Heteroatom-containing compounds and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutical compositions comprising the same. The compounds, their pharmaceutical compositions, and methods of using the same have various utilities as therapeutic agents, diagnostic agents, and research tools. The subject compositions and methods are particularly useful for enhancing immune responses and / or are applicable to treat cancer and other diseases.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 282,614, filed November 23, 2021, and U.S. Provisional Patent Application No. 63 / 406,215, filed September 13, 2022, each of which is incorporated by reference in its entirety. [Background technology]

[0002] PTPN2 encodes a protein tyrosine phosphatase involved in multiple intracellular signaling pathways in immune cells. PTPN2 can negatively regulate αβTCR T cell receptor (TCR) signaling by, for example, dephosphorylating and inactivating Src family kinases, including LCK. PTPN2 can also 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. Furthermore, PTPN2 mRNA expression levels in lung cancer tissue have been shown to be higher than those in normal lung tissue or adjacent normal tissue, and such overexpression of PTPN2 promotes lung cancer cell proliferation. Furthermore, two PTPN2 SNPs, rs2847297 and rs2847282, have been 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, there were approximately 10 million cancer deaths worldwide, and 17 million new cases were diagnosed. In the United States alone, cancer causes more than 500,000 deaths each year, with approximately 1.7 million new cases diagnosed per year (excluding basal cell and squamous cell skin cancer). Lung, liver, stomach, and intestinal cancers account for more than 4 in 10 of all cancer deaths worldwide.

[0005] Adoptive transfer of genetically modified lymphocytes, particularly T cells (i.e., CAR-T cells), is an emerging treatment for cancer. While its efficacy has been demonstrated in various hematological cancers, including ALL, CLL, DLBCL, FL, and multiple myeloma, its efficacy in treating solid tumors remains to be established. Current immune cell therapies (e.g., CAR-T therapy) suffer from a number of serious deficiencies. T cell production and clonal expansion are highly inefficient and costly. When introduced into patients, the antitumor activity and numbers of T cells can be reduced in the immunosuppressive microenvironment often found in tumors. CAR-T therapy is also limited by life-threatening toxicity in over 30% of patients. Toxicity primarily manifests as cytokine release syndrome (CRS), characterized by an early stage with fever, hypotension, and elevated levels of various cytokines, and a later stage associated with neurological events leading to death. Summary of the Invention

[0006] In view of the foregoing, there exists a significant need for alternative compositions and methods for treating cancer and / or conducting immunotherapy. The compositions and methods of the present disclosure address this need and also provide additional advantages. The ability of PTPN2 to act as a negative regulator of immune receptor-related pathways (e.g., TCR signaling) and promote cancer cell proliferation can be exploited for cancer and tumor treatment. Various aspects of the present disclosure provide compositions and methods for inducing lymphoid cell activity.

[0007] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2a ) or N; or W 1 is C(R 1a ) or N, and W 2 is C(R 2 ) or; R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a optionally substituted with; R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b optionally substituted with; X is N or C(R 3 ) and; Y is N or C(R 4 ) and; Z is N or C(R 5 ) and; R 3 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally substituted with; R 4 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20d optionally substituted with; R 5 is hydrogen, halogen, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R20e optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; J 1 is N, C, or C(R 8 ) and; J 2 is N, N(R 9 ), C(R 9 ), C(R9 )(R 9a ), or C(O); J 3 is N(R 10 ) or C(R 10 )(R 10a ) and; R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 )(R13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally substituted with; R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20i optionally substituted with; or R 9 and R 9a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally substituted with; R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally substituted with; or R 10 and R 10a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20m optionally substituted with; Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b )(wherein, C 1-6 Alkylene can be one, two, or three R 20n optionally substituted with ); or -C 1-6 Alkylene-OC(O)-R 16c (In the formula, C 1-6 Alkylene can be one, two, or three R 20n independently selected from (optionally substituted with); Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 20o optionally substituted with; R 16c is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 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 ), -OCH2C(O)OR 22 , and -OC(O)R 25 and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl can be one, two, or three R 20ooptionally substituted with; Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 25are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from 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 independently selected from 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 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 26 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 )(R13 ), -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally substituted with; [ka] indicates a single or double bond so that all valences are satisfied) is provided.

[0008] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, X is C(R 3 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, Y is C(R 4 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, Z is C(R 5 )

[0009] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, X is N. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, Y is N. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, Z is N.

[0010] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 1 is C(R 1 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 1 is C(R 1a In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 2 is C(R 2a In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 2 is C(R 2 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 1is N. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, W 2 is N.

[0011] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, J 2 is CH2. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, J 2 is C(H). In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, J 3 is N(H). In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, J 3 is C(R 10 )(R 10a In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, J 3 is CH(R 10 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 10 is hydrogen.

[0012] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of Formula (Ia): [ka] It has.

[0013] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of Formula (Ib): [ka] It has.

[0014] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of Formula (Ic): [ka] It has.

[0015] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the formula: [ka] It has.

[0016] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of Formula (IIa): [ka] It has.

[0017] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of Formula (IIb): [ka] It has.

[0018] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure of formula (IIc): [ka] It has.

[0019] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R4 is halogen, -OR 12 , and one, two, or three R 20d C optionally substituted with 1-6 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 4 is -OH.

[0020] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20e In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 5 is hydrogen, halogen, and one, two, or three R 20e C optionally substituted with 1-6 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 5 is hydrogen.

[0021] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 3 is a halogen and one, two, or three R 20c C optionally substituted with 1-6 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 3 is halogen. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 3 is F. In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 3 is Cl.

[0022] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S; 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, the 6- to 12-membered saturated heterocycloalkyl, and the 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0023] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is selected from triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl, and triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl are selected from R 6 and R 6’ and is substituted with one or more substituents independently selected from: 2 is selected from triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl, and triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl are selected from R 7and R 7’ and is substituted with one or more substituents independently selected from:

[0024] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] (In the formula, R 1b is C(R 6b ) and R 1d is C(R 6d ), then R 1c is N or N(R 6c’’ )isn't it); [ka] (In the formula, R 1 is not a substituted pyrrolyl); [ka] (In the formula, R 1 is not a substituted imidazolyl, R 1d and R 1e is N); or R 6 and R 6’ is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from: R 1b is O, S, N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1c is O, S, N, N(R 6c’’ ), C(R 6c ), or C(R 6c )(R 6c’ ) and; R 1d is O, S, N, N(R 6d’’ ), C(R 6d ), or C(R 6d)(R 6d’ ) and; R 1e is N or C(R 6e ) and; R 6b , R 6b’ , R 6c , R 6c’ , R 6d , R 6d’ , and R 6e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ , R 6c’’ , and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20aoptionally substituted with; R 2 teeth, [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2c and R 2d is N); [ka] (In the formula, R 2 is not a substituted pyrazolyl or pyrrolyl); [ka] (In the formula, R 2 is not a substituted pyrrolyl or imidazolyl); [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2d and R 2e is N or R 2b and R 2d is N or NH); or R 7 and R 7’ is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from: R 2b is O, S, N, N(R 7b’’ ), C(R 7b ), or C(R 7b )(R 7b’ ) and; R 2c is O, S, N, N(R 7c’’ ), C(R 7c ), or C(R 7c )(R 7c’ ) and; R 2d is O, S, N, N(R 7d’’ ), C(R 7d ), or C(R7d )(R 7d’ ) and; R 2e is N or C(R 7e ) and; R 7b , R 7b’ , R 7c , R 7c’ , R 7d , R 7d’ , and R 7e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 7b’’ , R 7c’’ , and R 7d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20b optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0025] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] is.

[0026] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 2 teeth, [ka] is.

[0027] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 and R 2 teeth, [ka] is selected from.

[0028] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6 and R 6’ and is substituted with one or more substituents independently selected from: 2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 7 and R 7’ and is substituted with one or more substituents independently selected from:

[0029] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 are indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzofuranyl, selected from benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl Indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzo Furanyl, benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl are R 6 and R 6’and is substituted with one or more substituents independently selected from: 2 are indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzofuranyl, selected from benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl Indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzo Furanyl, benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl are R 7 and R 7’ and is substituted with one or more substituents independently selected from:

[0030] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] and; R 6b is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; z6b is an integer from 0 to 4; R 2 teeth, [ka] and; R 7b is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; z7b is an integer of 0 to 4.

[0031] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 and R 2 teeth, [ka] is selected from.

[0032] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is R 6 and R 6’ and R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7 and R 7’ In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is R 6’ and R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7’In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is one R 6’ pyrazolyl substituted with R 2 is one R 7’ and pyrazolyl substituted with

[0033] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] and; R 1b is O, S, N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1d is O, S, N, N(R 6d’’ ), C(R 6d ), or C(R 6d )(R 6d’ ) and; R 6b , R 6b’ , R 6d , and R 6d’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 )(R13 ), -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 2 teeth, [ka] and; R 2b is O, S, N, N(R 7b’’ ), C(R 7b ), or C(R 7b )(R 7b’ ) and; R 2d is O, S, N, N(R 7d’’ ), C(R 7d ), or C(R 7d )(R 7d’ ) and; R 7b , R 7b’ , R 7d , and R 7d’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 7b’’ and R 7d’’ is hydrogen, -CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0034] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 2 teeth, [ka] is.

[0035] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0036] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0037] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 7 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0038] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 7’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0039] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 , R 6’ , R 7 , and R 7’ is C 1-6 Alkyl, [ka] are independently selected from

[0040] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from

[0041] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from; R 26 is hydrogen, 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

[0042] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6, R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from

[0043] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from

[0044] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, X, Y, Z, W 1 , and W 2 At least one of is N.

[0045] In one embodiment, a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2a ) or N; or W 1 is C(R 1a ) or N, and W 2 is C(R 2 ) Either; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C6-12 Aryl and 5- to 12-membered 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ optionally substituted with one or more substituents independently selected from: R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a optionally substituted with; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl, -OR12 , -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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ optionally substituted with one or more substituents independently selected from: R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR12 , -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b optionally substituted with; X is N or C(R 3 ) and; Y is N or C(R 4 ) and; Z is N or C(R 5 ) and; W 1 , W 2 , at least one of X, Y, and Z is N; R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally substituted with; R 4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20d optionally substituted with; R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; 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 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally substituted with; R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20i optionally substituted with; or R 9 and R 9a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally substituted with; R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally substituted with; or R 10 and R 10a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C2-9 Heterocycloalkyl can have one, two, or three R 20j optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 20m optionally substituted with; Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from; C 1-6 Alkylene can be one, two, or three R 20n optionally substituted with; Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 20ooptionally substituted with; Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 25are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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, C3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from 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 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 26 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(R14 )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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(R12 )(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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally substituted with; [ka] indicates a single or double bond so that all valences are satisfied) is provided.

