[0147] In one aspect, a method for enhancing immunity in a subject in need thereof is provided, comprising administering lymphoid cells to the subject and administering a compound described herein to the subject, thereby enhancing the subject's immunity. If desired, administering the compound described herein can be performed before, simultaneously with, or after administering the lymphoid cells. In some embodiments of the methods described herein, administering the compound described herein is performed separately from administering the lymphoid cells. In some embodiments, the cells of the subject typically exhibit PTPN2 expression or activity.

[0148] In one aspect, a method of enhancing anti-tumor or anti-cancer immunity in a subject in need thereof is provided, the method comprising: (a) contacting the subject's lymphoid cells with a compound described herein, thereby enhancing the subject's anti-tumor or anti-cancer immunity. In some embodiments, the contemplated immunity includes anti-tumor activity, anti-cancer activity, anti-viral infection activity, and / or anti-bacterial infection activity. In yet another aspect, a method of treating a tumor or cancer in a subject in need thereof is provided, the method comprising: (a) contacting the subject's lymphoid cells with a compound described herein, thereby treating the tumor or cancer in the subject. In some embodiments, the step of contacting the lymphoid cells is performed in vivo. In some embodiments, the contacting step is performed ex vivo, followed by introduction of the lymphoid cells into the subject. In some embodiments, the lymphoid cells contacted with the compounds disclosed herein comprise (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence, wherein each of the TFP and CAR exhibits specific binding to an antigen. Accordingly, in some embodiments, the method further comprises (b) introducing into the lymphoid cells (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence, wherein each of the TFP and CAR exhibits specific binding to an antigen. In some embodiments of the methods described herein, (a) is performed before, simultaneously with, or after (b). In one aspect, a method is provided for enhancing anti-tumor or anti-cancer immunity in a subject in need thereof, comprising (a) downregulating PTPN2 expression or activity in lymphoid cells of the subject, thereby enhancing anti-tumor or anti-cancer immunity in the subject.In yet another aspect, methods are provided for treating a tumor or cancer in a subject in need thereof, comprising: (a) downregulating PTPN2 expression or activity in lymphoid cells of the subject, thereby treating the tumor or cancer in the subject. In some embodiments of performing one or more of these methods, the downregulating is performed in vivo. In some embodiments, the downregulating is performed ex vivo, followed by introducing the lymphoid cells into the subject. In some embodiments, the method further comprises administering the lymphoid cells to the subject before, simultaneously with, or after the downregulating. In some embodiments, the downregulating comprises introducing a compound described herein into the lymphoid cells. In some embodiments, the downregulating comprises transiently downregulating PTPN2 expression or activity. If desired, the transient downregulation is performed once, or two, three, or more times. In some embodiments, the first intermittent administration regimen of a compound described herein is the same as the second intermittent administration regimen of the compound. In some embodiments, a first intermittent administration regimen of a compound described herein is different from a second intermittent administration regimen of the compound. In some embodiments, the method further includes (b) introducing into the lymphoid cells (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen. In some embodiments of the methods described herein, (a) is performed before, simultaneously with, or after (b).

[0149] In one aspect, provided is a method of increasing the efficacy or reducing the side effects of a cell therapy in a subject in need thereof, the method comprising: (a) administering to the subject cells comprising a CAR sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an antigen-binding domain and an intracellular signaling domain, the intracellular signaling domain being minimally required for activation of the CAR upon binding to an antigen; and (b) administering to the subject a compound described herein prior to, simultaneously with, or after (a). In some embodiments, the cells, including but not limited to lymphoid cells, retain PTPN2 expression or activity prior to (b). In some embodiments, the subject's cells typically exhibit PTPN2 expression or activity.

[0150] In one aspect, provided is a method of increasing the efficacy or reducing the side effects of cell therapy for a subject in need thereof, comprising: (a) administering to the subject a subtherapeutic amount of cells comprising a CAR sequence encoding a chimeric antigen receptor (CAR); and (b) administering to the subject a compound described herein prior to, concurrently with, or after (a). In some embodiments, the cells, including but not limited to lymphoid cells, retain PTPN2 expression or activity prior to (b).

[0151] In some embodiments, the compounds disclosed herein or utilized in this disclosure reduce PTPN2 signaling in cells. In some embodiments, the compounds disclosed herein do not regulate site-specific recombination of the gene encoding PTPN2. In some embodiments, the compounds disclosed herein are configured to bind to PTPN2 or exhibit binding specificity for PTPN2 compared to other tyrosine phosphatases. In some embodiments, the compounds described herein exhibit an IC of 5 μM or less for PTPN2. 50 Shows.

[0152] In some embodiments, practicing any of the subject methods further comprises monitoring one or more health parameters of the subject selected from the group consisting of body temperature, wheezing, sweating, fatigue, weight, insomnia, diarrhea, infection, and psychiatric disorders, concurrently with or after administration of a compound described herein and / or lymphoid cells. In some embodiments, the method further comprises detecting one or more inflammatory biomarkers selected from the group consisting of antibodies, cytokines, radicals, and coagulation factors disclosed herein, concurrently with or after administration of a compound described herein, lymphoid cells. In some embodiments, practicing the subject methods may involve (1) contacting cells with a compound described herein, (2) administering lymphoid cells to the subject, (3) downregulating PTPN2 expression or activity in the subject's cells, (4) administering a compound described herein to the subject, (5) contacting lymphoid cells of the subject with a compound described herein, and / or (6) downregulating PTPN2 expression or activity in the subject's lymphoid cells, performed before, concurrently with, or after administering another agent (second agent) or therapy to the subject. In some embodiments, the second agent is selected from the group consisting of a chemotherapeutic agent, a radioactive agent, a small molecule agent that targets a tumor marker, an antigen-binding agent that specifically binds to a tumor marker, and an immunomodulatory agent. In some embodiments, the second agent is a checkpoint inhibitor. In some embodiments, the second agent includes, but is not limited to, an inhibitor of PD1, PD-L1, LAG3, CTLA4, CD160, BTLA, LAIR1, TIM3, 2B4, CD93, OX40, Siglec-15, and TIGIT. In some embodiments, the second agent is an inhibitor of IDO or mTOR. In some embodiments, the combined second therapy is a cell therapy comprising stem cells or lymphoid cells.

