Compounds and Methods of Use

Abstract

Compounds of formula (A): Formula (A), and pharma- ceutically acceptable salts thereof, as well as pharmaceutical compositions, processes for preparation, and methods of treatment thereof, are provided, wherein R a , R a’ , ring A, ring B, and R 1 is as defined in any of the embodiments described herein. Provided herein are compounds, as well as compositions and methods thereof. In some embodiments, compounds are provided for inhibiting protein arginine methyltransferase 5 (PRMT5). In some embodiments, methods are provided for treating a disease or disorder, such as cancer. TIFF2025503969000797.tif32165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 303,409, filed January 26, 2022, and U.S. Provisional Application No. 63 / 435,210, filed December 23, 2022, which are incorporated by reference in their entireties herein for all purposes.

[0002] Provided herein are compounds, as well as compositions and methods thereof. In some embodiments, compounds are provided for inhibiting protein arginine methyltransferase 5 (PRMT5). In some embodiments, methods are provided for treating diseases or disorders, such as cancer. [Background technology]

[0003] Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates essential cellular functions, including regulation of cell cycle progression, apoptosis, and DNA damage response (Koh, C. et al., Curr Mol Bio Rep 2015, Wu et al., Nat Rev Drug Discovery 2021). MTAP is a key enzyme in the methionine salvage pathway, a six-step process that recycles methionine from methylthioadenosine (MTA), a product of polyamine synthesis. Loss of MTAP causes accumulation of its substrate, MTA, which has been reported to function as a SAM-competitive PRMT5 inhibitor (Kruykov et al., 2016, Marjon et al., 2016, and Markarov et al., 2016). Data from genome-wide genetic variation screens using shRNAs suggest a selective requirement for PRMT5 activity, especially in MTAP-deficient cancer cell lines (Kruykov et al., 2016; Marjon et al., 2016; Markarov et al., 2016). It is believed that the accumulation of MTA caused by MTAP deletion in these cell lines partially inhibits PRMT5, selectively sensitizing these cells to additional PRMT5 inhibition.

[0004] PRMT5 inhibitors that affect MTA accumulation by binding in an MTA-uncompetitive, non-competitive, or mixed mode manner, or in an MTA-cooperative binding manner, may show selectivity for MTAP-deficient tumor cells. Although several PRMT5 inhibitors are currently being explored for therapeutic use (e.g., cancer treatment), there are currently no such PRMT5 therapies approved by the US Food and Drug Administration that show selectivity for MTAP-deficient cancer cell lines. Thus, there is a need for PRMT5 inhibitors for the treatment of diseases such as cancer. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Koh, C. et al., Curr Mol Bio Rep 2015 [Non-Patent Document 2] Wu et al.,Nat Rev Drug Discovery 2021 Summary of the Invention

[0006] In one embodiment, provided herein is a compound of formula (A), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R 2 but independently, -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)ORa4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 )2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R a and R a ', independently, H, and C 1 -C 6 alkyl, Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b, and -S(=O) 2 N(R b ) 2 and each R b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); m is 0, 1, 2, or 3; (i)R 4 But -CH 3 If R 3 But not H. (ii) The compound is selected from the group consisting of compounds a) to k): a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide: [ka] b) N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide: [ka] c) N1-(6-amino-5,6,7,8-tetrahydroquinolin-3-yl)-N2-(3-fluoro-4-(pyridin-3-yl)benzyl)-N2-methyloxalamide: [ka] d) N1-Cyclopentyl-N1-(3-fluorobenzyl)-N2-(8-fluoroquinolin-3-yl)oxalamide: [ka] e) N1-(4-carbamoylbenzyl)-N2-(8-fluoroquinolin-3-yl)-N1-methyloxalamide: [ka] f) N1-benzyl-N1-methyl-N2-(quinolin-3-yl)oxalamide: [ka] g) N1-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-N2-(5-((dimethylamino)methyl)pyridin-3-yl)-N1-methyloxalamide: [ka] h) N1-(4-bromo-2-(3-chlorophenoxy)benzyl)-N2-(5-bromo-2-(4-methylpiperazin-1-yl)pyridin-3-yl)-N1-methyloxalamide: [ka] i) Methyl 4-((N-methyl-2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)acetamido)methyl)benzoate: [ka] j) N1-methyl-N1-(2-methylbenzyl)-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] k) N1-(furan-2-ylmethyl)-N1-methyl-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] or a pharma- ceutically acceptable salt thereof, which is not one of:

[0007] In one embodiment, a pharmaceutical composition is provided comprising a compound of Formula (A) as defined in any of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

[0008] In one embodiment, there is provided a method of treating an MTAP deficiency and / or MTA storage disorder in a subject in need thereof by administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (A) as defined in any of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition thereof. In some embodiments, the compound or composition is administered in combination with a second therapeutic agent.

[0009] In one embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from a subject, where MTA levels can be assessed directly (e.g., by ELISA or LC-MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample to a reference, wherein MTAP loss and / or MTA accumulation in the test sample compared to the reference indicates that the subject's cancer will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering to the subject identified in step b) an effective amount (e.g., a therapeutically effective amount) of a compound of formula (A) as defined in any of the embodiments described herein, or a pharmaceutical composition thereof.

[0010] In one embodiment, there is provided the use of a compound of formula (A) as defined in any of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition as described herein, for treating an MTAP deficiency and / or MTA storage disease in a subject in need thereof. In one embodiment, the compound or composition is configured to be administered in combination with a second therapeutic agent.

[0011] In one embodiment, there is provided a compound of formula (A) as defined in any of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition as described herein, for treating an MTAP deficiency and / or MTA storage disease in a subject in need thereof. In one embodiment, the compound or composition is configured to be administered in combination with a second therapeutic agent.

[0012] In one embodiment, there is provided the use of a compound of formula (A), or a pharma- ceutically acceptable salt thereof, as defined in any of the embodiments described herein, or a pharma- ceutical composition as described herein, in the manufacture of a medicament for treating an MTAP deficiency and / or an MTA storage disease in a subject in need thereof. In one embodiment, the medicament is configured to be administered in combination with a second therapeutic agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The disclosure herein presents example methods, parameters, etc., however, it should be recognized that such description is not intended as a limitation on the scope of the disclosure, but instead is provided as a description of example embodiments.

[0014] As generally described herein, provided are compounds (e.g., a compound of Formula (A), or a compound of Table 1, or a pharma- ceutically acceptable salt thereof) that are MTA-uncompetitive PRMT5 inhibitors useful for treating proliferative disorders associated with MTAP deficiency and / or MTA accumulation (e.g., cancer).

[0015] In some embodiments, compounds (e.g., a compound of Formula (A), or a compound of Table 1, or a pharma- ceutical acceptable salt thereof) are provided that are MTA uncompetitive, noncompetitive, or mixed mode PRMT5 inhibitors, or MTA cooperative binders useful for treating proliferative diseases associated with MTAP deficiency and / or MTA accumulation (e.g., cancer).

[0016] definition As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below, unless expressly indicated otherwise or the context in which they are used indicates otherwise.