[0046] In one embodiment, a compound of formula (IId-1), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; Each R 6 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -C(NR 14 )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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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(R12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13 is hydrogen, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 20m optionally substituted with; Each R 20f , 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 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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)R25 , -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 independently selected from 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 independently selected from 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 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from heteroaryl; Each R 26 is oxo, halogen, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f (optionally substituted with ).

[0047] In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from one or more R 6 In embodiments of the subject compounds (i.e., compounds described herein), or pharmaceutically acceptable salts or solvates thereof, R 1 teeth, [ka] is selected from.

[0048] In certain aspects, the disclosure provides a compound described herein, e.g., a compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof. In one aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0049] 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 subject compound described herein (i.e., a compound described herein), or a pharmaceutically acceptable salt or solvate thereof. The subject may be afflicted with a solid tumor or a liquid cancer (e.g., a cancer of the blood or bone marrow or lymph nodes, including leukemia, lymphoma, and myeloma).

[0050] In one aspect, provided is a method of enhancing the immunity of a cell, comprising contacting the cell with a compound described herein, 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.

[0051] In one aspect, provided is a method for enhancing the immunity of a cell, the method comprising: (a) contacting the cell with a compound described herein; 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 the immunity of the cell. In some embodiments, step (a) is performed before, simultaneously with, or after (b). In some embodiments, the cell retains PTPN2 expression or activity before (a). In some embodiments, the cell is a lymphoid cell. In some embodiments, the subject method further comprises administering the cell to a subject in need thereof. In some embodiments, the subject method further comprises administering a compound described herein to the subject before, simultaneously, or after administering the cell. In some embodiments, the subject's cells exhibit PTPN2 expression or activity before administering the compound described herein.

[0052] In one aspect, provided are methods for enhancing immunity in a subject in need thereof, the method comprising administering lymphoid cells to the subject, thereby enhancing the subject's immunity, wherein PTPN2 expression or activity in the lymphoid cells is downregulated by a subject compound disclosed herein (i.e., a compound described herein). In some embodiments, the subject method comprises transiently downregulating PTPN2 expression or activity in the lymphoid cells. In some embodiments, the lymphoid cells exhibit PTPN2 expression or activity prior to the transient downregulation. In some embodiments, the transient downregulation is performed once. In some embodiments, the transient downregulation is performed intermittently two or more times. In some embodiments, the transient downregulation comprises introducing a compound described herein into the cells. In some embodiments, 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 subject method further comprises administering a compound described herein to the subject before, simultaneously with, or after administering the lymphoid cells. In some embodiments, prior to administering a compound described herein, the subject's cells exhibit PTPN2 expression or activity.

[0053] In one aspect, provided are methods for enhancing the immunity of a subject in need thereof, the methods comprising: (a) selecting a subject exhibiting PTPN2 expression or activity; and (b) downregulating PTPN2 expression or activity in cells of the subject with a subject compound disclosed herein (i.e., a compound described herein), thereby enhancing the immunity of the subject. In some embodiments, step (b) is performed in vivo. In some embodiments, step (b) is performed ex vivo. In some embodiments, the subject method further comprises administering cells to the subject prior to, simultaneously with, or after downregulating. In some embodiments, downregulating comprises introducing a compound described herein into the cells. In some embodiments, downregulating comprises transiently downregulating PTPN2 expression or activity. In some embodiments, the transient downregulation is performed once. In some embodiments, the subject's 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 of the subject methods, the cells of the subject 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 of the subject methods, the selecting comprises performing a nucleic acid assay using at least a portion of the genome or transcriptome of the cells of the subject to detect the mutation. In some embodiments of the subject methods, the selecting comprises performing a protein assay to detect functionally active PTPN2 or functionally inactive PTPN2.

[0054] In one aspect, provided is a method of enhancing the immunity of a subject in need thereof, the method comprising: administering lymphoid cells to the subject; and administering a compound described herein to the subject, thereby enhancing the immunity of the subject. In some embodiments of the subject methods, administering a compound described herein is performed before, simultaneously with, or after administering the lymphoid cells. In some embodiments of the subject methods, administering a compound described herein is performed separately from administering the lymphoid cells. In some embodiments of the subject methods, prior to administering a compound described herein, the cells of the subject exhibit PTPN2 expression or activity. In one aspect, provided is a method of enhancing anti-tumor or anti-cancer immunity in a subject in need thereof, 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.

[0055] In one aspect, provided are methods of treating a tumor or cancer in a subject in need thereof, the method comprising: (a) contacting lymphocytes of the subject with a compound described herein, thereby treating the tumor or cancer in the subject. In some embodiments of the subject methods, the contacting is performed in vivo. In some embodiments of the subject methods, the contacting is performed ex vivo, followed by introducing the lymphocytes into the subject. In some embodiments, the subject methods further comprise administering the lymphocytes to the subject prior to, simultaneously with, or after the contacting. In some embodiments, the subject methods further comprise (b) introducing into the lymphocytes (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 of the subject methods, (a) is performed before, simultaneously with, or after (b).

[0056] In one aspect, a method is provided for enhancing anti-tumor or anti-cancer immunity in a subject in need thereof, the method comprising: (a) downregulating PTPN2 expression or activity in lymphoid cells of the subject, thereby enhancing the subject's anti-tumor or anti-cancer immunity.

[0057] In one aspect, provided is a method of 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 the subject methods, the downregulating is performed in vivo. In some embodiments of the subject methods, the downregulating is performed ex vivo, followed by introducing the lymphoid cells into the subject. In some embodiments, the subject methods further comprise administering the lymphoid cells to the subject prior to, 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. In some embodiments, the transient downregulating is performed once. In some embodiments of the subject methods, the transient downregulating is performed intermittently two or more times. In some embodiments, a subject method further includes (b) introducing into the lymphocyte (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 subject method, (a) is performed before, concurrently with, or after (b).

[0058] In one aspect, provided is a method for increasing the efficacy or reducing side effects of cell therapy for a subject in need thereof, the method comprising: (a) administering to the subject cells comprising a CAR sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain and an intracellular signaling domain, the intracellular signaling domain being minimally required for activation of the CAR after binding to an antigen; and (b) administering to the subject a compound described herein prior to, concurrently with, or after (a). In some embodiments, the cells retain PTPN2 expression or activity prior to (b). In some embodiments, the cells are lymphoid cells. In some embodiments, the subject's cells exhibit PTPN2 expression or activity prior to administering a compound described herein.

[0059] In one aspect, provided is a method for increasing the efficacy or reducing side effects of cell therapy for a subject in need thereof, the method 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, simultaneously with, or after (a). In some embodiments, the cells retain PTPN2 expression or activity prior to (b). In some embodiments, the cells are lymphoid cells. In some embodiments, the subject's cells exhibit PTPN2 expression or activity prior to administering the compound described herein. In some embodiments, the compounds described herein reduce PTPN2 signaling in the subject's cells. In some embodiments, the compounds described herein do not regulate site-specific recombination of the gene encoding PTPN2. In some embodiments, the compounds described herein do not affect editing of (i) the gene encoding PTPN2 or (ii) an additional gene operably linked to PTPN2. In some embodiments, the compounds described herein are configured to bind PTPN2. In some embodiments, the compounds described herein exhibit binding specificity for PTPN2 relative to other tyrosine phosphatases. In some embodiments, the compounds described herein have an IC for PTPN2 of 5 μM or less. 50 Shows.

[0060] In some embodiments, any of the subject methods further include, concurrently with or after administration of a compound and / or lymphocyte described herein, 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.

[0061] In some embodiments, any of the subject methods further comprises detecting one or more inflammatory biomarkers selected from the group consisting of antibodies, cytokines, radicals, and coagulation factors, concurrently with or after administering a compound described herein to lymphoid cells. In some embodiments of the subject methods, the cytokines include IL-1, IL-6, TNF-α, IL-10, or IL-1RA. In some embodiments of the subject methods, the cells of the subject comprise diseased cells. In some embodiments of the subject methods, the diseased cells are tumor cells or cancer cells. In some embodiments of the subject methods, the cells of the subject comprise lymphoid cells. In some embodiments of the subject methods, the lymphoid cells are 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 subject methods, the lymphoid cells are selected from the group consisting of CD4+ T cells, CD8+ T cells, and both CD4+ and CD8+ T cells.

[0062] In some embodiments of any of the subject methods, the subject is afflicted with a cancer selected from cancer of the bladder, bone, brain, breast, cervix, colon, lung, esophagus, head and neck, ovary, prostate, uterus, stomach, skin, and kidney tissue.

[0063] In some embodiments of any of the applicable subject methods, the steps of (1) contacting a cell with a compound described herein, (2) administering lymphoid cells to a subject, (3) downregulating PTPN2 expression or activity in the subject's cells, (4) administering a compound described herein to the subject, (5) contacting the subject's lymphoid cells with a compound described herein, and / or (6) downregulating PTPN2 expression or activity in the subject's lymphoid cells are performed before, simultaneously with, or after administration of another agent (second agent) or therapy to the subject.

[0064] In some embodiments of the aforementioned subject methods, the second agent may be selected from the group including, but not limited to, 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 is 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.

[0065] In some embodiments, a second therapy comprising stem cells or lymphocytes may be used in conjunction with the subject compounds disclosed herein (ie, compounds described herein).

[0066] In some embodiments of the subject methods, the TFP utilized in the subject cells comprises a TCR subunit comprising (1) a TCR extracellular domain capable of specific 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 specific 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 from the intracellular signaling domain of the epsilon chain, delta chain, and / or gamma chain of cluster of differentiation 3 (CD3). In some embodiments, the TCR intracellular domain comprises a stimulatory domain from the intracellular signaling domain of TCR alpha or from the intracellular signaling domain of TCR beta. In some embodiments, the TFP comprises a transmembrane domain comprising 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.

[0067] In some embodiments, the TFP comprises a costimulatory domain. In some embodiments of the subject methods, the costimulatory domain of the 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 to CD83, CDS, ICAM-1, GITR, BAFFR, and 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, C D11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF 4 (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.

[0068] In some embodiments, a CAR utilized in a subject method 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, wherein 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.

[0069] 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, ITGAM, CDll b, a costimulatory signaling domain comprising a functional signaling domain of a protein selected from the group consisting of 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. 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 after binding to an antigen. In some embodiments of the subject methods, 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 of the subject methods, 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.

[0070] In some embodiments of the subject method, the antigen bound by the subject cells is a tumor antigen or 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, Lewis Y, CD24, PDGFR-beta, SSEA-4, CD20, folate receptor alpha, ERBB2 (Her2 / neu), MUC1, EGFR, NCAM, prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAIX, LMP2, gplOO, bcr-ab l, tyrosinase, EphA2, fucosyl GMl, 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-la, 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 mutant, prostein, survivin and telomerase, PCTA-l / galectin 8, MelanA / MARTl, Ras mutant, hTERT, sarcoma translocation breakpoint, 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 subject method, 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 subject method, the antigen comprises a neoantigen encoded by a tumor-specific mutated gene.