[0153] In some embodiments of the methods described herein, the TFP comprises a TCR subunit comprising (1) a TCR extracellular domain capable of specifically binding to an antigen and (2) an intracellular signaling domain, and the TFP forms a TCR complex. In some embodiments, the TCR extracellular domain comprises element (1) an antigen-binding domain capable of specifically binding to an antigen, and element (2) an extracellular domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, and a CD3 delta TCR, or a portion thereof, wherein elements (1) and (2) are operably linked together. In some embodiments, the TCR intracellular domain comprises a stimulatory domain derived from the intracellular signaling domain of the epsilon chain, delta chain, and / or gamma chain of differentiation antigen 3 (CD3). In some embodiments, the TCR intracellular domain comprises a stimulatory domain derived from the intracellular signaling domain of a TCR alpha or a TCR beta. In some embodiments, the TFP comprises a transmembrane domain, including a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD 154. In some embodiments, the TFP comprises a costimulatory domain.In some embodiments, the costimulatory domain of TFP is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD1 1b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0154] In some embodiments of the methods described herein, the CAR comprises an antigen binding domain and an intracellular signaling domain. In some embodiments, the intracellular signaling domain of the CAR comprises a primary signaling domain and / or a costimulatory signaling domain, and the primary signaling domain comprises a functional signaling domain of a protein selected from CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon Rib), CD79a, CD79b, Fc gamma R11a, DAP10, or DAP12. In some embodiments, the intracellular signaling domain of the CAR is selected from the group consisting of CD27, CD28, 4-lBB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDlld, ITGAE, CD103, ITGAL, CDlla, LFA-1, I comprising a functional signaling domain of a protein selected from the group consisting of TGAM, CDllb, ITGAX, CDllc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D;and a costimulatory signaling domain. In some embodiments, the intracellular signaling domain of the CAR comprises a primary signaling domain and / or a costimulatory signaling domain, wherein the primary signaling domain and / or the costimulatory signaling domain are minimally required for activation of the CAR upon binding to an antigen. In some embodiments, the CAR is a first-generation CAR in which the primary signaling domain is a member selected from the group consisting of CD3 zeta, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof. In some embodiments, the CAR is a second-generation CAR in which (i) the primary signaling domain is a member selected from the group consisting of CD3 zeta, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof, and (ii) the costimulatory signaling domain is a different member selected from the group consisting of CD3 zeta, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof. In some embodiments of the methods described herein, the antigen is a tumor antigen or a cancer antigen, and tumor antigens include TSHR, CD19, CD123, CD22, CD30, CD171, CS-1, CLL-1, CD33, EGFRvIII, GD2, GD3, BCMA, Tn Ag, PSMA, RORl, FLT3, FAP, TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, mesothelin, IL-11Ra, PSCA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, CD20, folate receptor alpha, ERBB2 (Her2 / neu), MUC1, EGFR, NCAM, Prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAI X, LMP2, gplOO, bcr-abl, tyrosinase, EphA2, fucosylGMl, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1 / CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1,NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE Al, ETV6-AML, sperm protein 17, XAGE1, Tie2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53, p53 mutants, prostein, survivin and telomerase, PCTA-1 / galectin 8, MelanA / MART1, Ras mutants, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, TRP-2, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RUL, RU2, intestinal carboxylesterase, mut In some embodiments of the methods described herein, the antigen is selected from the group consisting of hsp70-2, CD79a, CD79b, CD72, LAIRl, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, and IGLL1. In some embodiments of the methods described herein, the antigen comprises a neoantigen encoded by a tumor-specific mutated gene. In some embodiments of the methods described herein, the side effect comprises cytokine release syndrome (CRS), an inflammatory disorder, or an autoimmune disorder.

[0155] In one aspect, modified cells are provided that include (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of the TFP and CAR exhibits specific binding to an antigen, and PTPN2 expression or activity in the cell is downregulated to enhance the immunity of the modified cell. In some embodiments, the modified cells exhibit a mutation in (i) a first gene encoding PTPN2 or (ii) a second gene operably linked to PTPN2, wherein the mutation inhibits PTPN2 expression and / or activity. In some embodiments, PTPN2 expression or activity is transiently downregulated in the modified cells. In some embodiments of the modified cells, PTPN2 expression or activity is downregulated by a compound described herein. In some embodiments, the subject compound that modifies the cell (i) does not regulate site-specific recombination of the gene encoding PTPN2, (ii) is configured to bind PTPN2, and / or (iii) exhibits binding specificity for PTPN2 relative to other tyrosine phosphatases. In some embodiments, the subject cell-modifying compounds have an IC of 5 μM or less against PTPN2. 50In some embodiments, the TFP (contained in the modified cells) comprises a TCR subunit comprising (1) a TCR extracellular domain capable of specifically binding to an antigen, and (2) an intracellular signaling domain, wherein the TFP forms a TCR complex. In some embodiments, the TCR extracellular domain comprises element (1) an antigen-binding domain capable of specifically binding to an antigen, and element (2) an extracellular domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, and a CD3 delta TCR, or a portion thereof, wherein elements (1) and (2) are operably linked together. In some embodiments, the TCR intracellular domain comprises a stimulatory domain derived from the intracellular signaling domain of the epsilon chain, delta chain, and / or gamma chain of differentiation antigen 3 (CD3). In some embodiments, the TCR intracellular domain comprises a stimulatory domain derived from the intracellular signaling domain of a TCR alpha or a TCR beta. In some embodiments, the TFP comprises a transmembrane domain, including a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.In some embodiments, the TFP is selected from the group consisting of, but not limited to, CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD 11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4 (CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL1, CD100(SEMA4D), C The costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of D69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D. In some embodiments, the engineered cell is an engineered lymphoid cell. In some embodiments, the engineered lymphoid cell is a member or variant thereof selected from the group consisting of T cells, B cells, NK cells, KHYG cells, T helper cells, regulatory T cells, memory T cells, tumor-infiltrating T cells (TILs), antigen-presenting cells, and dendritic cells. In some embodiments of the engineered cell, the engineered lymphoid cell is a variant of a member selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD4+ and CD8+ T cells.

[0156] In some embodiments, any of the subject compounds, modified cells, and any other agents described herein can also be applied (e.g., utilized) in any of the subject methods described herein. Similarly, any compounds, modified cells, and any other agents described in the context of the subject methods are embodied and contemplated as subject compositions. [Brief explanation of the drawings]

[0157] [Figure 1] A. MHC1 assay for PTPN2 cellular activity. The dots represent, from left to right, three vertical groups of dots representing replicate experiments: 1 ng / ml IFNγ DMSO, 100 μM of the first reference compound, 50 μM of the first reference compound, a subject compound from Table 6, a second reference compound, a third reference compound, another subject compound from Table 6, and yet another subject compound from Table 6, a fourth reference compound. B. The dots represent, from left to right, no IFNγ, IFNγ, 10 μM of the fourth reference compound, and 10 μM of the subject compound from Table 6. The Y-axis represents % MHC1 increase (normalized) from 0 to 200. C. The dots represent, from left to right, no IFNγ, IFNγ, 10 μM of a fourth reference compound, 10 μM of a subject compound from Table 6, 10 μM of another subject compound from Table 6, and 10 μM of yet another subject compound from Table 6; the Y-axis represents the % increase in MHC1 (normalized) from 0 to 200. The results demonstrate that subject compounds exhibiting PTPN2 inhibitory activity enhance MHC expression levels.