[0017] MTAP "MTAP" as used herein refers to the enzyme methylthioadenosine phosphorylase of the methionine salvage pathway, also known as S-methyl-5'-thioadenosine phosphorylase, also known as BDMF, DMSFH, DMSMFH, LGMBF, MSAP, and c86fus. External ID: OMIM:156540 MGI:1914152 HomoloGene:1838 chEMBL:4941 GeneCards:MTAP gene; Entrez 4507; RefSeq(mRNA):NM_002451; Location: Chr 9:21.8-21.93 Mb. By "wild type" MTAP we mean either encoded by NM_002451 or having the same amino acid sequence (NP_002442). (Schmid et al. Oncogene 2000,19,pp5747-54). As used herein, the terms "MTAP deficient," "MTAP deficiency," "MTAP-null," and the like refer to cells (including, but not limited to, cancer cells, cell lines, tissues, tissue types, tumors, etc.) that have significantly reduced post-translational modification, production, expression, levels, stability, and / or activity of MTAP compared to that in a control, e.g., a reference or normal or non-cancerous cell. The reduction can be at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the reduction is at least 20%. In some embodiments, the reduction is at least 50%. The terms "MTAP-deficient and / or MTA accumulating", "MTAP-deficient and / or MTA-accumulating", "MTAP-deficient and / or MTA upregulation" and the like, with respect to a cell(s) and the like, indicate that either the cell(s) and the like are deficient in MTAP and / or overproduce or accumulate MTA. MTAP-deficient cells include cells in which the MTAP gene is mutated, deleted, or transcriptionally silenced. As a non-limiting example, MTAP-deficient cells can have a homozygous deletion. MTAP knockdown is not lethal. In some embodiments, MTAP-deficient cells are also CDKN2A-deficient. MTAP deficiencies can be detected using any reagent or technique known in the art, such as immunohistochemistry using antibodies against MTAP, and / or genomic sequencing, and / or nucleic acid hybridization and / or amplification using at least one probe or primer comprising at least 12 contiguous nucleotides (nt) of the MTAP sequence (the primer is about 30 nt or less).

[0018] An "MTAP deficiency-related" or "MTAP-deficiency" or "MTAP deficient" disease (e.g., a proliferative disease, e.g., cancer) or a disease "associated with MTAP deficiency" (e.g., a proliferative disease, e.g., cancer) or a disease "characterized by MTAP deficiency" (e.g., a proliferative disease, e.g., cancer) or the like refers to a disease (e.g., a proliferative disease, e.g., cancer) in which a significant number of cells are MTAP deficient. For example, in an MTAP deficiency-associated disease, one or more diseased cells may have significantly reduced post-translational modification, production, expression, levels, stability and / or activity of MTAP. Examples of MTAP deficiency-associated diseases include, but are not limited to, cancers including, but not limited to, glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct sarcoma, brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon cancer or sarcoma (see FIG. 1). In patients affected by MTAP deficiency-associated diseases, some diseased cells (e.g., cancer cells) may be MTAP deficient, while other cells may not be. Similarly, some diseased cells may have MTA accumulation, whereas others do not. Thus, the present disclosure encompasses methods of treatment involving diseases of these tissues, or any other tissue, in which proliferation of MTAP-deficient and / or MTA-accumulating cells can be inhibited by administration of a PRMT5 inhibitor. Some cancer cells that are MTAP-deficient are also deficient in CDKN2A, and these cells have reduced post-translational modification, production, expression, levels, stability and / or activity of the CDKN2A gene or its product. The genes for MTAP and CDKN2A are in close proximity on chromosome 9p21, with MTAP located approximately 100 kb telomeric to CDKN2A. Many cancer cell types have CDKN2A / MTAP loss (loss of both genes). Thus, in some embodiments, MTAP-deficient cells are also deficient in CDKN2A.

[0019] MTA and MTA accumulation "MTA" refers to a PRMT5 inhibitor also known as methyl-thioadenosine, S-methyl-5'-thioadenosine, [5'deoxy-5'-(methylthio)-fl-D-ribofuranosyl]adenine, 5'-methyl-thioadenosine, 5'-deoxy, 5'-methylthioadenosine, and the like. MTA selectively inhibits PRMT5 methyltransferase activity. MTA is the only known catabolic substrate of MTAP. Terms such as "MTA accumulation," "MTA overproduction," "MTA upregulation," and the like refer to cells (including, but not limited to, cancer cells, cell lines, tissues, tissue types, tumors, and the like) that have a significant increase in the production, levels, and / or stability of MTA. MTA-accumulating cells include cells whose cells comprise at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher production, level, and / or stability of MTA than that of normal or non-cancerous cells. In some embodiments, MTA-accumulating cells include cells whose cells comprise at least 20% higher production, level, and / or stability of MTA than that of normal or non-cancerous cells. In some embodiments, MTA-accumulating cells include cells whose cells comprise at least 50% higher production, level, and / or stability of MTA than that of normal or non-cancerous cells. Determination of MTA accumulation in a test sample (e.g., a cell, such as a cancer cell, to be tested for MTA accumulation) and a reference sample, as well as other cells, tissues, samples, and the like, may be performed using any method known in the art. Such methods for detecting MTA include, by way of non-limiting example, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS / MS) as described in Stevens et al. J. Chromatogr. A. 2010, 1217, pp 3282-3288, and Kirovski et al. Am. J. Pathol. 2011, 178, pp 1145-1152, and references cited therein.Loss of MTAP is associated with accumulation of MTA (Williams-Ashman et al. Biochem. Pharm. 1982, 31, pp277-288, and Limm et al. Eur. J. Cancer. 2013, 49, Issue 6.

[0020] "MTA accumulation-related", "MTA-accumulation", "MTA-accumulating", "MTA overproduction", "MTA upregulation" disease (e.g., a proliferative disease, e.g., cancer) or a disease "associated with MTA accumulation" (e.g., a proliferative disease, e.g., cancer) or a disease "characterized by MTA accumulation" (e.g., a proliferative disease, e.g., cancer) and the like refer to a disease (e.g., a proliferative disease, e.g., cancer) in which a significant number of cells have MTA accumulation. Examples of MTA accumulation diseases include, but are not limited to, cancers including, but not limited to, glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct sarcoma, brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon cancer or sarcoma (see FIG. 1). In patients affected by MTAP deficiency-associated diseases, some diseased cells (e.g., cancer cells) may be MTAP-deficient while other cells may not be. In a patient who has or has been diagnosed with an MTA storage disease, some cells may have MTA accumulation, while other cells do not.

[0021] The increased therapeutic window between normal cells and MTAP-deficient / MTA-accumulating cells can be achieved by using inhibitors that bind PRMT5 uncompetitively with MTA. As used herein, "uncompetitive binding" and "uncompetitive inhibition" and "cooperative binding" and "cooperative inhibition" (e.g., MTA uncompetitive binding, MTA uncompetitive inhibition, MTA cooperative binding, MTA cooperative inhibition) refer to binding of an inhibitor to a protein (e.g., PRMT5) that is increased in the presence of a cofactor (e.g., MTA) over the binding of the same inhibitor in the absence of the cofactor. PRMT5 inhibitors known in the art are generally either SAM (S-adenosylmethionine) uncompetitive or SAM-competitive. Because the concentrations of SAM in wild-type and MTAP-null cells are similar, these inhibitors are expected to bind with similar potency to both cell types. In contrast, MTA-cooperative (and either SAM-competitive or exhibiting enhanced cooperativity with MTA compared to SAM) inhibitors bind significantly more potently in the presence of high concentrations of MTA, thus resulting in selective inhibition of PRMT5 in MTA-accumulating cells compared to normal cells.