[0071] In some embodiments, a subject method utilizing a subject compound disclosed herein (i.e., a compound described herein) is effective in reducing side effects, including cytokine release syndrome (CRS), an inflammatory disorder, or an autoimmune disorder.

[0072] In one aspect, modified cells are provided that have been exposed to a subject compound disclosed herein (i.e., a compound described herein). In another aspect, the modified cells comprise a compound described herein.

[0073] In another aspect, a modified cell is provided that 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, and wherein PTPN2 expression or activity in the cell is downregulated to enhance immunity of the modified cell.

[0074] In some embodiments of the modified subject cells, 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 some embodiments, PTPN2 expression or activity is downregulated by a compound described herein. In some embodiments, a compound described herein does not regulate site-specific recombination of the gene encoding PTPN2. In some embodiments, a compound described herein does not affect editing of (i) the gene encoding PTPN2 or (ii) an additional gene operably linked to PTPN2. In some embodiments of the modified subject cells, a compound described herein is configured to bind PTPN2, and in some embodiments, the compound exhibits specific binding to PTPN2 relative to other tyrosine phosphatases. In some embodiments, a compound described herein exhibits an IC for PTPN2 of 5 μM or less. 50 In some embodiments, the subject compounds (i.e., compounds described herein) exhibit selective inhibition of PTPN2 over another phosphatase, e.g., PTPN1B. In some embodiments, the subject compounds (i.e., compounds described herein) bind to and inhibit the activity of PTPN2 and PTPN1B.

[0075] In some embodiments of the modified subject cells, the utilized TFP comprises a TCR subunit comprising (1) a TCR extracellular domain capable of specific 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 specific 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 from the intracellular signaling domain of the epsilon chain, delta chain, and / or gamma chain of cluster of differentiation 3 (CD3). In some embodiments, the TCR intracellular domain comprises a stimulatory domain from the intracellular signaling domain of TCR alpha or from the intracellular signaling domain of TCR beta. In some embodiments, the TFP comprises a transmembrane domain comprising 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.

[0076] In some embodiments, the TFP comprises a costimulatory domain, which may be any of the following: 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), SLA MF7, 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, CD11 b, 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.

[0077] The modified subject cells can be modified lymphoid cells. In some embodiments, the modified lymphoid cells are variants of a member 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, the modified lymphoid cells are variants of a member selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD4+ and CD8+ T cells.

[0078] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.

[0079] 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. DETAILED DESCRIPTION OF THE INVENTION

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0081] The terms "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0082] "About," as used herein, when referring to a measurable value, e.g., amount, duration, etc., is meant to encompass a ±10% variation of the stated number or value.

[0083] The terms "polynucleotide," "nucleotide," "nucleotide sequence," "nucleic acid," and "oligonucleotide" are used interchangeably. They refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogs. Polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. The following are non-limiting examples of polynucleotides: 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, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, primers, cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA). Polynucleotides can contain modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.

[0084] "Nucleotide probe" or "probe" refers to a polynucleotide used in a hybridization reaction to detect or identify its corresponding target polynucleotide.

[0085] 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 a "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 (or alternatively, "expression level") of the PTPN2 gene can be determined, for example, by determining the level of the PTPN2 polynucleotide, polypeptide, or gene product.

[0086] "Aberrantly expressed" or "aberrant expression," when applied to a nucleotide sequence (e.g., a gene) or polypeptide sequence in a subject, refers to the 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 may be overexpressed (or abnormally high expression) or underexpressed (or abnormally low expression) compared to the expression level of a reference sample (i.e., the reference level). As used herein, overexpression is an increase in expression that may be at least 1.25-fold, or alternatively, at least 1-fold, or alternatively, at least 2-fold, or alternatively, at least 3-fold, or alternatively, at least 4-fold, or alternatively, at least 10-fold greater than that detected in the reference sample. As used herein, underexpression is a decrease in expression that may be at least 1.25-fold, or alternatively, at least 1-fold, or alternatively, at least 2-fold, or alternatively, at least 3-fold, or alternatively, at least 4-fold, or alternatively, at least 10-fold less than that detected in the reference sample. Underexpression also encompasses the absence of expression of a particular sequence as evidenced by the absence of detectable expression in a test subject when compared to a reference sample.

[0087] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within cells to elicit intracellular responses. A molecule may mediate its signaling effect through direct or indirect interaction with downstream molecules in the same or related pathway(s). For example, PTPN2 signaling may involve a host of downstream molecules, including, but not limited to, one or more of the following proteins: PI3-kinase and AKT.

[0088] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. A polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified (e.g., by 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 any natural and / or unnatural or synthetic amino acid, including glycine and both the D- or L-optical isomers, as well as amino acid analogs and peptidomimetics.

[0089] A "control" or "control sample" is a substitute sample or control used in an experiment for comparison purposes.

[0090] The term "reference level" refers to a control level used to evaluate the test level. In some examples, 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, as long as the reference level indicates a biomarker level that exceeds that of a first group of subjects who have a potential clinically beneficial response to treatment with a PTPN2 inhibitor, which is different from that of a second group of patients who have a biomarker level below the reference level. The reference level can be determined by measuring the expression level of the biomarker in neoplastic or non-neoplastic cancer cells from the same tissue as the cancer cell tissue being tested. In some examples, the reference level can be the level of the biomarker determined in vitro. The reference level can be determined by comparing the levels of the biomarker in a group of subjects with the same cancer. Two or more separate groups of subjects can be determined by identifying subsets of a cohort population with the same or similar levels of the biomarker. The reference level can then be determined based on the level that distinguishes these separate groups. The reference level may be a single numerical value that is equally applicable to all subjects, or the reference level may vary depending on the specific subpopulation of subjects. For example, elderly men may have a different reference level for the same cancer than young men, and women may have a different reference level for the same cancer than men. 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 cancer cells of a subject 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 from a population of individuals with cancer. The sensitivity of individuals with cancer to treatment with a PTPN2 inhibitor may be known. In some embodiments, the reference level is derived by comparing gene expression with a control gene (e.g., a housekeeping gene, e.g., actin) that is expressed at a relatively stable level in the same cellular environment. Comparison to the reference level may be a qualitative assessment or a quantitative determination.

[0091] The terms "determining," "measuring," "evaluating," "assessing," "assaying," "testing," and "analyzing" are used interchangeably herein to refer to any form of measurement, including determining whether an analyte is present (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 could reflect the measured intensity of a signal or a conversion of this signal intensity to another quantitative format, such as micrograms / mL. "Detecting the presence of" can include determining the amount of something present, as well as determining whether it is present or absent.

[0092] The terms "antagonist" and "inhibitor" are used interchangeably and refer to a compound or biological molecule capable of inhibiting the biological function of a target protein (e.g., PTPN2), whether by inhibiting the activity or expression of the target protein. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but compounds that inhibit the biological activity of the target protein by interacting with other members of a signal transduction pathway of which the target protein is a member are also specifically included in this definition. Alternatively or in addition, the activity of a target protein may involve interaction (e.g., binding) between the target protein and a substrate of the target protein, and the terms "antagonist" and "inhibitor" may refer to a compound capable of interacting (e.g., binding) with the target protein's counterpart to indirectly inhibit the biological activity of the target protein. In some cases, such a compound may bind both the target protein and one or more types of substrates. Preferred biological activities inhibited by the antagonist are associated with the onset, growth, maintenance, or spread of cancer or tumors.

[0093] The term "cell proliferation" refers to a change in cell number as a result of division. The term also encompasses cell growth in which cell morphology changes (e.g., increased size) consistent with a proliferative signal.

[0094] The terms "administer," "administering," "administration," and derivatives thereof refer to methods that can be used to enable delivery of an agent or composition to a desired site of biological effect. 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 modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, implantation, and the like. One of skill in the art will know of 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.

[0095] The term "systemic administration" refers to administration of 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 higher localization of the agent or composition at one or more desired sites. The desired site can be another site accessible by the blood or vascular system. Non-limiting examples of systemic administration routes include (1) direct introduction of the agent into the vascular system or (2) oral, pulmonary, or intramuscular administration, in which the agent is adsorbed, enters the vascular system, and is carried via the blood to one or more desired site(s) of action. In contrast, "non-systemic administration" refers to administration of an agent or composition such that the agent or composition is administered locally to a targeted site in the subject's body to produce a primarily local effect.

[0096] The terms "co-administration," "administered in combination with," and their grammatical equivalents include administration of two or more agents to a subject such that both agents and / or their metabolites can perform their respective functions. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0097] The term "effective amount" refers to that amount of a compound described herein sufficient to effect the intended use, including, but not limited to, stimulating or prolonging anti-tumor immunity or disease treatment (defined below). The effective amount may vary depending on the intended use (in vitro, ex vivo, or in vivo), or the subject and disease condition being treated, such as the subject's weight and age, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in target cells, such as cell death or cell activation. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the tissue to which it is administered, and the bodily delivery system used.

[0098] As used herein, the terms "treatment," "treating," "alleviating," and "ameliorating" are used interchangeably. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or reversal of the underlying disorder being treated (e.g., squamous cell carcinoma). Therapeutic benefit is also achieved with the eradication or reversal of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disorder. For prophylactic benefit, pharmaceutical compositions may be administered to patients at risk of developing a particular disease or who report one or more physiological symptoms of the disease, even if the disease may not have been diagnosed.

[0099] A "therapeutic effect," as used herein, encompasses therapeutic and / or prophylactic benefits, as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0100] The term "subject" includes, but is not limited to, humans of any age group, e.g., a pediatric subject (e.g., an infant, a toddler, or an 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); commercially relevant mammals, e.g., mammals including cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or commercially relevant birds, e.g., birds including chickens, ducks, geese, quail, and / or turkeys. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0101] The term "in vivo" refers to an event that takes place in the body of a subject.

[0102] The term "ex vivo" refers to an event that initially occurs outside a subject's body for subsequent in vivo application to the subject's body. For example, ex vivo preparation can involve the preparation of cells outside a subject's body for the purpose of introducing the prepared cells into the same or a different subject's body.

[0103] The term "in vitro" refers to an event that occurs outside the subject's body. For example, an in vitro assay encompasses any assay that is performed outside the subject's body. An in vitro assay encompasses cell-based assays in which live or dead cells are used. An in vitro assay also encompasses cell-free assays in which no intact cells are used.

[0104] The term "downregulating PTPN2 activity," as used herein, refers to slowing down, reducing, altering, inhibiting, and completely eliminating and / or preventing PTPN2 activity.