[0158] [Figure 2] We show that high expression of TIM3 and PD1 and low expression of Slamf6 in tumor-associated CD8+ cells, but not in spleen-associated cells, indicates exhaustion of tumor-infiltrating lymphocytes.

[0159] [Figure 3] 1 shows tumor growth inhibition using a B16F10 mouse model treated with a subject PTPN2 inhibitor disclosed herein.

[0160] [Figure 4]A shows the phenotype of tumor-infiltrating CD8 T cells on day 7 in the B16F10 model, and B shows the phenotype of tumor-infiltrating macrophages on day 7 in the B16F10 model. DETAILED DESCRIPTION OF THE INVENTION

[0161] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0162] The practice of some embodiments disclosed herein will employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics, and recombinant DNA, within the skill of one in the art. See, e.g., Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); Current Protocols in Molecular Biology (F.M.A.usubel, et al., eds.) series; Methods in Enzymology (Academic Press, Inc.) series; PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames, and G.R. Taylor, eds. (1995)); Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual; and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)).

[0163] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to which the claimed subject matter belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated by reference. When reference is made to a URL or other such identifier or address, it is understood that such identifiers may change and that particular information on the Internet may come and go, but that equivalent information may be found by searching the Internet. Reference thereto evidences the availability and general public dissemination of such information.

[0164] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0165] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0166] Definitions of standard chemical terms can be found in references including, but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0167] Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are art-recognized. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures can generally be performed in a conventional manner and as described in various general and more specific references cited and discussed throughout this specification.

[0168] It is understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, as these may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0169] As used herein, "about" when referring to a measurable value such as an amount, time, etc. is meant to encompass a ±10% variation of the stated number or value.

[0170] As used herein, "expression" refers to the process by which a polynucleotide is transcribed into mRNA and / or the process by which the transcribed mRNA (also referred to as a "transcript") is subsequently translated into a peptide, polypeptide, or protein. The transcript and the encoded polypeptide are collectively referred to as the "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. The level of expression of the PTPN2 gene (alternatively, "expression level") can be determined, for example, by determining the level of the PTPN2 polynucleotide, polypeptide, or gene product.

[0171] "Aberrantly expressed" or "aberrant expression," when applied to a nucleotide sequence (e.g., a gene) or polypeptide sequence of a subject, refers to abnormal production of mRNA transcribed and / or translated from the nucleotide sequence or the protein product encoded by the nucleotide sequence. A differentially expressed sequence can be overexpressed (or abnormally high expression) or underexpressed (or abnormally low expression) compared to the expression level of a reference sample (i.e., reference level). As used herein, overexpression is an increase in expression, which may be at least 1.25-fold, alternatively at least 1-fold, alternatively at least 2-fold, alternatively at least 3-fold, alternatively at least 4-fold, or alternatively at least 10-fold greater than the expression detected in the reference sample. As used herein, underexpression is a decrease in expression, which may be at least 1.25-fold, alternatively at least 1-fold, alternatively at least 2-fold, alternatively at least 3-fold, alternatively at least 4-fold, or alternatively at least 10-fold greater than the expression detected in the reference sample. Underexpression also encompasses the absence of expression of a particular sequence, evidenced by the absence of detectable expression in a test subject when compared to a reference sample.

[0172] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted in or within a cell, resulting in an intracellular response. A molecule can mediate its signaling effect through direct or indirect interaction with downstream molecules in the same pathway or related pathway(s). For example, PTPN2 signaling involves a number of downstream molecules, including, but not limited to, one or more of the following proteins: STAT1 and STAT5.

[0173] A "control" or "control sample" is a substitute sample or control used in an experiment for comparison purposes.

[0174] The term "reference level" refers to a control level used to evaluate the test level. In some instances, the reference level can be a control. For example, a biomarker can be considered underexpressed if its expression level is lower than the reference level. The reference level can be determined by multiple methods, provided that the resulting reference level accurately represents the level of the biomarker, and that a first patient group with a biomarker level above the reference level has a different probability of showing a clinically beneficial response to treatment with a PTPN2 inhibitor than a second patient group with a biomarker level below the reference level. The reference level can be determined, for example, by measuring the expression level of the biomarker in tumorous or non-tumorous cancer cells derived from the same tissue as the cancer cell tissue being tested. In some instances, the reference level can be the level of the biomarker determined in vitro. The reference level can be determined by comparing the biomarker levels of a group of subjects with the same cancer. Two or more distinct groups of subjects can be determined by identifying subsets of a cohort population with the same or similar biomarker levels. The reference level can then be determined based on the levels that distinguish these distinct groups. The reference level may be a single number that is equally applicable to all subjects, or the reference level may vary depending on the specific subpopulation of subjects. For example, an elderly man may have a different reference level than a young man with the same cancer, and a woman may have a different reference level than a man with the same cancer. Furthermore, the reference level may be several levels determined individually for each subject. For example, the reference level may be the ratio of the biomarker level in the subject's cancer cells to the biomarker level in normal cells within the same subject. In some embodiments, the reference level is a numerical range of gene expression obtained from statistical sampling of a population of individuals with cancer. The sensitivity of an individual with cancer to treatment with a PTPN2 inhibitor may be known.In some embodiments, the reference level is derived by comparing gene expression to a control gene (e.g., a housekeeping gene such as actin) that is expressed at a relatively stable level in the same cellular environment. Comparison to the reference level can be a qualitative assessment or a quantitative determination.

[0175] The terms "determining," "measuring," "assessing," "evaluating," "assaying," "testing," and "analyzing" are used interchangeably herein to refer to any form of measurement, including determining whether an analyte is present or absent (e.g., detecting). These terms can include both quantitative and / or qualitative determinations. Evaluating can be relative or absolute. A relative amount can be, for example, high, medium, or low. An absolute amount can represent the intensity of a measured signal or a conversion of this signal intensity to another quantitative format, such as micrograms / mL. "Detecting the presence" can include determining not only whether something is present or absent, but also the amount of something present.

[0176] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds or biological molecules capable of inhibiting the activity or expression of a target protein (e.g., PTPN2), thereby resulting in the inhibition of the biological function of the target protein. Thus, the terms "antagonist" and "inhibitor" are defined with respect to the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with a target; however, specifically included within this definition are compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway of which the target protein is a member. Alternatively or additionally, because the activity of a target protein may involve interaction (e.g., binding) between the target protein and a substrate of the target protein, the terms "antagonist" and "inhibitor" can also refer to compounds capable of indirectly inhibiting the biological activity of the target protein by interacting (e.g., binding) with the counterpart of the target protein. In some cases, such compounds may bind to both the target protein and one or more substrates. A preferred biological activity inhibited by an antagonist is related to the development, growth, persistence, or spread of cancer or tumors.