[0022] As further described herein, cancer cells, cancer types, or subjects having cancer may be described as "PRMT5 inhibitor sensitive," "sensitive to treatment with a PRMT5 inhibitor," "sensitive to PRMT5 therapeutic inhibition," or similar terms if they are amenable to treatment with a PRMT5 inhibitor, e.g., due to their MTAP deficiency and / or MTA accumulation characteristics.

[0023] PRMT5 "PRMT5" as used herein is the protein arginine methyltransferase 5 gene or protein, also known as HRMT1L5, IBP72, JBP1, SKB1, or SKB1Hs. External ID: OMIM: 604045, MGI:1351645, HomoloGene:4454, ChEMBL:1795116, GeneCards:PRMT5 gene; EC number 2.1.1.125. Ensembl ENSG00000100462; UniProt O14744; Entrez Gene ID:10419; RefSeq(mRNA):NM_001039619. The mouse homolog is NM_013768. Methyltransferases such as PRMT5 catalyze the transfer of one to three methyl groups from the cofactor S-adenosylmethionine (also known as SAM or AdoMet) to lysine or arginine residues of histone proteins. Arginine methylation is carried out by nine different protein arginine methyltransferases (PRMTs) in humans. Three types of methylarginine species exist: (1) monomethylarginine (MMA), (2) asymmetric dimethylarginine (ADMA), generated by type I methyltransferases (PRMT1, PRMT2, PRMT3, CARM1, PRMT6, and PRMT8), and (3) symmetric dimethylarginine (SDMA), generated by type II methyltransferases (PRMT5 and PRMT7). PRMT1 and PRMT5 are the major asymmetric and symmetric arginine methyltransferases, respectively. PRMT5 promotes symmetric dimethylation of histones at H3R8 and H4R3 (H4R3me2). Symmetric methylation of H4R3 is associated with transcriptional repression and may serve as a binding site for DNMT3A. PRMT5 loss results in decreased DNMT3A binding and gene activity. The tumor suppressor gene ST7 and chemokines RNATES, IP10, and CXCL11 are targeted and silenced by PRMT5. WO2011 / 079236.

[0024] Additional substrates include E2F1, p53, EGFR and CRAF. PRMT5 is part of a multiprotein complex that includes the coregulator WDR77 (also known as MEP50, a CDK4 substrate) during the G1 / S transition. Phosphorylation increases PRMT5 / WDR77 activity. WDR77 is a non-catalytic component of the complex and mediates interactions with binding partners and substrates. PRMT5 may also interact with pICIn or RioK1 adaptor proteins in a mutually exclusive manner, regulating complex composition and substrate specificity.

[0025] PRMT5, when interacting with several complexes, can affect its substrates either positively or negatively by arginine methylation and is involved in various cellular processes, including RNA processing, signal transduction, transcriptional regulation, and germ cell development. PRMT5 is a major pro-survival factor that regulates eIF4E expression and p53 translation. PRMT5 induces p53-dependent apoptosis and sensitizes various cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) without affecting the TRAIL resistance of non-transformed cells.

[0026] The term "PRMT5 inhibitor" refers to any compound that can inhibit the production, level, activity, expression or existence of PRMT5. These include, as non-limiting examples, any compound that inhibits gene transcription, RNA maturation, mRNA translation, protein post-translational modification, protein enzymatic activity, protein-substrate interaction, etc. The term also refers to any agent that inhibits the cellular function of PRMT5 protein, either by ATP competitive inhibition of active site, allosteric regulation of protein structure, disruption of protein-protein interaction, or by inhibiting the transcription, translation, post-translational modification, or stability of PRMT5 protein.

[0027] In some embodiments, a PRMT5 inhibitor interacts with PRMT5 and competes with another compound, protein, or other molecule required for PRMT5 function. As a non-limiting example, a PRMT5 inhibitor may compete with the cofactor S-adenosylmethionine (also known as SAM or AdoMet). In some embodiments, the PRMT5 inhibitor does not compete with MTA. In some embodiments, the PRMT5 inhibitor does not compete with MTA and competes with SAM. In some embodiments, the PRMT5 inhibitor does not compete with MTA and does not compete with SAM, but binds with higher potency to the MTA complex compared to the SAM complex.

[0028] chemical definition Definitions of certain functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Ed., 1999; th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0029] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present specification further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0030] "Enantiomeric excess" ("ee") or "% enantiomeric excess" ("% ee") of a composition, as used herein, refers to the excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee=(90-10) / 100=80%.

[0031] Thus, a composition that contains 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0032] "Diastereomeric excess" ("de") or "% diastereomeric excess" ("% de") of a composition, as used herein, refers to the excess of one diastereomer over one or more different diastereomers present in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers. de=(90-10) / 100=80%.

[0033] Thus, a composition that contains 90% of one diastereomer and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%. In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon, e.g. 13 C or 14 C, and oxygen can be, for example, 18 O, and nitrogen can be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) may represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element occupying a particular site on a compound.

[0034] During the ceremony, [ka] is a single bond that does not specify the stereochemistry of the moiety directly attached to it. When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included. The following terms are intended to have the meanings presented below with them and are useful in understanding the description and intended scope of the present invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within their scope as set forth below. Unless otherwise indicated, the term "substituted" is defined as set forth below. It should further be understood that the terms "group" and "radical" may be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0035] The term "unsaturated bond" refers to a double bond or a triple bond.

[0036] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0037] The term "saturated" refers to a moiety that does not contain any double or triple bonds, ie, that contains only single bonds. The addition of the suffix "-ene" indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of an alkyl, alkenylene is a divalent moiety of an alkenyl, alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, heteroalkenylene is a divalent moiety of a heteroalkenyl, heteroalkynylene is a divalent moiety of a heteroalkynyl, carbocyclylene is a divalent moiety of a carbocyclyl, heterocyclylene is a divalent moiety of a heterocyclyl, arylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl.

[0038] The term "azide" refers to the radical -N 3 Refers to... "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein. "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0039] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group (e.g., a 3- to 10-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, S, and oxidized forms thereof). In some embodiments, a heterocyclylalkyl is a C 1-2 Alkyl-heterocyclyl (e.g., -CH 2 -heterocyclyl, -CH 2 CH 2 -heterocyclyl, -CH(CH 3 In some embodiments, heterocyclylalkyl is -CH 2Exemplary heterocyclylalkyl groups include, but are not limited to, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. "Aralkyl" or "arylalkyl" is a subset of alkyl and aryl, as defined herein, and refers to an aryl group (e.g., C 6 -C 10 In some embodiments, arylalkyl refers to an alkyl group substituted with a C 1-2 Alkyl-aryl (e.g., -CH 2 -aryl, -CH 2 CH 2 -aryl, -CH(CH 3 In some embodiments, arylalkyl is -CH 2 -aryl (e.g., -CH 2 -phenyl, -CH 2 -naphthyl). "Alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 Alkyl" or "C 1 -C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom (C 1 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 "Alkyl"). C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g., -CH 3In certain embodiments, the alkyl group is a substituted C 1-10 It is an alkyl group. A common abbreviation for alkyl is Me(-CH 3 ), Et(-CH 2 CH 3 ), i Pr(-CH(CH 3 ) 2 ), n Pr(-CH 2 CH 2 CH 3 ), n Bu(-CH 2 CH 2 CH 2 CH 3 ),or i Bu(-CH 2 CH(CH 3 ) 2 ) are mentioned.