[0105] The term "effector function" refers to a specialized function of a cell. An effector function of a T cell can be, for example, cytolytic activity or helper activity, including secretion of cytokines. Thus, the term "intracellular signaling domain" refers to the portion of a protein that transmits an effector function signal and instructs the cell to perform a specialized function.

[0106] The term "autologous" refers to any material originating from the same individual that is later reintroduced into the same individual.

[0107] The term "allogeneic" refers to any material derived from a different animal of the same species as the individual into which the material is introduced. Two or more individuals are said to be allogeneic to each other if the genes at one or more loci are not identical. In some embodiments, allogeneic materials from individuals of the same species may not be genetically similar enough to interact antigenically.

[0108] The term "costimulatory molecule" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that contribute to an efficient immune response. Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA and Toll ligand receptors, as well as OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), and 4-1BB (CD137). Further examples of such costimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, 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, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, L These include ligands that specifically bind to FA-1, ITGB7, NKG2D, NKG2C, 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, CD19a, and CD83. The costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule. Costimulatory molecules can be represented in the following protein families: TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), and activating NK cell receptors.Examples of such molecules include ligands that specifically bind to CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3, and CD83. The intracellular signaling domain can comprise the entire intracellular portion of the molecule from which it is derived, or the entire native intracellular signaling domain, or a functional fragment or derivative thereof.

[0109] The terms "immune effector cell" and "effector cell" are used interchangeably herein. They refer to cells that are involved in promoting an immune response, e.g., 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.

[0110] The terms "immunity" and "immune response" are used interchangeably herein. When applied to a subject, it refers to the subject's ability to mount an immune response via his / her immune cells against an antigen, including but not limited to, a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen. When applied to a cell, it refers to the cell's ability to generate a cellular response, directly or indirectly, against an antigen, including but not limited to, a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen.

[0111] The term "lymphoid cell(s)" refers to any cell or cells responsible for the generation of antibody-mediated immunity (or immune response), including lymphocytes, lymphoblasts, and plasma cells. Lymphoid cells include granulocytes, e.g., basophils, eosinophils, and neutrophils; mast cells; monocytes, which can evolve into macrophages; antigen-presenting cells, e.g., dendritic cells; and lymphocytes, e.g., 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.

[0112] The terms "tumor marker," "tumor antigen," and "tumor-associated antigen" are used interchangeably herein and refer to molecules or fragments thereof expressed on or secreted within cancer cells or molecules or fragments thereof that are otherwise derived from cancer cells (e.g., circulating tumor DNA or circulating tumor RNA), and are useful for detecting cancer cells or preferentially targeting drugs to cancer cells. A tumor antigen can be a marker expressed by both normal and cancer cells, such as a lineage marker, e.g., CD19 on B cells. A tumor antigen can also be a cell surface molecule that is overexpressed or underexpressed in cancer cells compared to normal cells. A tumor antigen can also be a cell surface molecule that is inappropriately synthesized in cancer cells, such as a molecule that contains deletions, additions, or mutations compared to molecules expressed on normal cells. A tumor antigen, either in its entirety or as fragments (e.g., MHC / peptides), may be expressed only on the cell surface of cancer cells and not synthesized or expressed on the surface of normal cells. Tumor antigens include neoantigens encoded by tumor-specific mutated genes.

[0113] The term "temporarily downregulated," as used herein, generally means that the downregulation of the expression or activity of a target molecule (e.g., PTPN2) is not permanent. Temporary downregulation may not be permanent downregulation. In some cases, temporary downregulation may involve downregulating (e.g., reducing) the expression or activity of a target molecule for a period of time, followed by maintaining at least a portion of the previously downregulated expression or activity level of the target molecule. Temporary downregulation may involve intermittent downregulation of a target molecule (e.g., PTPN2).

[0114] The term "intermittent" is used herein to describe a process that is not continuous. An intermittent process may be followed by interruptions 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," as used herein, refers to a dosing regimen that includes administration of a pharmaceutical composition followed by a rest period.

[0115] The term "side effect," as used herein, refers to any complication, unwanted, or pathological outcome of a therapy (e.g., cell therapy, immunotherapy, etc.) that occurs in addition to or instead of the desired treatment outcome of the therapy. Examples of side effects may include, but are not limited to, (i) off-target cytotoxicity, (ii) on-target extratumoral toxicity, and / or (iii) autoimmunity (e.g., chronic autoimmunity). In one example, a side effect of cell therapy involving a T cell receptor fusion protein (TFP) and / or a chimeric antigen receptor (CAR) may include graft-versus-host disease. In another example, a side effect of cell therapy involving a TFP and / or a CAR may include death of cells configured to express the TFP and / or the CAR.

[0116] Other examples of side effects of cell therapy may include, but are not limited to, disorders mediated by phagocytes, including macrophages and neutrophil granulocytes (polymorphonuclear leukocytes, PMNs), and / or T cells. Examples include inflammatory skin diseases, including psoriasis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; CNS inflammatory disorders, such as multiple sclerosis; uveopathy; allergic conditions, such as eczema and asthma, and other conditions involving T cell infiltration and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison ivy); autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes, multiple sclerosis, Raynaud's disease, and the like. These include immune reactions associated with cytokine- and T-lymphocyte-mediated delayed hypersensitivity typically seen in autoimmune thyroiditis, Sjogren's syndrome, juvenile-onset diabetes, and tuberculosis; sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia; multiple organ injury syndromes secondary to sepsis or trauma; autoimmune hemolytic anemia; myasthenia gravis; antigen-antibody complex-mediated diseases; and / or all types of transplant rejection, including graft-versus-host or host-versus-graft disease.

[0117] The term "efficacy" of a treatment or method, as used herein, can be measured based on changes 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 total alleviation of the disease or condition, or a reduction in one or more symptoms of the disease or condition. In one example, a response is achieved when a subject suffering from a tumor exhibits a reduction in tumor size after a treatment or method provided in the present disclosure. In some examples, efficacy can be measured by assessing cancer cell death, tumor reduction (e.g., as evidenced by a reduction in tumor size), and / or inhibition of tumor growth, progression, and distribution.

[0118] 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 the art. See, e.g., Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds.); the series Methods in Enzymology (Academic Press, Inc.), 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)).

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to which the claimed subject matter pertains. In the event that there are multiple definitions for terms 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 referring to a URL or other such identifier or address, it is understood that such identifiers may change and specific information on the Internet may be subject to change, but that equivalent information may be found by searching the Internet. Such reference evidences the availability and public dissemination of such information.

[0120] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in the 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 stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0121] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0122] Standard definitions of chemical terms are given in Carey and Sundberg's "Advanced Organic Chemistry 4 th" Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0123] Unless specific definitions are provided, nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and pharmaceutics and pharmaceutical chemistry described herein are art-recognized. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed, for example, using manufacturer's specification kits or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed in a conventional manner and as described in the various general and more specific references cited and discussed throughout this specification.

[0124] 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, and as such 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.

[0125] As used herein, C1-C x Includes C1-C2, C1-C3...C1-C x Includes C1-C x refers to the number of carbon atoms (excluding any substituents) that make up the moiety it designates.

[0126] An "alkyl" group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, an "alkyl" group can have 1 to 6 carbon atoms (wherever it appears herein, a numerical range such as "1 to 6" refers to each integer in the given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). The alkyl group of the compounds described herein can be designated as "C1-C6 alkyl" or a similar designation. By way of example only, "C1-C6 alkyl" indicates that there are 1 to 6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, and hexyl. An alkyl group can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (ie, an alkylene group).

[0127] "Alkoxy" refers to the group "-O-alkyl" where alkyl is as defined herein.

[0128] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. In some embodiments, an alkenyl group can have 2 to 6 carbons. An alkenyl group can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0129] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0130] "Amino" refers to the group -NH2.

[0131] The term "alkylamine" or "alkylamino" refers to -N(alkyl) x H y A group wherein alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the nitrogen to which they are attached, can optionally form a cyclic ring system. "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein.

[0132] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons (n ​​is an integer). Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatic compounds can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0133] As used herein, the term "aryl" refers to a monocyclic aromatic ring in which each of the atoms forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic) in which (1) at least one ring is carbocyclic and aromatic, 2) the bond to the rest of the compound is directly connected to a carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system in (2) is not connected (e.g., fused) to a heteroaryl ring in a polycyclic ring system, either directly or through one or more aromatic rings. The aryl ring can be formed by 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group). As used herein, the aryl radical is a monocyclic, bicyclic, or tricyclic ring system. In embodiments, an aryl is a monocyclic ring. In embodiments, an aryl is a fused-ring polycyclic system. In embodiments, an aryl is a bridged-ring polycyclic system. In some embodiments, an aryl is a "fused-ring aryl," wherein the aryl ring is fused to a cycloalkyl or heterocycloalkyl ring.

[0134] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has biological properties similar to those of a carboxylic acid group. A compound having a carboxylic acid moiety may have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and may have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere will ionize to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include: [ka] These include, but are not limited to:

[0135] The term "cycloalkyl" refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or a polycyclic carbocyclic (i.e., containing no heteroatom(s)) ring system (e.g., bicyclic or tricyclic) in which 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) the bond to the remainder of the compound is directly connected to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of 2) is not connected (e.g., fused or spirocyclic) to a heterocycloalkyl ring in a polycyclic ring system, either directly or through one or more saturated or partially unsaturated and non-aromatic rings. A cycloalkyl can be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In embodiments, a cycloalkyl is a monocyclic ring. In embodiments, a cycloalkyl is a fused-ring polycyclic system. In embodiments, a cycloalkyl is a bridged-ring polycyclic system. In embodiments, a cycloalkyl is a spirocyclic polycyclic ring system. 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).

[0136] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to a monocyclic aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur; or a polycyclic ring system (e.g., bicyclic or tricyclic) in which 1) at least one ring is aromatic and contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur; and 2) the bond to the remainder of the compound is directly or via one or more aromatic rings bonded (e.g., fused) to an aromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur of the aromatic or aryl ring system. As used herein, a heteroaryl radical can be a monocyclic, bicyclic, or tricyclic ring system in which at least one of the rings in the ring system is fully unsaturated (i.e., aromatic) and contains a heteroatom. In embodiments, a heteroaryl is a monocyclic ring. In embodiments, a heteroaryl is a fused-ring polycyclic system. In embodiments, a heteroaryl is a bridged-ring polycyclic system. In some embodiments, a "fused-ring heteroaryl" is one in which the heteroaryl ring is fused to a cycloalkyl, aryl, or heterocycloalkyl ring. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).