[0177] The term "cell proliferation" refers to the phenomenon of a change in cell number as a result of division. The term also encompasses cell growth in which cell morphology changes (e.g., size increases) in concert with proliferation signals.

[0178] The terms "administer," "administering," "administration," and derivatives thereof refer to methods that can be used to deliver an agent or composition to a desired site of biological action. These methods include, but are not limited to, parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion, and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration can be by any route, including parenteral. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other methods of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, implantation, and the like. Those skilled in the art will know additional methods for administering a therapeutically effective amount of a composition of the present disclosure to prevent or alleviate one or more symptoms associated with a disease.

[0179] The term "systemic administration" refers to administering an agent or composition such that the agent or composition is distributed throughout the subject's body. Distribution of the agent or composition throughout the subject's body can be uniform. Alternatively, distribution can be preferential, resulting in the agent or composition being more locally localized to one or more desired sites. The desired sites can be the blood or other sites accessible by the vasculature. Non-limiting examples of systemic administration routes include (1) introducing the agent directly into the vasculature, or (2) administration by oral, pulmonary, or intramuscular administration, where the agent is absorbed, enters the vasculature, and is carried via the blood to one or more desired site(s) of action. In contrast, "non-systemic administration" refers to administering an agent or composition locally to a desired target site in the subject's body, resulting in a primarily localized effect.

[0180] The terms "co-administration," "administered in combination with," and their grammatical equivalents include administering two or more agents to a subject, thereby allowing both agents and / or their metabolites to perform their respective functions. Co-administration includes administration at the same time as separate compositions, administration at different times as separate compositions, or administration in a composition in which both agents are present.

[0181] The term "subject" includes, but is not limited to, humans of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult) and / or other primates (e.g., a cynomolgus monkey or a rhesus monkey); mammals, e.g., mammals of commercial value such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, e.g., birds of commercial value such as chickens, ducks, geese, quail, and / or turkeys. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0182] The term "downregulating PTPN2 activity," as used herein, refers to slowing, decreasing, altering, inhibiting, as well as completely eliminating and / or preventing PTPN2 activity.

[0183] The term "effector function" refers to a specialized function of a cell. The effector function of a T cell can be, for example, cytolytic activity or helper activity, including cytokine secretion. Thus, the term "intracellular signaling domain" refers to the portion of a protein that transmits the effector function signal and enables the cell to perform the specialized function.

[0184] The terms "immune effector cell" and "effector cell" are used interchangeably herein and refer to cells that are involved in an immune response, e.g., promoting an immune effector response. Examples of immune effector cells include T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and bone marrow-derived phagocytes.

[0185] The term "lymphoid cell" or "lymphoid cell(s)" refers to any cell involved in the development of cell or antibody-mediated immunity, including lymphocytes, lymphoblasts, and plasma cells. Lymphoid cells include granulocytes, such as basophils, eosinophils, and neutrophils; mast cells; monocytes that can develop into macrophages; antigen-presenting cells, such as dendritic cells; and lymphocytes, such as natural killer cells (NK cells), B cells, and T cells (including activated T cells). In some instances, T cells include both naive and memory cells (e.g., central memory or T cells). CM , Effector Memory or T EM and Effector Memory RA or T EMRA ), effector cells (e.g., cytotoxic T cells or CTL or Tc cells), helper cells (e.g., Thl, Th2, Th3, Th9, Th7, TfH), regulatory cells (e.g., Treg and Trl cells), natural killer T cells (NKT cells), tumor-infiltrating lymphocytes (TIL), lymphocyte-activated killer cells (LAK), αβT cells, γδT cells, and similar unique classes of T cell lineages.

[0186] As used herein, the term "transiently downregulated" generally means that the downregulation of the expression or activity of a target molecule (e.g., PTPN2) is not permanent. Transient downregulation does not have to be permanent. In some cases, transient downregulation may involve downregulating (e.g., reducing) the expression or activity of a target molecule for a period of time, followed by restoring at least a portion of the expression or activity level of the target molecule that was previously downregulated. Transient downregulation may include intermittent downregulation of a target molecule (e.g., PTPN2).

[0187] The term "intermittent" is used herein to describe a process that is not continuous. An intermittent process may be followed by an interruption or cessation. Multiple intermittent processes may involve alternating starting and stopping of the same or different processes. In some embodiments, the term "intermittent dosing regimen" is used herein to refer to a dosing regimen in which administration of a pharmaceutical composition is followed by a rest period.

[0188] As used herein, the term "side effect" refers to any complication, undesired result, or pathological consequence of a therapy that occurs in addition to, or instead of, the desired therapeutic outcome of the therapy. Examples of side effects can include, but are not limited to, (i) off-target cytotoxicity, (ii) on-target extratumoral toxicity, and / or (iii) autoimmunity (e.g., chronic autoimmunity).

[0189] The term "effectiveness" of a treatment or method, as used herein, can be measured based on a change in the course of a disease or condition in response to such treatment or method. For example, the effectiveness of a treatment or method of the present disclosure can be measured by its effect on the signs or symptoms of a subject's disease or condition, e.g., a subject's tumor or cancer. A response can be achieved when a subject with a disease or condition experiences partial or complete relief of the disease or condition, or a reduction in one or more symptoms of the disease or condition. As an example, a response is achieved when a subject suffering from a tumor exhibits a decrease in tumor size after a treatment or method provided herein. In some examples, efficacy can be measured by assessing cancer cell death, tumor shrinkage (e.g., as evidenced by a decrease in tumor size), and / or inhibition of tumor growth, progression, and dissemination.

[0190] "Amino" refers to the -NH2 radical.

[0191] "Cyano" refers to the -CN radical.

[0192] "Nitro" refers to the -NO2 radical.

[0193] "Oxa" refers to the -O- radical.

[0194] "Oxo" refers to the =O radical.

[0195] "Thioxo" refers to the =S radical.

[0196] "Imino" refers to the =NH radical.

[0197] "Oximo" refers to the =N-OH radical.

[0198] "Hydrazino" refers to the =N-NH2 radical.

[0199] The term "moiety" refers to a specific segment of a molecule's functionality. A chemical moiety is a recognized chemical entity embedded in or attached to a molecule.

[0200] "Optionally" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0201] The term "optionally substituted" or "substituted" means that the referenced group can be substituted with one or more additional groups individually and independently selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halo, acyl, acyloxy, -COH, -CO-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g., -NH, -NHR, -N(R)), and protected derivatives thereof. By way of example, optional substituents are L, ... s R s where each L s is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-C6 alkyl)-, or -(C2-C6 alkenyl)-; s are independently selected from H, (C-C alkyl), (C-C cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C-C heteroalkyl. Protecting groups that may form the protective derivatives of the above substituents can be found in references such as Greene and Wuts, above.

[0202] As used herein, C1-C xC1-C2, C1-C3~C1-C x Includes C1-C x refers to the number of carbon atoms that make up the designated moiety (excluding optional substituents).