[0040] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2-), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. The alkylene group may be substituted or unsubstituted with one or more substituents described herein.

[0041] "Alkenyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 Alkenyl refers to the radical of a straight or branched chain hydrocarbon group having from 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C 2 The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0042] "Alkynyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 "Alkynyl" refers to the radical of a straight or branched chain hydrocarbon group having from 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C 2The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). 2-4 Examples of alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) and others. C 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 Unless otherwise specified, each instance of alkynyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0043] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1 - 6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC 1 In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 Exemplary heteroalkyl groups include -CH 2 OH, -CH 2 OCH 3 , -CH2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 Examples include:

[0044] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (see "C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C 6 In some embodiments, an aryl group has 10 ring carbon atoms (e.g., "C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0045] In certain embodiments, the aryl group is halo, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, cyano, hydroxy, C 1 -C 8 It is substituted with one or more groups selected from alkoxy and amino.

[0046] Representative examples of substituted aryl include the following: [ka] R 56 and R 57 may be hydrogen, and R 56 and R 57 At least one of each independently represents C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58SOR 59 NR 58 SO 2 R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , S.O. 2 NR 58 R 59 , S-alkyl, SO alkyl, SO 2 Alkyl, S aryl, SO aryl, SO 2 aryl, or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. 60 and R 61 are independently hydrogen, C 1 -C 8 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, Substituted C 6 -C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl. A "fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0047] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), with ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, depending on valence. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, with the point of attachment being on the heteroaryl ring, in which case, unless otherwise specified, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, in which case the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0048] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl. In some embodiments, the heteroaryl group is a bicyclic 8- to 12-membered aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("8- to 12-membered bicyclic heteroaryl"). In some embodiments, the heteroaryl group is an 8-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (an "8-10 membered bicyclic heteroaryl").In some embodiments, the heteroaryl group is a 9-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("9-10 membered bicyclic heteroaryl"). Unless otherwise specified, each heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0049] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0050] Representative examples of heteroaryl include: [ka] where each Z is carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl.

[0051] In the structures described herein, it is understood that a substituent attached to a polycyclic (e.g., bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl, or heteroaryl having bonds across two or more rings means that the substituent may be attached at any position on each of the rings.

[0052] "Heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group (e.g., a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from O, N, and S, as well as oxidized forms thereof) where the point of attachment is on the alkyl portion. In some embodiments, a heteroarylalkyl is a C 1-2 Alkyl-heteroaryl (e.g., -CH 2 -heteroaryl, -CH 2 CH 2 -heteroaryl, -CH(CH 3 In some embodiments, heteroarylalkyl is -CH 2 Exemplary heteroarylalkyl groups include, but are not limited to, pyridinylmethyl, pyrimidinylmethyl, furanylmethyl, thiophenylmethyl, pyrrolylmethyl, pyrazolylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyridinylethyl, pyrimidinylethyl, furanylethyl, thiophenylethyl, pyrrolylethyl, pyrazolylethyl, imidazolylethyl, thiazolylethyl, oxazolylethyl, thiazolylethyl, and the like.

[0053] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyl) and partially saturated ring systems. In some embodiments, carbocyclyl groups have from 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and others. 3-8 The carbocyclyl group may be any of the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and others. 3-10 The carbocyclyl group may be any of the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) etc.

[0054] As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") systems, etc.), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in which case the number of carbons continues to designate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0055] As used herein, the term "cycloalkyl" refers to a group having the indicated number of rings and carbon atoms (e.g., C 3 -C 14 Monocyclic, C 4 -C 14 Bicyclic, C 5 -C 14 Tricyclic, or C 6 -C 14 In some embodiments, a "cycloalkyl" is a monocyclic cycloalkyl. In some embodiments, a monocyclic cycloalkyl has 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a monocyclic cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Monocyclic cycloalkyl. 5-6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ) are listed. C 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) are listed. C 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ) are mentioned.

[0056] In some embodiments, a "cycloalkyl" is a bicyclic cycloalkyl. In some embodiments, a bicyclic cycloalkyl has 4 to 14 ring carbon atoms ("C 4-14 In some embodiments, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms ("C 4-12 In some embodiments, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms ("C 4-10 In some embodiments, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 In some embodiments, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms ("C 6-10 In some embodiments, a bicyclic cycloalkyl group has 8 to 10 ring carbon atoms ("C 8-10 In some embodiments, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms ("C 7-9 An example of a bicyclic cycloalkyl is bicyclo[1.1.0]butane (C 4 ), bicyclo[1.1.1]pentane (C 5 ), spiro[2.2]pentane (C 5 ), bicyclo[2.1.0]pentane (C 5 ), bicyclo[2.1.1]hexane (C 6 ), bicyclo[3.1.0]hexane (C 6 ), spiro[2.3]hexane (C 6 ), bicyclo[2.2.1]heptane(norbornane)(C 7 ), bicyclo[3.2.0]heptane (C 7 ), bicyclo[3.1.1]heptane (C 7 ), bicyclo[3.1.1]heptane (C 7), bicyclo[4.1.0]heptane (C 7 ), spiro[2.4]heptane (C 7 ), spiro[3.3]heptane (C 7 ), bicyclo[2.2.2]octane (C 8 ), bicyclo[4.1.1]octane (C 8 ), Octahydropentalene (C 8 ), bicyclo[3.2.1]octane (C 8 ), bicyclo[4.2.0]octane (C 8 ), spiro[2.5]octane (C 8 ), spiro[3.4]octane (C 8 ), bicyclo[3.3.1]nonane (C 9 ), octahydro-1H-indene (C 9 ), bicyclo[4.2.1]nonane (C 9 ), spiro[3.5]nonane (C 9 ), spiro[4.4]nonane (C 9 ), bicyclo[3.3.2]decane (C 10 ), bicyclo[4.3.1]decane (C 10 ), spiro[4.5]decane (C 10 ), bicyclo[3.3.3]undecane (C 11 ), decahydronaphthalene (C 10 ), bicyclo[4.3.2]undecane (C 11 ), spiro[5.5]undecane (C 11 ) and bicyclo[4.3.3]dodecane (C 12 ) are mentioned. In some embodiments, a "cycloalkyl" is a tricyclic cycloalkyl. In some embodiments, a tricyclic cycloalkyl has 6 to 14 ring carbon atoms ("C 6-14 In some embodiments, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms ("C 8-12 In some embodiments, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms ("C 10-12 An example of a tricyclic cycloalkyl is adamantine (C 12) are mentioned.

[0057] Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0058] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ("3- to 10-membered heterocyclyl"), each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, a heterocyclyl is a 3- to 10-membered non-aromatic ring system having 1, 2, or 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, including ring carbon atoms and oxidized forms thereof. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, depending on valence. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0059] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ("5- to 10-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ("5- to 8-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ("5- to 6-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0060] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. C 6Exemplary 5-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepin ... 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine, such as N-methylpiperazine. Particular examples include azetidine, piperidone, and piperazone.

[0061] "Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero may apply to any of the hydrocarbyl groups described above having 1 to 5, especially 1 to 3, heteroatoms, such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, etc.

[0062] "Acyl" means the radical -C(=O)R 20 R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is an acyl group, R 20 is a group other than hydrogen. Representative acyl groups are formyl (-CHO), acetyl (-C(=O)CH 3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH 2 Ph), --C(=O)-C 1 -C 8 Alkyl, -C(=O)-(CH 2 ) t(C 6 -C 10 aryl), -C(=O)-(CH 2 ) t (5-10 membered heteroaryl), -C(=O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -C(=O)-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is a halo or hydroxy substituted C 1 -C 8 Alkyl, or C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl, or unsubstituted C 1 -C 4 It is substituted with haloalkoxy or hydroxy.