[0137] A "heterocycloalkyl" group or a "heteroalicyclic" group or a "heterocyclyl" group refers to a cycloalkyl group in which at least one skeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. In embodiments, the nitrogen, phosphorus, or sulfur atom can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Heterocycloalkyl refers to a monocyclic saturated or partially unsaturated non-aromatic ring or polycyclic ring system (e.g., bicyclic or tricyclic) containing one or more heteroatoms, where 1) at least one ring is saturated or partially unsaturated and non-aromatic and contains one or more heteroatoms, and 2) the bond to the remainder of the compound is directly or via one or more saturated or partially unsaturated non-aromatic rings containing one or more heteroatoms in the saturated or partially unsaturated non-aromatic ring or ring system that is a non-aromatic ring bonded (e.g., fused) to the saturated or partially unsaturated non-aromatic ring containing one or more heteroatoms in the ring system. Heterocycloalkyls can be saturated or partially unsaturated. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In embodiments, a heterocycloalkyl is a monocyclic ring. In embodiments, a heterocycloalkyl is a fused-ring polycyclic system. In embodiments, a heterocycloalkyl is a bridged-ring polycyclic system. In embodiments, a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise stated, a heterocycloalkyl has 2 to 13 carbons in the ring or ring system. 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) that comprise 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).

[0138] The term "halo" or, alternatively, "halogen" means fluoro, chloro, bromo, and iodo.

[0139] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens can be the same or they can be different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0140] 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.

[0141] 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. Also, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl" may have 1 to 6 carbon atoms.

[0142] The term "oxo" refers to the =O radical.

[0143] 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.

[0144] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often a recognized chemical entity embedded in or attached to a molecule.

[0145] As used herein, the substituent "R," alone or without a number designation, refers to a substituent selected from among alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0146] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0147] The term "optionally substituted" or "substituted," unless otherwise specified, means that the referenced group can be substituted with one or more additional group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, oxo, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, 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 include, but are not limited to, L s R s and each Ls 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)-; each R 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 sources such as Greene and Wuts, above.

[0148] "Aralkyl" is a group of the formula -R c -aryl (R c refers to a radical of 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 portion of the aralkyl radical is optionally substituted as described above for an aryl group.

[0149] "Aralkenyl" refers to a group of the formula -R d -aryl (R d refers to a radical of the group aralkenyl, where a is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0150] "Aralkynyl" refers to a group of the formula -R e -aryl (R e refers to a radical of the group aralkynyl, where a is an alkynylene chain as defined above. The aryl 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.

[0151] "Aralkoxy" is a group of the formula -OR c -aryl (R c refers to a radical attached through an oxygen atom of 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 portion of the aralkyl radical is optionally substituted as described above for an aryl group.

[0152] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0153] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted with 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.

[0154] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0155] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0156] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclyl(R c refers to a radical of the formula: (wherein R is an alkylene chain as defined above). If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0157] "Heterocyclylalkoxy" refers to a group of the formula -OR c -heterocyclyl(R c refers to a radical attached through the oxygen atom of a heterocyclyl group (which is an alkylene chain as defined above). If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0158] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, where 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.

[0159] "C-heteroaryl" refers to a heteroaryl radical, as defined above, where 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.

[0160] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl (R c refers to a radical of the formula: (wherein R 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.

[0161] "Heteroarylalkoxy" refers to a group of the formula -OR c -heteroaryl (R c refers to a radical attached through the oxygen atom of a heteroaryl (which 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.

[0162] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, all stereoisomers of the compounds disclosed herein are intended to be contemplated by the present disclosure. The compounds described herein contain an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all 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 around a central ring, e.g., ortho-, meta-, and para-isomers around a benzene ring.

[0163] "Tautomer" refers to a molecule capable of a proton shift from one atom of the molecule to another atom of the same molecule. The compounds presented herein, in certain embodiments, exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: [ka] Includes:

[0164] In some instances, the compounds disclosed herein exist in tautomeric forms. The structures of the compounds are shown in one tautomeric form for clarity. Alternate tautomeric forms, such as the structure shown below, are expressly included in the present disclosure. [ka]

[0165] The compounds disclosed herein may, in some embodiments, be, for example, 2 H, 3 H, 11 C. 13 C and / or 14 The compounds are used in different isotopic enriched forms, enriched in the context of C. In one particular embodiment, the compounds are 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.

[0166] 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 hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structure except for the replacement of a carbon with a condensed carbon are within the scope of this disclosure.

[0167] The compounds of the present disclosure may 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 at 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.

[0168] In certain embodiments, the compounds disclosed herein comprise: 1 Some or all of the H atoms 2 is replaced with an H atom. Synthetic methods for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0169] 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.

[0170] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co.

[0171] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is shown, by way of example only, in the following reaction scheme. [ka]

[0172] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4), can be used to transfer deuterium to reaction substrates under reducing conditions. The use of LiAlD4 is shown, by way of example only, in the following reaction scheme: [ka]

[0173] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and, by way of example only, to effect reductive displacement of aryl carbon-halogen bonds, as shown in the following reaction scheme: [ka]

[0174] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds 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.

[0175] "Pharmaceutically acceptable acid addition salts" refer to those salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, which retain the biological effectiveness and properties of the free bases and which 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, aliphatic and aromatic sulfonic acids, and the like, including, for example, 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, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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. Salts of amino acids, such as arginate, gluconate, and galacturonate, are also contemplated (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.

[0176] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. 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).

[0177] As used herein, "prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference). The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound.

[0178] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Also included are tissues, cells, and their progeny of biological entities obtained in vivo or cultured in vitro.

[0179] The terms "therapeutic agent," "therapeutic agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. Beneficial effects include enabling a diagnostic determination; ameliorating a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally combating a disease, symptom, disorder, or pathological condition.

[0180] As used herein, "treatment" or "treating," or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or a subject reporting one or more physiological symptoms of a disease, even if the disease, condition, or symptom may not yet be manifest. Typically, prophylactic benefit includes reducing the frequency of occurrence and / or worsening of one or more diseases, conditions, or symptoms under treatment (e.g., between treated and untreated populations, or between treated and untreated states of a subject).

[0181] 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 condition being treated, the subject's weight and age, the severity of the disease condition, 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 in multiple doses. A component may be described herein as having at least an effective amount, or at least an effective amount related to a particular goal or purpose, such as any of those described herein. The term "effective amount" also applies to a dose that provides an image for detection by an appropriate imaging method. The specific dose 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 bodily delivery system used.

[0182] An "antigen" is a site or molecule that contains an epitope and thus also binds specifically to an antibody.

[0183] An "antigen-binding unit" can be the whole or fragment(s) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. Full-length antibodies can be, for example, monoclonal, recombinant, chimeric, deimmunized, humanized, and human antibodies. Examples of fragments of full-length antibodies include variable heavy (VH), variable light (VL), heavy chains (VHH or VL) found in camelids, e.g., camels, llamas, and alpacas. HH), heavy chains found in sharks (V-NAR domains), single domain antibodies (sdAb, i.e., "nanobodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (or half antibodies). Examples of modified antibody fragments may include, but are not limited to, scFv, di-scFv or bis(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0184] The terms "antibody" and "antibody" encompass any antigen-binding unit, including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelidized antibodies, chimeric antibodies, and any other epitope-binding fragment.

[0185] The term "in vivo" refers to an event that takes place in the body of a subject.

[0186] The term "ex vivo" refers to an event that initially occurs outside a subject's body for subsequent in vivo application to the subject's body. For example, ex vivo preparation can involve the preparation of cells outside a subject's body for the purpose of introducing the prepared cells into the same or a different subject's body.

[0187] The term "in vitro" refers to an event that occurs outside the subject's body. For example, an in vitro assay encompasses any assay that is performed outside the subject's body. An in vitro assay encompasses cell-based assays in which live or dead cells are used. An in vitro assay also encompasses cell-free assays in which no intact cells are used.

[0188] Compounds including compounds having PTPN2 inhibitor activity (i.e., PTPN2 inhibitors) are described herein below. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2a ) or N; or W 1 is C(R 1a ) or N, and W 2 is C(R 2 ) or; R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a optionally substituted with; R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b optionally substituted with; X is N or C(R 3 ) and; Y is N or C(R 4 ) and; Z is N or C(R 5 ) and; R 3 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally substituted with; R 4 is halogen, -CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R20d optionally substituted with; R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 )(R13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; J 1 is N, C, or C(R8 ) 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 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally substituted with; R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20i optionally substituted with; or R 9 and R 9a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally substituted with; R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(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 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally substituted with; or R 10 and R 10a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 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 20m optionally substituted with; Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b )(wherein, C 1-6 Alkylene can be one, two, or three R 20n optionally substituted with ); or -C 1-6 Alkylene-OC(O)-R 16c (In the formula, C 1-6 Alkylene can be one, two, or three R 20n independently selected from (optionally substituted with); Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 20o optionally substituted with; R16c is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 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 ), -OCH2C(O)OR 22 , and -OC(O)R 25 and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10Aryl, -CH2-C 1-9 Heteroaryl, and C 1-9 Heteroaryl can be one, two, or three R 20o optionally substituted with; Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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(R22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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, C1-6 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 independently selected from 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 independently selected from 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 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R 26 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR12 , -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally substituted with; [ka] indicates a single or double bond so that all valences are satisfied) is provided.

[0189] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (Ia): [ka] It has.

[0190] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (Ib): [ka] It has.

[0191] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (Ic): [ka] It has.

[0192] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the formula: [ka] It has.

[0193] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (IIa): [ka] It has.

[0194] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (IIb): [ka] It has.

[0195] In embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structure of Formula (IIc): [ka] It has.

[0196] In embodiments, the compound of formula (IIa) has the structure of formula (IId): [ka] ,for example, [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0197] In one embodiment, a compound of formula (IId-1), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; Each R 6 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -C(NR 14 )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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’-CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(NR 14 )N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13 is hydrogen, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 20moptionally substituted with; Each R 20f , 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 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 Heteroaryl is a heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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 independently selected from heteroaryl; Each R 22 is H, C 1-6 Alkyl, C1-6 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 independently selected from 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 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from heteroaryl; Each R 26 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f (optionally substituted with ).

[0198] In an embodiment, for a compound of formula (II-d1): R 1 is C 5-10 cycloalkyl, 5- to 10-membered heterocycloalkyl, C aryl, and 5- to 10-membered heteroaryl; 5-10 Cycloalkyl, 5- to 10-membered heterocycloalkyl, C aryl, and 5- to 10-membered heteroaryl may be one or more R 6 wherein the ring heteroatoms of the 5- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are independently selected from N, O, and S; Each R6 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(NR 14 )N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 )- are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, and C 6-10 Aryl can be one, two, or three R 26 is optionally replaced by

[0199] In embodiments, for compounds of formula (II-d1), R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from one or more R 6 In embodiments, R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from halogen, —CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(NR 14 )N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 )-, and optionally substituted with one or more substituents independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, and C 6-10 Aryl can be one, two, or three R 26 In some embodiments, each R 13 is hydrogen, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 In some embodiments, R 1 is -C(NR 14 )N(R 12 )(R 13 ), for example, —C(NH)NH2 or —C(NH)NHCN.