[0203] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0204] "Alkoxy" or "alkoxyl" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0205] "Alkenyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In some embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0206] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O-R ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0207] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, connecting the radical group to the rest of the molecule, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon atom in the alkylene chain or any two carbon atoms within the chain. In some embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene comprises 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene comprises 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene comprises 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene comprises 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(Ra )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0208] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, connecting a radical group to the rest of the molecule. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise in the specification, an alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a(wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0209] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, connecting a radical group to the rest of the molecule. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise in the specification, an alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a(wherein t is 1 or 2) and -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl)).

[0210] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. An aromatic can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0211] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and 5 to 18 carbon atoms, and at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in this specification, the term "aryl" or the prefix "ara" (such as in "aralkyl") means any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)Ra , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and is meant to include aryl radicals optionally substituted with one or more substituents independently selected from:

[0212] "Aralkyl" is a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl chain portion of the aralkyl radical is optionally substituted as described above for an aryl group.

[0213] "Aralkenyl" refers to a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. The aryl chain portion of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0214] "Aralkynyl" refers to a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above. The aryl chain part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0215] "Aralkoxy" is a group of the formula -OR c -refers to a radical attached through an oxygen atom of an aryl, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl chain portion of the aralkyl radical is optionally substituted as described above for an aryl group.

[0216] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is fused to an aryl, heteroaryl, heterocycloalkyl, or second cycloalkyl ring. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In some embodiments, cycloalkyl groups include groups having 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).

[0217] In some embodiments, "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkyl contains 5 to 7 carbon atoms. In some embodiments, a cycloalkyl is attached to the remainder of the molecule by a single bond. A cycloalkyl is saturated (i.e., contains only one C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated cycloalkyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0218] "Cycloalkylalkyl" refers to a group of the formula -R c -cycloalkyl radical, where Rc is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical can be optionally substituted.

[0219] "Cycloalkylalkynyl" refers to a group of the formula -R c -refers to a cycloalkyl radical, where R c is an alkynylene chain as defined above. The alkynylene chain and the cycloalkyl radical may be optionally substituted as defined above.

[0220] "Cycloalkylalkoxy" refers to a group of the formula -OR c -refers to a radical attached through an oxygen atom of a cycloalkyl, where R c is an alkylene chain as defined above.

[0221] As used herein, a "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and / or chemical properties to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include: [ka] These include, but are not limited to:

[0222] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0223] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens may be the same or different. Non-limiting examples of haloalkyls include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0224] "Fluoroalkyl" refers to an alkyl radical, as defined above, substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0225] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl include -CF, -CHF, -CHF, -CHCF, -CFCF, -CFCF, -CF(CH), and the like. Non-limiting examples of fluoroalkoxy groups include -OCF, -OCHF, -OCHF, -OCHCF, -OCFCF, -OCFCF, -OCF(CH), and the like.

[0226] The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) can be located at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A "heteroalkyl" may have 1 to 6 carbon atoms, excluding the number of heteroatoms.

[0227] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered part of a larger substructure.

[0228] As used herein, unless otherwise stated, the substituent "R" appearing alone without a number designation refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon), and heterocycloalkyl.

[0229] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl can be saturated or partially unsaturated. In some embodiments, the heterocycloalkyl ring is fused to an aryl, heteroaryl, cycloalkyl, or second heterocycloalkyl ring. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In some embodiments, the heterocycloalkyl ring is a bridged heterocycloalkyl ring. Unless otherwise specified, a heterocycloalkyl can have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0230] In some embodiments, "heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, unless stated otherwise in the specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocycloalkyl radical is partially saturated or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0231] "N-heterocycloalkyl" or "N-linked heterocycloalkyl" refers to a heterocycloalkyl radical, as defined above, containing at least one nitrogen, where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical. Examples of such N-heterocycloalkyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolidinyl, and imidazolidinyl.

[0232] "C-heterocycloalkyl" or "C-linked heterocycloalkyl" refers to a heterocycloalkyl radical, as defined above, containing at least one heteroatom, where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical. Examples of such C-heterocycloalkyl radicals include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, and the like.

[0233] "Heterocycloalkylalkyl" refers to a group of the formula -R c -heterocycloalkyl radical, where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of a heterocycloalkylalkyl radical can be optionally substituted. The heterocycloalkyl portion of a heterocycloalkylalkyl radical can be optionally substituted.

[0234] "Heterocycloalkylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through an oxygen atom of a heterocycloalkyl, where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of a heterocycloalkylalkoxy radical can be optionally substituted. The heterocycloalkyl portion of a heterocycloalkylalkoxy radical can be optionally substituted.

[0235] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. A heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[ 1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] Pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,In some embodiments, unless stated otherwise in the specification, the term "heteroaryl" includes, but is not limited to, alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t ORa (wherein t is 1 or 2) and -R b -S(O) t N(R a ) 2 (wherein t is 1 or 2) (wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is meant to include heteroaryl radicals as defined above optionally substituted with one or more substituents selected from: a straight or branched alkylene or alkenylene chain, each of the above substituents being unsubstituted unless otherwise specified.

[0236] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0237] "C-heteroaryl" refers to a heteroaryl radical as defined above, wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0238] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0239] "Heteroarylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through an oxygen atom of a heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0240] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise indicated, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans) unless otherwise specified. Similarly, all possible isomers, as well as their racemic and optically pure forms, and tautomeric forms, are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers based on a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0241] "Tautomer" refers to a molecule capable of proton transfer from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomer equilibrium include the following: [ka]

[0242] In some cases, compounds disclosed herein exist in tautomeric forms. The structures of the compounds are depicted in one tautomeric form for clarity. The other tautomeric form is expressly included in the disclosure, for example, the structure depicted below: [ka]

[0243] The compounds disclosed herein may, in some embodiments, be present in different isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C and / or 14 The compound is used in a form enriched in C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0244] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0245] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F,16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0246] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 The deuterium atom is replaced by an H atom. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0247] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989,45(21),6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0248] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to effect the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical manufacturers such as Aldrich Chemical Co.

[0249] Iodomethane d Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as 3 (CD3I), are readily available and can be utilized to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme: [ka]

[0250] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4), are utilized to transfer deuterium to reaction substrates under reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme: [ka]

[0251] Utilizing deuterium gas and a palladium catalyst, unsaturated carbon-carbon bonds are reduced and reductive displacement of aryl carbon-halogen bonds is achieved, as illustrated, by way of example only, in the reaction scheme below. [ka]

[0252] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of a compound described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0253] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Thus, exemplary salts include sulfate, disulfate, hydrogen sulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0254] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. (supra).

[0255] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers modified by, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein, the term "amino acid" refers to either natural and / or unnatural or synthetic amino acids, including glycine and both D- and L-optical isomers, as well as amino acid analogs and peptidomimetics.