[0063] The term aminoalkyl refers to a group in which one or more of the hydrogen atoms are independently replaced by -NH 2 It refers to a substituted alkyl group that is substituted by a group.

[0064] The term hydroxyalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with an --OH group.

[0065] The terms "alkylamino" and "dialkylamino" refer to -NH(alkyl) and -N(alkyl), respectively. 2In some embodiments, alkylamino refers to the α-NH(C 1 -C 4 In some embodiments, the alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, iso-butylamino, sec-butylamino, or tert-butylamino. In some embodiments, the dialkylamino is -N(C 1 -C 6 Alkyl) 2 In some embodiments, dialkylamino is dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, or methyltertbutylamino.

[0066] The term "aryloxy" refers to an -O-aryl radical. In some embodiments, the aryloxy group is phenoxy.

[0067] The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkoxy" includes haloalkoxy groups where the halo is fluorine. In some embodiments, the haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0068] "Alkoxy" refers to the group -OR 29 R 29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., those having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms. In certain embodiments, R 29 is amino, substituted amino, C 6 -C 10 Aryl, aryloxy, carboxyl, cyano, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent selected from the group consisting of: -. Exemplary "substituted alkoxy" groups include -O-(CH 2 ) t (C 6 -C 10 Aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group is present, which itself is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyl, or unsubstituted C 1 -C 4 It may be substituted by haloalkoxy or hydroxy. A specific exemplary "substituted alkoxy" group is -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -Cyclopropyl, -OCH 2 CH 2 OH and -OCH 2 CH 2 N(CH 3 ) 2 It is.

[0069] "Amino" is the radical -NH 2 Refers to...

[0070] An "oxo group" refers to -C(=O)-.

[0071] "Substituted amino" refers to a group of the formula -N(R 38 ) 2 R refers to the amino group of 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 8 Alkenyl, C 3 -C 8 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3-C 10 Cycloalkyl, or halo- or hydroxy-substituted C 1 -C 8 Alkyl, halo or hydroxy substituted C 3 -C 8 Alkenyl, halo or hydroxy substituted C 3 -C 8 Alkynyl, or -(CH 2 ) t (C 6 -C 10 Aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C 10 cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl), t is an integer of 0 to 8, each of which is selected from unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroalkyl, or unsubstituted C 1 -C 4 substituted by haloalkoxy or hydroxy, or R 38 The groups are linked to form an alkylene group.

[0072] Exemplary "substituted amino" groups include -NR 39 -C 1 -C 8 Alkyl, -NR 39 -(CH 2 ) t (C 6 -C 10 Aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C3 -C 10 cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1 -C 8 represents an alkyl group, where any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl, or unsubstituted C 1 -C 4 It may be substituted by haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0073] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa, -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -C 1 - 10 Alkyl (e.g., aralkyl, heteroaralkyl), -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. R aa Each instance of is independently -C 1-10 Alkyl, -C 1-10 Perhaloalkyl, -C2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O)(N(R cc ) 2 ) 2, -C 1-10 Alkyl, -C 1-10 Perhaloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with X - is the counter ion, R cc Each instance of is independently hydrogen, -C 1-10 Alkyl, -C 1-10 Perhaloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each instance of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3H、-OH、-OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 、-N(R ff ) 3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO 2 H、-CO 2 R ee 、-OC(=O)R ee 、-OCO 2 R ee 、-C(=O)N(R ff ) 2 、-OC(=O)N(R ff ) 2 、-NR ff C(=O)R ee 、-NR ff CO 2 R ee 、-NR ff C(=O)N(R ff ) 2 、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff ) 2 、-OC(=NR ff )N(R ff ) 2 、-NR ff C(=NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee ) 2 , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 ,-OP(=O)(OR ee ) 2 , -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents can be linked to form =O or =S, and X - is the counter ion, R ee Each instance of is independently -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkynyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff Each instance of is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkynyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg Each instance of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 3 + X - , -NH(C 1-6 Alkyl) 2 + X - , -NH 2 (C 1-6Alkyl) + X - , -NH 3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 Alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 Alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 Alkyl) 2 , -NHC(=NH)NH2 , -NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl) 2 , -SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 , -SO 2 C 1-6 Alkyl, -SO 2 O.C. 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl) 3 , -OSi(C 1-6 Alkyl) 3 -C(=S)N(C 1-6 Alkyl) 2 , -C(=S)NH(C 1-6 alkyl), -C(=S)NH 2 , -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 Alkyl) 2 , -P(=O)(C 1-6 Alkyl) 2 , -OP(=O)(C 1-6 Alkyl) 2 , -OP(=O)(OC 1-6 Alkyl) 2 , -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, where X- is the counter ion.

[0074] For example, an amide group (e.g., -C(=O)R aa Nitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0075] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl Teoc, 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, Bamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-Dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzene carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclo carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate Bamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,These include, but are not limited to, 6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0076] Sulfonamide groups (e.g., -S(=O) 2 R aa Nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclo. Pentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrolin-3 -yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethyl Thiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(penta-acylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0077] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2, -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , and -P(=O)(N(R bb ) 2 ) 2 These include, but are not limited to, R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0078] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, and 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl )methyl, 3-(imidazol)-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethyl isopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate acetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p -Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- These include, but are not limited to, (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0079] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 Raa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , and -P(=O)(N(R bb ) 2 ) 2 These include, but are not limited to, R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0080] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate. In certain embodiments, the leaving group is halogen, alkanesulfonyloxy, arenesulfonyloxy, diazonium, alkyldiazene, aryldiazene, alkyltriazene, aryltriazene, nitro, alkylnitrate, arylnitrate, alkylphosphate, arylphosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxyammonia, alkylamine, arylamine, hydroxyl group, alkyloxy group, or aryloxy. In some cases, the leaving group is toluenesulfonate (tosylate, -OT), methanesulfonate (mesylate, -OM), p-bromobenzenesulfonyloxy (brosylate, -OB), -OS(=O) 2 (CF 2 ) 3 CF 3(nonaflate, -ONf), or a sulfonate ester such as trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0081] "Carboxy" refers to the radical -C(=O)OH.

[0082] "Cyano" refers to the radical -CN.

[0083] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0084] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl (-CF 3 ), difluoromethyl (-CHF 2 ), fluoromethyl (-CH 2 F), chloromethyl (-CH 2 Cl), dichloromethyl (-CHCl 2 ), tribromomethyl (-CH 2 Br), but are not limited to these.

[0085] "Hydroxy" refers to the radical -OH.

[0086] "Nitro" is the radical -NO2 Refers to...

[0087] "Thioketo" refers to the group ═S.