[0200] In embodiments, for compounds of formula (II-d1), R 1 teeth, [ka] (In the formula, R 1b is C(R 6b ) and R 1d is C(R 6d ), then R 1c is N or N(R 6c’’ )isn't it); [ka] (In the formula, R 1 is not a substituted pyrrolyl); and [ka] (In the formula, R 1 is not a substituted imidazolyl, R 1d and R 1e is selected from (where N); R 1b is N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1c is N, N(R 6c’’ ), C(R 6c ), or C(R 6c )(R 6c’ ) and; R 1d is N, N(R 6d’’ ), C(R 6d ), or C(R 6d )(R 6d’ ) and; R 1e is N, C, or C(R 6e ) and; R 6b , R 6b’ , R 6c , R 6c’ , R 6d , R 6d’ , and R 6e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R6b’’ , R 6c’’ , and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; Each R 6 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0201] In some embodiments, for compounds of Formula (II-d1), R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from.

[0202] In some embodiments, for compounds of Formula (II-d1), each R 20f , 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 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0203] In one embodiment, a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2a ) or N; or W 1 is C(R 1a ) or N, and W 2 is C(R 2 ) Either; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered 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(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ optionally substituted with one or more substituents independently selected from: R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a optionally substituted with; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ optionally substituted with one or more substituents independently selected from: R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b optionally substituted with; X is N or C(R 3 ) and; Y is N or C(R 4 ) and; Z is N or C(R 5 ) and; W 1 , W 2 , at least one of X, Y, and Z is N; R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20c optionally substituted with; R 4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20d optionally substituted with; R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20e optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; 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 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20h optionally substituted with; R 9 and R 9a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20i optionally substituted with; or R 9 and R 9a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally substituted with; R 10 and R 10a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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)2R15 , and -CH2S(O)2N(R 12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20j optionally substituted with; or R 10 and R 10a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally substituted with; Each R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 substituted with; Each R 13is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from haloalkyl; Each R 15 are independently selected C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Heteroalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 20m optionally substituted with; Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from; C 1-6 Alkylene can be one, two, or three R 20n optionally substituted with; Each R 16a and R 16b is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, -CH2-C 3-10 Cycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 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 20o optionally substituted with; Each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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(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 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from heteroaryl; Each R 22 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from 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 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; Each R26 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 optionally substituted with; Each R 27 is oxo, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20f optionally substituted with; [ka] indicates a single or double bond so that all valences are satisfied) is provided.

[0204] In some embodiments, X is C(R 3 In an embodiment, Y is C(R 4 In additional embodiments, Z is C(R 5 In some embodiments, X is N. In additional embodiments, Y is N. In embodiments, Z is N. In some embodiments, W 1 is C(R 1 In additional embodiments, W 1 is C(R 1a In some embodiments, W 2 is C(R 2a In an embodiment, W 2 is C(R 2 In additional embodiments, W 1 is N. In some embodiments, W 2 is N. In an embodiment, J 2 is CH. In some embodiments, J 2 is C(H). In additional embodiments, J 3 is N(H). In an embodiment, J 3 is C(R 10 )(R 10a In some embodiments, J 3 is CH(R 10 In some embodiments, R 10 is hydrogen.

[0205] In embodiments, R4 is halogen, -OR 12 , and one, two, or three R 20d C optionally substituted with 1-6 In some embodiments, R 4 is -OH.

[0206] In embodiments, R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C 2-6Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20e In embodiments, R 5 is hydrogen, halogen, and one, two, or three R 20e C optionally substituted with 1-6 In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is —OH. In some embodiments, R 5 is halogen. In some embodiments, R 5 is -F.

[0207] In additional embodiments, R 3 is a halogen and one, two, or three R 20c C optionally substituted with 1-6 In embodiments, R 3 is halogen. In embodiments, R 3 is F. In some embodiments, R 3 is Cl.

[0208] In an embodiment, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S; R 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl;5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, the 6- to 12-membered saturated heterocycloalkyl, and the 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0209] In an embodiment, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S; R 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, the 6- to 12-membered saturated heterocycloalkyl, and the 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0210] In an embodiment, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S; R 2 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, the 6- to 12-membered saturated heterocycloalkyl, and the 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0211] In embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0212] In embodiments, R 2 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In embodiments, R 2 is not phenyl. In embodiments, R 2 is R 7 and R 7’ In embodiments, R is not phenyl substituted with one or more substituents independently selected from 2 is not phenyl substituted with methoxy. 2 is not phenyl substituted with 3-methoxy.

[0213] In an embodiment, R 1 is selected from triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl, and triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl are selected from R 6 and R 6’ and is substituted with one or more substituents independently selected from: R 2 is selected from triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl, and triazolyl, pyrazolyl, pyrrolyl, imidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl are selected from R 7 and R 7’and is substituted with one or more substituents independently selected from:

[0214] In embodiments, R 1 is R 6 In an embodiment, R is a triazolyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is a pyrazolyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is pyrrolyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is imidazolyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is phenyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is pyridyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is pyrimidinyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is a pyridazinyl substituted with one or more substituents independently selected from 1 is R 6 In an embodiment, R is pyrazinyl substituted with one or more substituents independently selected from 1 is R 6 and triazinyl substituted with one or more substituents independently selected from:

[0215] In embodiments, R 2 is R 7 In an embodiment, R is a triazolyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7In an embodiment, R is pyrrolyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is imidazolyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is phenyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is pyridyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is pyrimidinyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is a pyridazinyl substituted with one or more substituents independently selected from 2 is R 7 In an embodiment, R is pyrazinyl substituted with one or more substituents independently selected from 2 is R 7 and triazinyl substituted with one or more substituents independently selected from:

[0216] In embodiments, R 1 is R 6’ In an embodiment, R is a triazolyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is a pyrazolyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is pyrrolyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is imidazolyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is phenyl substituted with one or more substituents independently selected from 1 is R 6’In an embodiment, R is pyridyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is pyrimidinyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is a pyridazinyl substituted with one or more substituents independently selected from 1 is R 6’ In an embodiment, R is pyrazinyl substituted with one or more substituents independently selected from 1 is R 6’ and triazinyl substituted with one or more substituents independently selected from:

[0217] In embodiments, R 2 is R 7’ In an embodiment, R is a triazolyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is pyrrolyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is imidazolyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is phenyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is pyridyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is pyrimidinyl substituted with one or more substituents independently selected from 2 is R 7’ In an embodiment, R is a pyridazinyl substituted with one or more substituents independently selected from 2 is R 7’In an embodiment, R is pyrazinyl substituted with one or more substituents independently selected from 2 is R 7’ and triazinyl substituted with one or more substituents independently selected from:

[0218] In embodiments, R 1 teeth, [ka] (In the formula, R 1b is C(R 6b ) and R 1d is C(R 6d ), then R 1c is N or N(R 6c’’ )isn't it); [ka] (In the formula, R 1 is not a substituted pyrrolyl); [ka] (In the formula, R 1 is not a substituted imidazolyl, R 1d and R 1e is N); or R 6 and R 6’ is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from: R 1b is O, S, N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1c is O, S, N, N(R 6c’’ ), C(R 6c ), or C(R 6c )(R 6c’ ) and; R 1d is O, S, N, N(R 6d’’ ), C(R 6d ), or C(R6d )(R 6d’ ) and; R 1e is N or C(R 6e ) and; R 6b , R 6b’ , R 6c , R 6c’ , R 6d , R 6d’ , and R 6e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ , R 6c’’ , and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20a optionally substituted with; R 2 teeth, [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2c and R 2d is N); [ka] (In the formula, R 2 is not a substituted pyrazolyl or pyrrolyl); [ka] (In the formula, R 2 is not a substituted pyrrolyl or imidazolyl); [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2d and R 2e is N or R 2b and R 2d is N or NH); or R 7 and R 7’ is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from: R 2b is O, S, N, N(R 7b’’ ), C(R 7b ), or C(R 7b )(R 7b’ ) and; R 2c is O, S, N, N(R 7c’’ ), C(R 7c ), or C(R 7c )(R 7c’ ) and; R 2d is O, S, N, N(R 7d’’), C(R 7d ), or C(R 7d )(R 7d’ ) and; R 2e is N or C(R 7e ) and; R 7b , R 7b’ , R 7c , R 7c’ , R 7d , R 7d’ , and R 7e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 7b’’ , R 7c’’ , and R 7d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl can be one, two, or three R 20b optionally substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0219] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0220] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0221] In some embodiments, R 1 and R 2 teeth, [ka] is selected from.

[0222] In some embodiments, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6 and R 6’ and is substituted with one or more substituents independently selected from: R2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 7 and R 7’ and is substituted with one or more substituents independently selected from:

[0223] In some embodiments, R 1are indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzofuranyl, selected from benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl Indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzo Furanyl, benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl are R 6 and R 6’ and is substituted with one or more substituents independently selected from: R 2are indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzofuranyl, selected from benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl Indazolyl, 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl, benzoxazolyl, benzthiazolyl, naphthyl, indenyl, indolinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, purinyl, benzofuranyl, isobenzo Furanyl, benzo[c]thiophenyl, benzo[b]thiophenyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrazinyl, pyrido[2,3-d]pyrazinyl, and pteridinyl are R 7 and R 7’ and is substituted with one or more substituents independently selected from:

[0224] In some embodiments, R 1 teeth, [ka] and; R 6b is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; z6b is an integer from 0 to 4; R 2 teeth, [ka] and; R 7b is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 )(R13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; z7b is an integer of 0 to 4.

[0225] In some embodiments, R 1 and R 2 teeth, [ka] is selected from.