[0256] The terms "polynucleotide," "nucleotide," "nucleotide sequence," "nucleic acid," and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure and may perform any function, known or unknown. Non-limiting examples of polynucleotides include: coding or non-coding regions of a gene or gene fragment, locus(s) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, small interfering RNA (siRNA), small hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNAs), morpholinos and locked nucleic acids (LNAs), glycol nucleic acids (GNAs), threose nucleic acids (TNAs), 2'-fluoro, 2'-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0257] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (such as into mRNA or other RNA transcripts) and / or the process by which the transcribed mRNA is subsequently translated into a peptide, polypeptide, or protein. The transcript and the encoded polypeptide may be collectively referred to as a "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0258] The terms "therapeutic agent," "therapeutic agent," or "therapeutic agent" are used interchangeably and refer to a molecule or compound that, when administered to a subject, produces some beneficial effect. Beneficial effects include enabling a diagnostic determination, ameliorating a disease, symptom, disorder, or pathological condition, reducing or preventing the occurrence of a disease, symptom, disorder, or condition, and generally counteracting a disease, symptom, disorder, or pathological condition.

[0259] As used herein, "treatment" or "treating," or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any improvement or effect associated with treatment on one or more diseases, conditions, or symptoms being treated. For prophylactic benefit, the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject who reports one or more physiological symptoms of a disease even if the disease, condition, or symptom has not yet manifested. Typically, prophylactic benefit includes reducing the incidence and / or worsening of one or more diseases, conditions, or symptoms being treated (e.g., between a treated and an untreated population, or between the condition of treated and untreated subjects). In some embodiments, "treatment," "treating," "alleviating," or "ameliorating" does not include prophylactic benefit.

[0260] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to produce a beneficial or desired result. A therapeutically effective amount may vary depending on one or more of the subject and disease state being treated, the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or multiple doses. Components may be described herein as having at least an effective amount, or at least an effective amount relevant to a particular goal or purpose, such as those described herein. The term "effective amount" also applies to an amount that provides an image for detection by an appropriate imaging method. Specific doses may vary depending on one or more of the particular agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system in which the agent is delivered.

[0261] The term "in vivo" refers to an event that takes place inside a subject's body.

[0262] The term "ex vivo" refers to events that initially occur outside a subject's body for subsequent in vivo application within the subject's body. For example, ex vivo preparation can involve preparing cells outside a subject's body with the intent of introducing the prepared cells into the same or a different subject.

[0263] The term "in vitro" refers to an event that occurs outside a subject's body. For example, an in vitro assay includes any assay performed outside a subject's body. An in vitro assay includes cell-based assays that use live or dead cells. An in vitro assay includes cell-free assays that do not use intact cells.

[0264] compound The compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, are PTPN2 inhibitors and have a wide range of uses in therapeutics, diagnostics, and other biomedical research.

[0265] In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), O, C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15, -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12)(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12)(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by R 12a is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22, -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25, -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied, however, i) Ring A [ka] at least two of which are double bonds, ii)J 3 If is CH2, R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12a , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by iii) The compound is [ka] isn't it).

[0266] The following formula, for example, is [ka] It will be understood that the formula is a representation of an equivalent resonance structure of a compound in which at least two of the [ka]

[0267] In some embodiments, J 3 is C(R 10 )(R 10a ), then R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12a , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12, -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f is optionally replaced by

[0268] In some embodiments, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, and ring A [ka] At least two of the are double bonds.

[0269] In some embodiments, W 1 is N, N(R 1 ), O, C(R1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, and ring A [ka] At least two of the are double bonds.

[0270] In some embodiments, the compound is a compound of Formula (Ia): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of R is N. 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0271] In some embodiments, the compound is a compound of formula (Ib): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of R is N. 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0272] In some embodiments, the compound is a compound of formula (Ic): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of R is N. 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0273] In some embodiments, the compound is a compound of formula (Ig): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O. R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0274] In some embodiments, the compound is a compound of formula (Ih): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O. R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0275] In some embodiments, the compound is a compound of formula (Ii): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O. R 5 , R 6 , R7 , R 9 , R 9a , and R 10 is as described herein).

[0276] In some embodiments, the compound is a compound of formula (Ij): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N, or O. R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0277] In some embodiments, the compound is a compound of formula (Ik): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N, or O. R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0278] In some embodiments, the compound is a compound of formula (Im): [ka] (In the formula, W 1 , W2 , W 3 , and W 4 At least one of N, N(R 3 ), N(R 4 ), or O. R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0279] In some embodiments, the compound is a compound of formula (Iv): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 4 ), N, or O. R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0280] In some embodiments, the compound is a compound of formula (Iw): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 4 ), N, or O. R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0281] In some embodiments, the compound is a compound of formula (Ix): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 4 ), N, or O. R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0282] In some embodiments, the compound is a compound of formula (Io): [ka] W 1 , W 2 , W 4 , X, Y, Z, J 1 , J 2 , and J 3 is as described herein. In some embodiments, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 4 is C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0283] In some embodiments, the compound is a compound of formula (Ioa): [ka] (W 1 , W 2 , W 4 , R5 , R 6 , R 7 , R 9 , R 9a , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 4 is C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0284] In some embodiments, the compound is a compound of formula (Iob): [ka] (W 1 , W 2 , W 4 , R 5 , R 6 , R 7 , R 9 , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 4 is C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0285] In some embodiments, the compound is a compound of formula (Ioc): [ka] (W 1 , W2 , W 4 , R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 ) and W 2 is C(R 2 ) and W 4 is C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0286] In some embodiments, the compound is a compound of formula (Ip): [ka] (W 1 , W 3 , W 4 , X, Y, Z, J 1 , J 2 , and J 3 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 3 is C(R 3 ) and W 4 is C(R 4 )

[0287] In some embodiments, the compound is a compound of formula (Ipa): [ka] (W 1 , W3 , W 4 , R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 3 is C(R 3 ) and W 4 is C(R 4 )

[0288] In some embodiments, the compound is a compound of formula (Ipb): [ka] (W 1 , W 3 , W 4 , R 5 , R 6 , R 7 , R 9 , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 3 is C(R 3 ) and W 4 is C(R 4 )

[0289] In some embodiments, the compound is a compound of formula (Ipc): [ka] (W 1 , W 3 , W 4 , R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 (wherein W is as described herein). In some embodiments, W 1 is C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 3 is C(R 3 ) and W 4 is C(R 4 )

[0290] In some embodiments, the compound is a compound of formula (Ipd): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0291] In some embodiments, the compound is a compound of formula (Ir): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0292] In some embodiments, the compound is a compound of formula (Is): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10is as described herein).