[0088] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous change, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein that result in the formation of a stable compound. Any and all such combinations are contemplated to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0089] Exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb) 2 、-N(R bb ) 3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R aa 、-NR bb C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-OC(=NR bb )N(R bb ) 2 、-NR bb C(=NR bb )N(R bb ) 2 、-C(=O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 Raa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)R aa 、-S(=O)(=NR bb )R aa 、-OS(=O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 -C(=S)N(R bb ) 2 、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(R bb ) 2 、-P(=O)(NR bb ) 2 、-OP(=O)(NR bb ) 2 、-NR bb P(=O)(OR cc ) 2 、-NR bb P(=O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc )3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups or the two geminal hydrogens on the carbon atom are ═O, ═S, ═NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of is independently -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently hydrogen, -OH, -ORaa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc Each instance of is independently hydrogen, -C 1-10 Alkyl, -C1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, Each R dd are independently halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff ) OR ee , -OC(=NRff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 ,-OP(=O)(OR ee ) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R ggor two geminal R dd the substituents may be linked to form =O or =S; R ee Each instance of is independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff Each instance of is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg Each instance of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 3 + X - , -NH(C 1-6 Alkyl)2 + X - , -NH 2 (C 1-6 Alkyl) + X - , -NH 3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 Alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 Alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2 , -NHC(NH)N(C 1-6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl) 2 , -SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 , -SO 2 C 1-6 Alkyl, -SO 2 O.C. 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl) 3 , -OSi(C 1-6 Alkyl) 3 -C(=S)N(C 1-6 Alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 Alkyl) 2 , -OP(=O)(C 1-6 Alkyl) 2 , -OP(=O)(OC 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, where X -is the counter ion.

[0090] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HSO 4 - , S.O. 4 -2 Examples of the cations include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.). Nitrogen atoms may be substituted or unsubstituted depending on the valence, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR. aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(Rcc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R cc the groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc , and R dd is as defined above. These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary recitation of substituents.

[0091] Other definitions As used herein, the term "salts" refers to any and all salts, including pharma- ceutically acceptable salts.

[0092] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lauryl sulfate, glycerol ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-butyl esters. + (C 1-4 Alkyl) 4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, and the like.

[0093] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0094] Disease, disorder, and condition are used interchangeably herein.

[0095] As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate actions that occur while a subject is suffering from a specified disease, disorder or condition and reduce the severity of the disease, disorder or condition or slow or slow the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from a specified disease, disorder or condition ("prophylactic treatment"). In one embodiment, it is contemplated that the compounds provided herein are used in therapeutic treatment methods in which the actions occur while a subject is suffering from a particular disease, disorder or condition, resulting in a reduction in the severity of the disease, disorder or condition, or a slow or slow progression of the disease, disorder or condition. In an alternative embodiment, it is contemplated that the compounds provided herein are used in prophylactic treatment methods in which the actions occur before a subject begins to suffer from a particular disease, disorder or condition, resulting in the prevention of a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or the prevention of the recurrence of the disease, disorder or condition.

[0096] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, such as treating a disease or disorder described herein. As will be appreciated by those skilled in the art, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the age, health, and condition of the subject. An effective amount includes therapeutic and prophylactic treatments (i.e., includes a "therapeutically effective amount" and a "prophylactically effective amount").

[0097] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit to the therapeutic treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit to the therapeutic treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids symptoms or pathogenesis of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0098] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0099] compound Provided herein is a compound of formula (A). Unless the context otherwise requires, references throughout the specification to a "compound of formula (A)" or a "compound of formula (A)" include, for example, formula (A), formula (I), formula (I_1), formula (I_1a), formula (I_1b), formula (I_1c), formula (I_2), formula (I_2a), formula (I_3), formula (I_3a), formula (I_4), formula (I_4a), formula (I_4b), formula (I_5), formula (I_5a), formula (I_5b), formula (I_5c), formula (I_5d), formula (II), formula (II_1), formula (II_2), formula (III), formula (III_1), formula (IV), formula (V), formula (VI). , refers to all embodiments of Formula (A), including compounds of Formula (A_1), Formula (A_1a), Formula (A_1b), Formula (A_1c), Formula (A_2), Formula (A_2a), Formula (A_3), Formula (A_3a), Formula (A_4), Formula (A_4a), Formula (A_4b), Formula (A_5), Formula (A_5a), Formula (A_5b), Formula (A_5c), Formula (A_5d), Formula (A-II), Formula (A-II_1), Formula (A-II_2), Formula (A-III), Formula (A-III_1), Formula (A-IV), Formula (AV), Formula (A-VI) (i.e., Formulas (A)-Formula (A-VI)), as well as compounds of Table 1.

[0100] In one embodiment, the present invention provides a compound of formula (A), and pharma- ceutically acceptable salts thereof. In one embodiment, the present invention provides a compound of formula (A) as a free base. In one embodiment, the present invention provides a compound of formula (A) as a pharma- ceutically acceptable salt.

[0101] In one embodiment, provided herein is a compound of formula (A), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R 2 but independently, -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2, -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O)2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(Ra6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R a and R a ', independently, H, and C 1 -C 6 alkyl, Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b , and -S(=O) 2 N(R b ) 2 Each R is selected from the group consisting of b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); m is 0, 1, 2, or 3; (i)R 4 But -CH 3 If R 3 But not H. (ii) The compound is selected from the group consisting of compounds a) to k): a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide: [ka] b) N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide: [ka] c) N1-(6-amino-5,6,7,8-tetrahydroquinolin-3-yl)-N2-(3-fluoro-4-(pyridin-3-yl)benzyl)-N2-methyloxalamide: [ka] d) N1-Cyclopentyl-N1-(3-fluorobenzyl)-N2-(8-fluoroquinolin-3-yl)oxalamide: [ka] e) N1-(4-carbamoylbenzyl)-N2-(8-fluoroquinolin-3-yl)-N1-methyloxalamide: [ka] f) N1-benzyl-N1-methyl-N2-(quinolin-3-yl)oxalamide: [ka] g) N1-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-N2-(5-((dimethylamino)methyl)pyridin-3-yl)-N1-methyloxalamide: [ka] h) N1-(4-bromo-2-(3-chlorophenoxy)benzyl)-N2-(5-bromo-2-(4-methylpiperazin-1-yl)pyridin-3-yl)-N1-methyloxalamide: [ka] i) Methyl 4-((N-methyl-2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)acetamido)methyl)benzoate: [ka] j) N1-methyl-N1-(2-methylbenzyl)-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] k) N1-(furan-2-ylmethyl)-N1-methyl-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] or a pharma- ceutically acceptable salt thereof, which is not one of:

[0102] In one embodiment, provided is a compound of formula (A), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 7 in any available position, Ring A 1 and A 2each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 in any available position, Each R 2 but independently, -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 is selected from the group consisting of Each R4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2, -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6)R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R 7 but independently, -D, =O, -CN, halo, -SF 5 , -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(=O)OR a7 , -NR a7 C(=O)R a7 , -NR a7 C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)R a7 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O)(=NR a7 )R a7 , -NR a7 S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 R 7Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., 0, 1, 2, 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or a combination thereof), Each R 8 are independently halo, =O, -CN, -OH, -NH 2 , -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -NH(C 1 -C 6 alkyl), -NH(C 1 -C 6 haloalkyl), -N(C 1 -C 6 Alkyl) 2 , -N(C 1 -C 6 Haloalkyl) 2 , -C(O)NH 2 , -NHC(O)(C 1 -C 6 Alkyl), C 3 -C 9 Cycloalkyl and C 1 -C 6 heteroalkyl; Each R a and R a ', independently, H, and C 1 -C 6 alkyl, Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR bS(=O) 2 R b , and -S(=O) 2 N(R b ) 2 Each R is selected from the group consisting of b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); Each R a7 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C substituted with 0 or 1 =O 1 -C 6 Heteroalkyl, C 3 -C 9 cycloalkyl or 3-10 membered heterocyclyl substituted with 0 or 1 =O, -Me, or combinations thereof; m is 0, 1, 2, or 3; (i)R 4 But -CH 3 If R 3 But not H. (ii) The compound is selected from the group consisting of compounds a) to k): a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide: [ka] b) N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide: [ka] c) N1-(6-amino-5,6,7,8-tetrahydroquinolin-3-yl)-N2-(3-fluoro-4-(pyridin-3-yl)benzyl)-N2-methyloxalamide: [ka] d) N1-Cyclopentyl-N1-(3-fluorobenzyl)-N2-(8-fluoroquinolin-3-yl)oxalamide: [ka] e) N1-(4-carbamoylbenzyl)-N2-(8-fluoroquinolin-3-yl)-N1-methyloxalamide: [ka] f) N1-benzyl-N1-methyl-N2-(quinolin-3-yl)oxalamide: [ka] g) N1-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-N2-(5-((dimethylamino)methyl)pyridin-3-yl)-N1-methyloxalamide: [ka] h) N1-(4-bromo-2-(3-chlorophenoxy)benzyl)-N2-(5-bromo-2-(4-methylpiperazin-1-yl)pyridin-3-yl)-N1-methyloxalamide: [ka] i) Methyl 4-((N-methyl-2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)acetamido)methyl)benzoate: [ka] j) N1-methyl-N1-(2-methylbenzyl)-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] k) N1-(furan-2-ylmethyl)-N1-methyl-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] or a pharma- ceutically acceptable salt thereof, which is not one of:

[0103] In one embodiment, provided herein is a compound of formula (A), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 2 -C 6 Alkyl, -C 2 -C 6Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 9 Carbocyclyl, C 6 -C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R 2 but independently, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 )2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -ORa4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 Ra5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R a and R a ', independently, H, and C 1 -C 6 alkyl, Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2, -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b , and -S(=O) 2 N(R b ) 2 Each R is selected from the group consisting of b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); m is 0, 1, 2, or 3; R 4 But -CH 3 If R 3 But not H. The compound is a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide, b) A compound, or a pharma- ceutically acceptable salt thereof, which is not N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide.

[0104] In one embodiment, provided is a compound of formula (A), or a pharma- ceutically acceptable salt thereof, wherein: [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 7 in any available position, Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 2 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 9 Carbocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 in any available position, Each R 2 but independently, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2, -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3, -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R 7 Independently, -D, =O, -CN, halo, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(=O)OR a7 , -NR a7 C(=O)R a7 , -NR a7 C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)R a7 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O)(=NR a7 )R a7 , -NRa7 S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 R 7 Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., 0, 1, 2, 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or a combination thereof), Each R 8 are independently halo, =O, -CN, -OH, -NH 2 , -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -NH(C 1 -C 6 alkyl), -NH(C 1 -C 6 haloalkyl), -N(C 1 -C 6 Alkyl) 2 , -N(C 1 -C 6 Haloalkyl) 2 , C 3 -C 9 Cycloalkyl and C 1 -C 6 heteroalkyl; Each R a and R a ', independently, H, and C 1 -C 6 alkyl, Each R a2 , R a3 , R a4 , R a5 , and Ra6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b, -S(=O)(=NR b )R b , -NR b S(=O) 2 R b , and -S(=O) 2 N(R b ) 2 Each R is selected from the group consisting of b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); Each R a7 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C substituted with 0 or 1 =O 1 -C 6 Heteroalkyl, C 3 -C 9 cycloalkyl, or 3-10 membered heterocyclyl substituted with 0 or 1 =O, -Me, or a combination thereof, or a pharma- ceutically acceptable salt thereof. m is 0, 1, 2, or 3; R 4 But -CH 3 If R 3 But not H. The compound is a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide, b) is not N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide.

[0105] As generally defined herein, each R aare independently H or C 1 -C 6 In some embodiments, each R a is independently H or -Me. In some embodiments, each R a is independently H. In some embodiments, each R a is, independently, -Me.

[0106] As generally defined herein, each R a’ are independently H or C 1 -C 6 In some embodiments, each R a’ is independently H or -Me. In some embodiments, each R a’ is independently H. In some embodiments, each R a is independently -Me. In some embodiments, each R a’ is -Et.

[0107] In some embodiments, R a is H and R a’ In some embodiments, R a is H and R a’ is -Me or -Et. In some embodiments, R a is H and R a’ is -Et.

[0108] In some embodiments, provided is a compound of formula (I), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R 2 but independently, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2, -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O)2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(Ra6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 is selected from the group consisting of Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b , and -S(=O) 2 N(R b ) 2 Each R is selected from the group consisting of b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); m is 0, 1, 2, or 3; (i)R 4 But -CH 3 If R 3 But not H. (ii) The compound is selected from the group consisting of compounds a) to k): a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide: [ka] b) N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide: [ka] c) N1-(6-amino-5,6,7,8-tetrahydroquinolin-3-yl)-N2-(3-fluoro-4-(pyridin-3-yl)benzyl)-N2-methyloxalamide: [ka] d) N1-Cyclopentyl-N1-(3-fluorobenzyl)-N2-(8-fluoroquinolin-3-yl)oxalamide: [ka] e) N1-(4-carbamoylbenzyl)-N2-(8-fluoroquinolin-3-yl)-N1-methyloxalamide: [ka] f) N1-benzyl-N1-methyl-N2-(quinolin-3-yl)oxalamide: [ka] g) N1-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-N2-(5-((dimethylamino)methyl)pyridin-3-yl)-N1-methyloxalamide: [ka] h) N1-(4-bromo-2-(3-chlorophenoxy)benzyl)-N2-(5-bromo-2-(4-methylpiperazin-1-yl)pyridin-3-yl)-N1-methyloxalamide: [ka] i) Methyl 4-((N-methyl-2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)acetamido)methyl)benzoate: [ka] j) N1-methyl-N1-(2-methylbenzyl)-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] k) N1-(furan-2-ylmethyl)-N1-methyl-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: [ka] or a pharma- ceutically acceptable salt thereof, which is not one of:

[0109] In some embodiments, provided is a compound of formula (I), or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Ring A is [ka] is selected from the group consisting of Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each R 1 But independently, -C 2 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 9 Carbocyclyl, C 6 -C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R 2 but independently, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2, -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 is selected from the group consisting of Each R 3 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 is selected from the group consisting of Each R 4 but independently, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 is selected from the group consisting of Each R 5 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5, -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 is selected from the group consisting of Each R 6 independently, H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2is selected from the group consisting of Each R a2 , R a3 , R a4 , R a5 , and R a6 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, C 3 -C 9 and each of alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R 9 Independently, =O, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b )2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b , and -S(=O) 2 N(R b ) 2 and each R b However, independently, H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C 3 -C 9 cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); m is 0, 1, 2, or 3; R 4 But -CH 3 If R 3 But not H. The compound is N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide, N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide, or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the compound of formula (A) is a compound of formula (A'): [ka] and In the formula, rings A, R a’ , ring B, and R 1 is as defined in any of the embodiments described herein. In some embodiments, Ra’ The stereochemistry at the center attached to R is (S). a’ The stereochemistry at the bond center is (R).

[0111] In some embodiments, the compound of formula (A) is a compound of formula (I): [ka] wherein ring A, R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein

[0112] As generally defined herein, ring A is [ka] is selected from the group consisting of During the ceremony, Ring A 1 and A 2 each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any of the embodiments herein.