[0226] In some embodiments, R 1 is R 6 and R 6’ is pyrazolyl substituted with one or more substituents independently selected from R 2 is R 7 and R 7’ and pyrazolyl substituted with one or more substituents independently selected from:

[0227] In some embodiments, R 1 is R 6’ is pyrazolyl substituted with one or more substituents independently selected from R 2 is R 7’ and pyrazolyl substituted with one or more substituents independently selected from:

[0228] In some embodiments, R 1 is C 5-10 cycloalkyl, 5- to 10-membered heterocycloalkyl, C aryl, and 5- to 10-membered heteroaryl; 5-10Cycloalkyl, 5- to 10-membered heterocycloalkyl, C aryl, and 5- to 10-membered heteroaryl may be one or more R 6 wherein the ring heteroatoms of the 5- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are independently selected from N, O, and S; Each R 6 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(NR 14 )N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 )- are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, and C 6-10 Aryl can be one, two, or three R 26 is optionally replaced by

[0229] In some embodiments, R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from one or more R 6 In embodiments, R 1is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from halogen, —CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(NR 14 )N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 )-, and optionally substituted with one or more substituents independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, and C 6-10 Aryl can be one, two, or three R 26 is optionally replaced by

[0230] In some embodiments, R 1 teeth, [ka] (In the formula, R 1b is C(R 6b ) and R 1d is C(R 6d ), then R 1c is N or N(R 6c’’ )isn't it); [ka] (In the formula, R 1 is not a substituted pyrrolyl); and [ka] (In the formula, R 1 is not a substituted imidazolyl, R 1d and R 1e is selected from (where N); R 1b is N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1c is N, N(R 6c’’ ), C(R 6c ), or C(R 6c )(R 6c’ ) and; R 1d is N, N(R 6d’’ ), C(R 6d ), or C(R 6d )(R 6d’ ) and; R 1e is N, C, or C(R 6e ) and; R 6b , R 6b’ , R 6c , R 6c’ , R 6d , R 6d’ , and R 6e is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(R12 )(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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ , R 6c’’ , and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; Each R 6 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 optionally substituted with; Each R 6’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R12 )(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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0231] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from.

[0232] In some embodiments, R 1is one R 6’ pyrazolyl substituted with R 2 is one R 7’ In some embodiments, R is a pyrazolyl substituted with 1 teeth, [ka] and; R 1b is O, S, N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1d is O, S, N, N(R 6d’’ ), C(R 6d ), or C(R 6d )(R 6d’ ) and; R 6b , R 6b’ , R 6d , and R 6d’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ and R 6d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 2 teeth, [ka] and; R 2b is O, S, N, N(R 7b’’ ), C(R 7b ), or C(R 7b )(R 7b’ ) and; R 2d is O, S, N, N(R 7d’’ ), C(R 7d ), or C(R 7d )(R 7d’ ) and; R 7b , R 7b’ , R 7d , and R 7d’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 7b’’ and R 7d’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 6’ and R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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(R12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0233] In some embodiments, R 1 teeth, [ka] is.

[0234] In some embodiments, R 2 teeth, [ka] is.

[0235] In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered 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 ) and C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ is optionally substituted with one or more substituents independently selected from

[0236] In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6’ In some embodiments, R1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 6 In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl.

[0237] In some embodiments, R 1 -OR 12 , -SR 12 , -N(R 12 )(R 13 ), and -C(O)OR 12 is selected from.

[0238] In some embodiments, R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a In some embodiments, R 1a is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a In some embodiments, R 1a is C 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a In some embodiments, R 1a is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0239] In some embodiments, R 6 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, R 6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, R 6’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0240] In some embodiments, each R 6 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 6 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 6 is C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, each R is independently selected from heteroaryl. 6 is halogen, -CN, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 are independently selected from

[0241] In some embodiments, each R 6’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15, -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 6’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 6’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9In some embodiments, each R is independently selected from heteroaryl. 6’ may independently be 1, 2, or 3 R 26 C optionally substituted with 1-6 It is alkyl.

[0242] In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and R 6’ and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6 and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 6’and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl, and the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0243] In some embodiments, R 1 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 6 and R 6’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 6 and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 6’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 1 is C 5-12 and selected from cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl, wherein the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0244] In embodiments, R 1 teeth, [ka] In an embodiment, R 1 teeth, [ka] (In the formula, R 1b is C(R 6b ) and R 1d is C(R 6d ), then R 1c is N or N(R 6c’’ ) is not). In an embodiment, R 1 teeth, [ka] (In the formula, R 1 is not a substituted pyrrolyl). In embodiments, R 1 teeth, [ka] (In the formula, R 1 is not a substituted imidazolyl, R 1d and R 1e is N). In an embodiment, R 1 is R 6 and R 6’ In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 1 is R 6 In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 1 is R 6’ In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 1 teeth, [ka] In an embodiment, R 1 teeth, [ka] In an embodiment, R 1 teeth, [ka] is.

[0245] In some embodiments, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6 and R 6’In some embodiments, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6’ In some embodiments, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6 and R 6’ R is substituted with one or more substituents independently selected from 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 6 In some embodiments, R 1 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12heteroaryl.

[0246] In some embodiments, R 1 is R 6 and R 6’ In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 1 is R 6 In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 1 is R 6’ In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 1 is one R 6’ and pyrazolyl substituted with

[0247] In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered 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 ) and C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7’ In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 5- to 12-membered heteroaryl are R 7In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 aryl, and 5- to 12-membered heteroaryl. In some embodiments, R 2 -OR 12 , -SR 12 , -N(R 12 )(R 13 ), and -C(O)OR 12 is selected from.

[0248] In some embodiments, R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b In some embodiments, R 2a is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b In some embodiments, R 2a is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b In some embodiments, R 2a is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6alkynyl.

[0249] In some embodiments, R 7 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, R 7’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 is optionally replaced by

[0250] In some embodiments, each R 7 is halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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(R12 )(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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 7 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, each R is independently selected from heteroaryl. 7 is halogen, -CN, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 are independently selected from

[0251] In some embodiments, each R 7’ -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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(R12 )(R 13 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 7’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 26 In some embodiments, each R 7’ is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, each R is independently selected from heteroaryl. 7’ may independently be 1, 2, or 3 R 26 C optionally substituted with 1-6 It is alkyl.

[0252] In some embodiments, R 2 is C 5-12Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 Aryl and 5- to 12-membered heteroaryl are R 7and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 Cycloalkyl, 5-12 membered partially unsaturated heterocycloalkyl, 6-12 membered saturated heterocycloalkyl, C 7-12 aryl, and 5- to 12-membered heteroaryl, and the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0253] In some embodiments, R 2 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 7 and R 7’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 7and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; 5-12 Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are R 7’ and the ring heteroatoms of the 5-12 membered partially unsaturated heterocycloalkyl, the 6-12 membered saturated heterocycloalkyl, and the 5-12 membered heteroaryl are independently selected from C, N, O, and S. In some embodiments, R 2 is C 5-12 and selected from cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl, wherein the ring heteroatoms of the 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S.

[0254] In embodiments, R 2 teeth, [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2c and R 2d is N). In an embodiment, R 2 teeth, [ka] (In the formula, R 2 is not a substituted pyrazolyl or pyrrolyl). 2 teeth, [ka] (In the formula, R 2 is not a substituted pyrrolyl or imidazolyl. 2 teeth, [ka] (In the formula, R 2 is not a substituted imidazolyl, R 2d and R 2e is N or R 2b and R 2d is N or NH. In an embodiment, R 2 is R 7 and R 7’ In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 2 is R 7’ In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 2 is R 7’ In an embodiment, R is a fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] is.

[0255] In some embodiments, R 2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 7 and R 7’ In some embodiments, R 2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 7’ In some embodiments, R 2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 heteroaryl, bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C 1-12 Heteroaryl is R 7’ In some embodiments, R 2 is a bicyclic C 4-12 Cycloalkyl, Bicyclic C 2-11 Heterocycloalkyl, Bicyclic C 7-12 Aryl and Bicyclic C1-12 heteroaryl.

[0256] In some embodiments, R 2 is R 7 and R 7’ In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7 In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 2 is R 7’ In some embodiments, R is a pyrazolyl substituted with one or more substituents independently selected from 2 is one R 7’ and pyrazolyl substituted with

[0257] In some embodiments, R 6 , R 6’ , R 7 , and R 7’ is C 1-6 Alkyl, [ka] are independently selected from

[0258] In some embodiments, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from

[0259] In some embodiments, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from; R 26is hydrogen, 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

[0260] In some embodiments, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] are independently selected from

[0261] In some embodiments, R 6 , R 6’ , R 7 , and R 7’ teeth, [ka] In some embodiments, R6 teeth, [ka] In some embodiments, R 6’ teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7’ teeth, [ka] are independently selected from

[0262] In some embodiments, R 6 is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 6 is -CH2-R 26 and R 26 is C 6-10 Aryl and C 1-9 heteroaryl, C 6-10 Aryl and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 6 is -CH2-R 26 and R26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 and each R 27 is independently selected from halogen. 6 is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is a heteroaryl group consisting of one R 27 optionally substituted with R 27 are independently selected from halogens.

[0263] In some embodiments, R 6’ is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 6’ is -CH2-R 26 and R 26 is C 6-10Aryl and C 1-9 heteroaryl, C 6-10 Aryl and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 6’ is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 and each R 27 is independently selected from halogen. 6’ is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is a heteroaryl group consisting of one R 27 optionally substituted with R 27 are independently selected from halogens.

[0264] In some embodiments, R 7 is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 7 is -CH2-R 26 and R 26 is C 6-10 Aryl and C 1-9 heteroaryl, C 6-10 Aryl and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 7 is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 and each R 27 is independently selected from halogen. 7 is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is a heteroaryl group consisting of one R 27 optionally substituted with R 27 are independently selected from halogens.

[0265] In some embodiments, R 7’ is -CH2-R26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 7’ is -CH2-R 26 and R 26 is C 6-10 Aryl and C 1-9 heteroaryl, C 6-10 Aryl and C 1-9 Heteroaryl can be one, two, or three R 27 In some embodiments, R 7’ is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 27 and each R 27 is independently selected from halogen. 7’ is -CH2-R 26 and R 26 is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl; 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 Heteroaryl is a heteroaryl group consisting of one R 27 optionally substituted with R 27 are independently selected from halogens.

[0266] In some embodiments, X, Y, Z, W 1 , and W 2 At least one of is N.