[0293] In some embodiments, the compound is a compound of formula (Ipd): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0294] In some embodiments, the compound is a compound of formula (Ir): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) is R 5 , R 6, R 7 , R 9 , and R 10 is as described herein).

[0295] In some embodiments, the compound is a compound of formula (Is): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0296] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), O, C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where: i)W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, ii) W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R 9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15, -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12)(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12)(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied, However, the compound is [ka] isn't it).

[0297] In some embodiments, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, and W 6 is N or C, where i) W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, and ii) W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0298] In some embodiments, W 1is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where i) W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O, and ii) W 1 , W 2 , W 3 , and W 4At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0299] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIa): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R7 , R 9 , R 9a , and R 10 is as described herein).

[0300] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIb): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0301] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIc): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0302] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIId): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0303] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIe): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0304] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIf): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 , W 2 , W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R7 , R 9 , R 9a , and R 10 is as described herein).

[0305] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIg): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0306] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIh): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0307] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIi): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0308] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIj): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0309] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIk): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0310] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIl): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0311] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIm): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 2 and W 3 At least one of C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0312] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIn): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N(R 2 ), C(R2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 2 and W 3 At least one of C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0313] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIo): [ka] (In the formula, W1 is N or C(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 2 and W 3 At least one of C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0314] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIp): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0315] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIq): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R7 , R 9 , R 9a , and R 10 is as described herein).

[0316] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIr): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), C(O), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 1 and W 2 At least one of C(O), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR2 ), S(O)(R 2 ), or P(O)(R 2 ) R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0317] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIs): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0318] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIt): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0319] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIu): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), C(O), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W1 , W 2 , W 3 , and W 4 At least one of N, N(R 1 ), N(R 2 ), N(R 3 ), N(R 4 ), or O and W 3 , and W 4 At least one of C(O), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0320] In one embodiment, there is provided a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), O, C(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and X is N or C(R 5 ) and Y is N or C(R 6 ) and Z is N or C(R 7 ) and J 1 is N, C, or C(R 8 ) and J 2 is N, N(R9 ), C(R 9 ), C(R 9 )(R 9a ), or C(O), J 3 is N(R 10 ) or C(R 10 )(R 10a ) and R 1 and R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15, -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20a or R 1 and R 1a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20a optionally replaced by R 2 and R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20b or R 2 and R 2a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20b optionally replaced by R 3 and R 3a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20c or R 3 and R 3a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9Heterocycloalkyl can have one, two, or three R 20c optionally replaced by R 4 and R 4a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20d or R 4 and R 4a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20d optionally replaced by R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally replaced by R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally replaced by R 7 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20g optionally replaced by R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12)(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally replaced by R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20i or R 9 and R 9a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R20i optionally replaced by R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -R 16 , -OR 16 , -N(R 12 )(R 16 ), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 12 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13) independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is one, two, or three R 20j or R 10 and R 10a is combined with C 3-6 Cycloalkyl or C 2-9 Form a heterocycloalkyl, where C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally replaced by Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6haloalkyl, or R 12 and R 13 together with the nitrogen to which they are attached, form one, two, or three R 20k C optionally replaced with 2-9 forming a heterocycloalkyl ring, Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20k optionally replaced by Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from 1-6 Alkylene can be one, two, or three R 20l optionally replaced by Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally replaced by Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , R 20j , R 20k , R 20l , and R 20m is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 22 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a group containing halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24)C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 23 is H and C 1-6 independently selected from alkyl, Each R 24 is H and C 1-6 independently selected from alkyl, Each R 25 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; [ka] indicates a single or double bond where all valences are satisfied).

[0321] In some embodiments, W 1 is N, N(R 1 ), O, C(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N, N(R 2 ), O, C(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N, N(R 3 ), O, C(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N, N(R 4 ), C(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and W 5 is N or C, W 6 is N or C, where i) W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 At least one of N, N(R 1), N(R 2 ), N(R 3 ), N(R 4 ), or O, and ii) W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 )

[0322] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVa): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a, and R 10 is as described herein).

[0323] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVb): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0324] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVc): [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0325] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVd): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0326] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVe): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , and R 10 is as described herein).

[0327] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVf): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 1 , W 2 , W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), P(O)(R 2 ), S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR4 ), S(O)(R 4 ), or P(O)(R 4 ) R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0328] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVg): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0329] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVh): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R10 is as described herein).

[0330] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVi): [ka] (In the formula, W 1 is N or C(R 1 ) and W 2 is N or C(R 2 ) and W 3 is N(R 3 ), C(R 3 )(R 3a ), S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), or P(O)(R 3 ) and W 4 is N(R 4 ), C(R 4 )(R 4a ), S(O), S(O)2, S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) and where W 3 , and W 4 At least one of S(O), S(O)2, S(O)(NR 3 ), S(O)(R 3 ), P(O)(R 3 ), S(O)(NR 4 ), S(O)(R 4 ), or P(O)(R 4 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0331] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVj): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 and W 2 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0332] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IVk): [ka] (In the formula, W 1 is N(R 1 ), C(R 1 )(R 1a ), S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), or P(O)(R 1 ) and W 2 is N(R 2 ), C(R 2 )(R 2a ), S(O), S(O)2, S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) and W 3 is N or C(R 3 ) and W 4 is N or C(R 4 ) and where W 1 and W 2 At least one of S(O), S(O)2, S(O)(NR 1 ), S(O)(R 1 ), P(O)(R 1 ), S(O)(NR 2 ), S(O)(R 2 ), or P(O)(R 2 ) is R 5 , R 6 , R 7 , R 9 , R 9a , and R 10 is as described herein).

[0333] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IV1): [ka] (In the formula, ...