[0267] In some embodiments, each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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)OR22 , -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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-10 Cycloalkyl, 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 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0268] In one embodiment, a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, W 1 is C(R 1 ) and W 2 is C(R 2a ) or W 1 is C(R 1a ) and W 2 is C(R 2 ) and; R 1 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl, 6- to 12-membered heteroaryl, and [ka] C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 6- to 12-membered heteroaryl are R 6 and R 6’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 6- to 12-membered heteroaryl are independently selected from N, O, and S; R 1b is O, S, N, N(R 6b’’ ), C(R 6b ), or C(R 6b )(R 6b’ ) and; R 1c is O, S, N, N(R 6c’’ ), C(R 6c ), or C(R 6c )(R 6c’ ) and; R1d is O, S, N, N(R 6d’’ ), C(R 6d ), or C(R 6d )(R 6d’ ) and; R 1f is O, S, N, N(R 6f’’ ), C(R 6f ), or C(R 6f )(R 6f’ ) and; R 6b , R 6b’ , R 6c , R 6c’ , R 6d , R 6d’ , R 6f , and R 6f’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 6b’’ , R 6c’’ , R 6d’’ , and R 6f’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20a optionally substituted with; R 1a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) and C 1-6 Alkyl, C2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20a optionally substituted with; R 2 is C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl, 6- to 12-membered heteroaryl, and [ka] and a 5-membered heteroaryl having C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, C 6-12 Aryl and 6- to 12-membered heteroaryl are R 7 and R 7’ wherein the ring heteroatoms of the 5- to 12-membered heterocycloalkyl and 6- to 12-membered heteroaryl are independently selected from N, O, and S; R 2b is O, S, N, N(R 7b’’ ), C(R 7b ), or C(R 7b )(R 7b’ ) and; R 2c is O, S, N, N(R 7c’’ ), C(R 7c ), or C(R 7c )(R 7c’ ) and; R 2d is O, S, N, N(R 7d’’ ), C(R 7d ), or C(R 7d )(R 7d’ ) and; R 2f is O, S, N, N(R 7f’’ ), C(R 7f ), or C(R 7f )(R 7f’ ) and; R 7b , R 7b’ , R 7c , R 7c’ , R 7d , R 7d’, R 7f , and R 7f’ is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 7b’’ , R 7c’’ , R 7d’’ , and R 7f’’ is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl-OR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl can be one, two, or three R 20b optionally substituted with; R 2a is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 ) are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl can be one, two, or three R 20b optionally substituted with; R 4 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 ) and 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 20d optionally substituted with; 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, 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 ) and 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 substituted with; Each R 6 and R 7 is halogen, oxo, -CN, C 1-6Alkyl, 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 ) are independently selected from 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 26 optionally substituted with; Each R 6’ and R 7’ -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 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)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 ) are independently selected from 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 26 optionally substituted with; 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(R10 ) or C(R 10 )(R 10a ) and; 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 ) and 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 substituted with; 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 ) are independently selected from 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 20i optionally substituted with; or R 9 and R 9a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20i optionally substituted with; 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 ) are independently selected from 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 20j optionally substituted with; or R 10 and R 10a is combined into C 3-6 Cycloalkyl or C 2-9 Forming a heterocycloalkyl, C 3-6 Cycloalkyl and C 2-9 Heterocycloalkyl can have one, two, or three R 20j optionally substituted with; 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-C6-10 Aryl, and C 1-9 heteroaryl; 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 substituted with; Each R 13 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; or R 12 and R 13 may contain one, two, or three R's together with the nitrogen to which they are attached. 20l C optionally substituted with 2-9 forming a heterocycloalkyl ring; Each R 14 is hydrogen, C 1-6 Alkyl, and C 1-6 independently selected from 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, 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 R20m optionally substituted with; Each R 16 -C 1-6 Alkylene-OP(O)(OR 16a )(OR 16b ) and -P(O)(OR 16a )(OR 16b ) independently selected from; C 1-6 Alkylene can be one, two, or three R 20n optionally substituted with; 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; 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 20o optionally substituted with; Each R 20a , R 20b , R 20d , R 20e , R 20f , R 20h , R 20i , R 20j , R 20k , R 20l , R 20m , R 20n , and R 20o is oxo, -CN, 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 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, and C 1-9Heteroaryl is a heteroaryl group consisting of halogen, oxo, -CN, one or more R 26 C optionally substituted with 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 independently selected from 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, C2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 independently selected from 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; Each R 26 is oxo, 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 Ary...

Claims

1. A compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 264】 (In the formula, W １ is C(R １ ) and W ２ is C(R ２ａ ) or N; R １ is C ５－１２ cycloalkyl, 5- to 12-membered heterocycloalkyl, C ６－１２ aryl, and 5- to 12-membered heteroaryl; ５－１２ cycloalkyl, 5- to 12-membered heterocycloalkyl, C ６－１２ Aryl and 5- to 12-membered heteroaryl are R ６ and R ６’ wherein the ring heteroatoms of said 5- to 12-membered heterocycloalkyl and 5- to 12-membered heteroaryl are independently selected from N, O, and S; R ２ａ are independently hydrogen, halogen, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -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 ) and C １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Alkynyl is one, two, or three R ２０ｂ optionally substituted with; R ３ is halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 ) and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｃ optionally substituted with; R ４ is halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 ) and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｄ optionally substituted with; R ５ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 ) and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｅ optionally substituted with; Each R6 is halogen, oxo, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２６ optionally substituted with; Each R6' is -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl, —OR １２ , -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -C(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２６ optionally substituted with; R ９ and R ９ａ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｉ optionally substituted with; or R ９ and R ９ａ are combined to form C ３－６ Cycloalkyl or C ２－９ Form a heterocycloalkyl, ３－６ Cycloalkyl and C ２－９ Heterocycloalkyl can have one, two, or three R ２０ｉ optionally substituted with; R10 is hydrogen, halogen, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｊ optionally substituted with; Each R １２ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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 substituted with; Each R １３ is hydrogen, C １－６ Alkyl, and C １－６ haloalkyl; or R １２ and R １３ may contain one, two, or three R together with the nitrogen to which they are attached. ２０ｌ C optionally substituted with ２－９ forming a heterocycloalkyl ring; Each R １４ is hydrogen, C １－６ Alkyl, and C １－６ independently selected from haloalkyl; Each R １５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｍ optionally substituted with; Each R １６ is -C １－６ Alkylene-OP(O)(OR １６ａ ) (OR １６ｂ ) and -P(O)(OR １６ａ ) (OR １６ｂ ) (wherein the C １－６ Alkylene can be one, two, or three R ２０ｎ optionally substituted with; or -C １－６ Alkylene-OC(O)-R １６ｃ (In the formula, C １－６ Alkylene can be one, two, or three R ２０ｎ independently selected from Each R １６ａ and R １６ｂ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ Cycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, and C １－９ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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 ２０ｏ optionally substituted with; R １６ｃ is halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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, —CH ２ -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 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 ), -OCH ２ C(O)OR ２２ , and -OC(O)R ２５ is selected from C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, —CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Aryl, —CH ２ -C ６－１０ Aryl, —CH ２ -C １－９ Heteroaryl, and C １－９ Heteroaryl is one, two, or three R ２０ｏ optionally substituted with; Each R ２０ｂ , R ２０ｃ , R ２０ｄ , R ２０ｅ , R ２０ｉ , R ２０ｊ , R ２０ｋ , R ２０ｌ , R ２０ｍ , R ２０ｎ , and R ２０ｏ is oxo, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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, —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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, —CH ２ -C ３－１０ 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 a heteroaryl group selected from the group consisting of halogen, oxo, —CN, one or more R ２６ C optionally substituted with 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 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 independently selected from 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 independently selected from 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 ３－１０ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ heteroaryl; Each R ２６ is oxo, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２７ optionally substituted with; Each R ２７ is oxo, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２０ｆ optionally substituted with; Each R 20f is oxo, halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —CH 2 —C 3-10 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, —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 , and are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —CH 2 —C 3-10 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 include 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 ) optionally substituted with 1, 2, or 3 groups independently selected from —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 ).

2. R ４ The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

3. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

4. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

5. R ３ The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein:

6. R １ is C ５－１２ cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl; ５－１２ Cycloalkyl, 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are substituted with one or more substituents independently selected from R6 and R6', and the ring heteroatoms of said 5- to 12-membered partially unsaturated heterocycloalkyl, 6- to 12-membered saturated heterocycloalkyl, and 5- to 12-membered heteroaryl are independently selected from C, N, O, and S; 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. R １ teeth, 【Chemistry 273】 (In the formula, R １ｂ is C(R ６ｂ ) and R １ｄ is C(R ６ｄ ), then R １ｃ is N or N(R ６ｃ’’ )isn't it); 【Chemistry 274】 (In the formula, R １ is not a substituted pyrrolyl); 【Chemistry 275】 (In the formula, R １ is not a substituted imidazolyl, R １ｄ and R １ｅ is N); or R ６ and R ６’ fluoro-substituted pyrazolyl optionally further substituted with 1, 2, or 3 substituents independently selected from R １ｂ is O, S, N, N(R ６ｂ’’ ), C(R ６ｂ ), or C(R ６ｂ ) (R ６ｂ’ ) and R １ｃ is O, S, N, N(R ６ｃ’’ ), C(R ６ｃ ), or C(R ６ｃ ) (R ６ｃ’ ) and R １ｄ is O, S, N, N(R ６ｄ’’ ), C(R ６ｄ ), or C(R ６ｄ ) (R ６ｄ’ ) and R １ｅ is N or C(R ６ｅ ) and R ６ｂ , R ６ｂ’ , R ６ｃ , R ６ｃ’ , R ６ｄ , R ６ｄ’ , and R ６ｅ is hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ The heteroaryl is optionally substituted with 1, 2, or 3 R; R ６ｂ’’ , R ６ｃ’’ , and R ６ｄ’’ is hydrogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ Heteroaryl-OR １２ , -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -C(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ The heteroaryl is optionally substituted with 1, 2, or 3 R; 【Chemical 265】 indicates a single or double bond so that all valences are satisfied, 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

8. R １ teeth, 【Chemistry 283】 and R ６ｂ is halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ 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 C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ The heteroaryl is optionally substituted with 1, 2, or 3 R; z6b is an integer from 0 to 4; 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

9. R １ is R ６ and R ６’ 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, which is pyrazolyl substituted with one or more substituents independently selected from:

10. R ６ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, C １－９ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryl is one, two, or three R ２６ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with:

11. R6 is C １－６ Alkyl, 【Chemistry 290】 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

12. R6 is 【Chemistry 291】 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

13. R6 is 【Chemistry 294】 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

14. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein W 2 is CH, R 9 is hydrogen, R 9a is hydrogen, and R 10 is hydrogen.

15. Structure of formula (IId-1): 【Chemistry 297】 2. The compound of claim 1, having the formula:

16. R １ is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolinyl, pyridinyl, tetrahydropyridinyl, piperidinyl, and piperazinyl, each of which is selected from one or more R ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

17. R １ teeth, 【Chemistry 298】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 18】 【Chemical 401】 【Chemical 402】 【Chemical 403】 【Chemical 404】 【Chemical 405】 【Chemical 406】 【Chemical 407】 【Chemical 408】 【Chemical 409】 【Chemical 410】 【Chemical 411】 【Chemical 412】 【Chemical 413】 【Chemical 414】 【Chemical 415】 【Chemical 416】 or a pharmaceutically acceptable salt or solvate thereof.

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

20. 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

21. 19. A composition for use in a method for enhancing the immunity of a subject in need thereof, said composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, said method comprising: (a) selecting said subject exhibiting PTPN2 and / or PTP1B expression or activity; and (b) downregulating the expression or activity of PTPN2 and / or PTP1B in cells of the subject with the compound, thereby enhancing the immunity of the subject. The composition comprising:

22. The composition described in claim 21, wherein the downregulation of the expression or activity of PTPN2 and / or PTP1B in the cells of the subject is performed before, simultaneously with, or after administration of another drug or therapy to the subject.

23. A composition for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof.

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