Claims

1. A compound of formula (I-3), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 881】 (In the formula, W １ is N, N(R １ ), C(R １ ), C(R １ ) (R １ａ ), C(O), S(O), S(O) ２ , S(O)(NR １ ), S(O)(R １ ), or P(O)(R １ ) and W ２ is N, N(R ２ ), C(R ２ ), C(R ２ ) (R ２ａ ), C(O), S(O), S(O) ２ , S(O)(NR ２ ), S(O)(R ２ ), or P(O)(R ２ ) and W ３ is N, N(R ３ ), C(R ３ ), C(R ３ ) (R ３ａ ), C(O), S(O), S(O) ２ , S(O)(NR ３ ), S(O)(R ３ ), or P(O)(R ３ ) and W ４ is N, N(R ４ ), C(R ４ ), C(R ４ ) (R ４ａ ), C(O), S(O), S(O) ２ , S(O)(NR ４ ), S(O)(R ４ ), or P(O)(R ４ ) and W ５ is N or C, W ６ is N or C, where W １ , W ２ , W ３ , W ４ , W ５ , and W ６ At least one of N, N(R １ ), N(R ２ ), N(R ３ ), or N(R ４ ) and X is N or C(R ５ ) and Y is N or C(R ６ ) and Z is N or C(R ７ ) and J １ is N, C, or C(R ８ ) and J ２ is N, N(R ９ ), C(R ９ ), C(R ９ ) (R ９ａ ), or C(O); J ３ is N(R １０ ) and R １ and R １ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ａ or R １ and R １ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ａ Optionally replaced by R ２ and R ２ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｂ or R ２ and R ２ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｂ Optionally replaced by R ３ and R ３ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｃ or R ３ and R ３ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｃ Optionally replaced by R ４ and R ４ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｄ or R ４ and R ４ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｄ Optionally replaced by R ５ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ), wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｅ Optionally replaced by R ６ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １６ , -N(R １２ ) (R １６ ), -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ), wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｆ Optionally replaced by R ７ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ), wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｇ Optionally replaced by R ８ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ), wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｈ Optionally replaced by R ９ and R ９ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｉ or R ９ and R ９ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｉ Optionally replaced by R １０ and R １０ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, -R １６ , -OR １６ , -N(R １２ ) (R １６ ), -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)OR １２ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N (R １２ ) (R １３ )-, S(=O)(=NH)N(R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ , and -CH ２ S (O) ２ N (R １２ ) (R １３ ) independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｊ or R １０ and R １０ａ is combined with C ３－６ Cycloalkyl or C ２－９ heterocycloalkyl, wherein said C ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｊ Optionally replaced by Each R １２ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, and C １－９ heteroaryl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｋ Optionally replaced by Each R １３ is hydrogen, C １－６ Alkyl, and C １－６ haloalkyl, or R １２ and R １３ together with the nitrogen to which they are attached, may be one, two, or three R ２０ｋ C optionally substituted with ２－９ forming a heterocycloalkyl ring, Each R １４ is hydrogen, C １－６ Alkyl, and C １－６ haloalkyl; Each R １５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｋ Optionally replaced by Each R １６ is -C １－６ Alkylene-OP(O)(OR １６ａ ) (OR １６ｂ ) and -P(O)(OR １６ａ ) (OR １６ｂ ) independently selected from １－６ Alkylene is one, two, or three R ２０ｌ Optionally replaced by Each R １６ａ and R １６ｂ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, and C １－９ heteroaryl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｍ Optionally replaced by Each R ２０ａ , R ２０ｂ , R ２０ｃ , R ２０ｄ , R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , R ２０ｉ , R ２０ｊ , R ２０ｋ , R ２０ｌ , and R ２０ｍ is oxo, -CN, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, -OR ２１ , -SR ２１ , -N(R ２２ )(R ２３ )、-C(O)OR ２２ 、-C(O)N(R ２２ )(R ２３ )、 -C(O)C(O)N(R ２２ )(R ２３ )、-OC(O)N(R ２２ )(R ２３ )、-N(R ２４ )C(O)N(R ２２ )(R ２３ )、-N(R ２４ )C(O)OR ２２ 、-N(R ２４ )C(O)R ２５ 、-N(R ２４ )S(O) ２ R ２５ 、-C(O)R ２５ 、-S(O) ２ R ２５ 、-S(O) ２ N(R ２２ )(R ２３ )、-OCH ２ C(O)OR ２２ 、 and -OC(O)R ２５ are each independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, and C １－９ Heteroaryl is halogen, oxo, -CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ２１ , -SR ２１ , -N(R ２２ ) (R ２３ ), -C(O)OR ２２ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -OC(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)OR ２５ , -N(R ２４ )C(O)R ２５ 、-N(R ２４ )S(O) ２ R ２５ 、-C(O)R ２５ 、 -S (O) ２ R ２５ , -S(O) ２ N (R ２２ ) (R ２３ ), and -OC(O)R ２５ and optionally substituted with 1, 2, or 3 groups independently selected from Each R ２１ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl; Each R ２２ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl; Each R ２３ is H and C １－６ independently selected from alkyl, Each R ２４ is H and C １－６ independently selected from alkyl, Each R ２５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl; 【Chemistry 882】 indicates a single or double bond where all valences are satisfied, however, Ring A 【Chemistry 883】 at least two of which are double bonds).

2. X is C(R ５ 2. The compound of claim 1, wherein:

3. Y is C(R ６ 3. The compound of claim 2, wherein:

4. Z is C(R ７ 4. The compound of claim 3, wherein:

5. The compound of claim 1 having the structure of formula (Ia-3), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 885】

6. W １ is N and W ２ C(R ２ ), and W ３ C(R ３ ), and W ４ C(R ４ 6. The compound of claim 5, wherein:

7. R ２ is hydrogen, R ３ is hydrogen, R ４ 7. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

8. R ５ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is selected from hydrogen and halogen.

9. R ６ The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is --OH.

10. R ７ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is hydrogen.

11. R ９ is hydrogen, R ９ａ is hydrogen, R １０ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

12. R ２ But, -OR １２ and R １２ But, C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, and -CH ２ -C ２－９ heterocycloalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, and -CH ２ -C ２－９ Heterocycloalkyl is one, two, or three R ２０ｋ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, optionally substituted with:

13. R ２ but, 【Chemistry 891】 6. The compound of claim 5, selected from: or a pharma- ceutically acceptable salt or solvate thereof.

14. R ２ But -N(R １２ ) (R １３ ) and R １３ are independently hydrogen; R １２ But, C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, and -CH ２ -C １－９ heteroaryl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, -CH ２ -C ６－１０ Aryl, C １－９ Heteroaryl, and -CH ２ -C １－９ Heteroaryl is one, two, or three R ２０ｋ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, optionally substituted with:

15. R ２ but, 【Chemistry 892】 6. The compound of claim 5, selected from: or a pharma- ceutically acceptable salt or solvate thereof.

16. R ２ But, C １－６ Alkyl, C ２－９ Heterocycloalkyl, C １－９ Heteroaryl, -OR １２ , -N(R １２ ) (R １３ ), -C(O)R １５ , -C(O)N(R １２ ) (R １３ ), wherein C １－６ Alkyl, C ２－９ Heterocycloalkyl, and C １－９ Heteroaryl is one, two, or three R ２０ｂ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, optionally substituted with:

17. R ３ is hydrogen, halogen, -CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -OR １２ , -SR １２ , and -N(R １２ ) (R １３ ), wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C ２－９ Heterocycloalkyl is one, two, or three R ２０ｃ 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, optionally substituted with:

18. A compound, or a pharma- ceutically acceptable salt or solvate thereof, selected from: 【Hua 898-1】 【Hua 898-2】 【Hua 898-3】 【Hua 898-4】 【Hua 898-5】 【Hua 898-6】 【Hua 898-7】

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for enhancing immunity in a subject in need thereof, comprising: (a) selecting said subject exhibiting PTPN2 expression or activity; (b) downregulating the expression or activity of PTPN2.

21. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer in combination with cell therapy in a subject in need thereof.

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