[0113] In one embodiment, Ring A 1 and A 2are each independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S, or an oxidized form thereof, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S, or an oxidized form thereof, or phenyl.

[0114] In one embodiment, each ring A 3 is independently a 5- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the heterocyclyl and heteroaryl contain at least one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from the group consisting of N, O, S, or oxidized forms thereof.

[0115] In one embodiment, ring A is [ka] In the formula, A 1 , R 2 , and m are as defined in any of the embodiments described herein.

[0116] In one embodiment, ring A is [ka] In the formula, A 2 , R 2 , and m are as defined in any of the embodiments described herein.

[0117] In one embodiment, ring A is [ka] In the formula, A 3 , R 2 , and m are as defined in any of the embodiments described herein.

[0118] In some embodiments, ring A is [ka] is selected from the group consisting of In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any of the embodiments described herein.

[0119] In some embodiments, ring A is [ka] is selected from the group consisting of In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any of the embodiments described herein.

[0120] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0121] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0122] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0123] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0124] In some embodiments, ring A is [ka] is selected from the group consisting of In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any of the embodiments described herein.

[0125] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0126] In some embodiments, ring A is [ka] is selected from the group consisting of In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any of the embodiments described herein.

[0127] In some embodiments, ring A is [ka] wherein R 2and m is as defined in any of the embodiments described herein.

[0128] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0129] In some embodiments, ring A is [ka] wherein R 2 and m is as defined in any of the embodiments described herein.

[0130] In some embodiments, ring A is [ka] where R 2 and m is as defined in any of the embodiments described herein.

[0131] In some embodiments, ring A is [ka] where R 2 and m is as defined in any of the embodiments described herein.

[0132] In some embodiments, ring A is [ka] where R 2 and m is as defined in any of the embodiments described herein.

[0133] In some embodiments, ring A is [ka] where R 2 and m is as defined in any of the embodiments described herein.

[0134] In some embodiments, ring A is [ka] where R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0135] In some embodiments, ring A is [ka] where R 3 and R 4 is as defined in any of the embodiments described herein.

[0136] As generally defined herein, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2.

[0137] In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2.

[0138] In some embodiments, m is 0.

[0139] In some embodiments, m is 1.

[0140] In some embodiments, m is 2.

[0141] In some embodiments, m is 3.

[0142] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0143] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0144] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0145] In some embodiments, ring A is [ka] wherein R 2 is as defined in any of the embodiments described herein.

[0146] In some embodiments, ring A is [ka] wherein R 2 is as defined in any of the embodiments described herein.

[0147] In some embodiments, ring A is [ka] wherein R 2 is as defined in any of the embodiments described herein.

[0148] In some embodiments, ring A is [ka] wherein R 2 is as defined in any of the embodiments described herein.

[0149] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0150] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0151] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0152] In some embodiments, ring A is

[0153] [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein. In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0154] In some embodiments, ring A is [ka] wherein R 2 , R 3 , and R 4 is as defined in any of the embodiments described herein.

[0155] In some embodiments, ring A is [ka] wherein R 2, R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0156] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0157] In some embodiments, ring A is [ka] wherein R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0158] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0159] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0160] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0161] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0162] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0163] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0164] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0165] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0166] In some embodiments, ring A is [ka] wherein R 2 , R 3 , and R 4 is as defined in any of the embodiments described herein.

[0167] In some embodiments, ring A is [ka] wherein R 2 , R 3 , and R 4 is as defined in any of the embodiments described herein.

[0168] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] It is.

[0169] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0170] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0171] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0172] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0173] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0174] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0175] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0176] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0177] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0178] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0179] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0180] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0181] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0182] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0183] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0184] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0185] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0186] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0187] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0188] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0189] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0190] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0191] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0192] In some embodiments, ring A is

[0193] [ka] In certain embodiments, ring A is selected from the group consisting of: [ka] is selected from the group consisting of:

[0194] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] It is. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] It is.

[0195] In some embodiments, the compound of formula (A) is a compound of formula (A_1): [ka] where R a , R a’ , ring B, R 1 , R2 , and m are as defined in any of the embodiments described herein.

[0196] In some embodiments, the compound of formula (A) is a compound of formula (A_1a): [ka] where R a , R a’ , ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0197] In some embodiments, the compound of formula (A) is a compound of formula (A_1b): [ka] where R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein.

[0198] In some embodiments, the compound of formula (I) is a compound of formula (A_1c): [ka] wherein ring R a , R a’ , B, and R 1 is as defined in any of the embodiments described herein

[0199] In some embodiments, the compound of formula (A) is a compound of formula (A_2): [ka] where R a , R a’ , ring B, R 1 , R 3 , R 4 , R 5 , and R 6is as defined in any of the embodiments described herein.

[0200] In some embodiments, the compound of formula (A) is a compound of formula (A_2a): [ka] where R a , R a’ , ring B, R 1 , R 3 , and R 4 is as defined in any of the embodiments described herein.

[0201] In some embodiments, the compound of formula (A) is a compound of formula (A_3): [ka] where R a , R a’ , ring B, R 1 , R 2 , R 3 , R 4 , and m are as defined in any of the embodiments described herein.

[0202] In some embodiments, the compound of formula (A) is a compound of formula (A_3a): [ka] where R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein.

[0203] In some embodiments, the compound of formula (A) is a compound of formula (A_4): [ka] where R a , R a’ , ring B, R 1 , R 2, and m are as defined in any of the embodiments described herein.

[0204] In some embodiments, the compound of formula (A) is a compound of formula (A_4a): [ka] where R a , R a’ , ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0205] In some embodiments, the compound of formula (A) is a compound of formula (A_4b): [ka] where R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein.

[0206] In some embodiments, the compound of formula (A) is a compound of formula (A_5): [ka] where R a , R a’ , ring B, R 1 , R 2 , and m are as defined in any of the embodiments described herein.

[0207] In some embodiments, the compound of formula (A) is a compound of formula (A_5a): [ka] where R a , R a’ , ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0208] In some embodiments, the compound of formula (A) is a compound of formula (A_5b): [ka] where R a , R a’ , ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0209] In some embodiments, the compound of formula (A) is a compound of formula (A_5c): [ka] where R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein.

[0210] In some embodiments, the compound of formula (A) is a compound of formula (A_5d): [ka] where R a , R a’ , ring B, and R 1 is as defined in any of the embodiments described herein.

[0211] In some embodiments, the compound of formula (I) is a compound of formula (I_1): [ka] wherein ring B, R 1 , R 2 , and m are as defined in any of the embodiments described herein.

[0212] In some embodiments, the compound of formula (I) is a compound of formula (I_1a): [ka] wherein ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0213] In some embodiments, the compound of formula (I) is a compound of formula (I_1b): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0214] In some embodiments, the compound of formula (I) is a compound of formula (I_1c): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0215] In some embodiments, the compound of formula (I) is a compound of formula (I_2): [ka] wherein ring B, R 1 , R 3 , R 4 , R 5 , and R 6 is as defined in any of the embodiments described herein.

[0216] In some embodiments, the compound of formula (I) is a compound of formula (I_2a): [ka] wherein ring B, R 1 , R 3 , and R 4is as defined in any of the embodiments described herein.

[0217] In some embodiments, the compound is a compound of formula (I_3): [ka] wherein ring B, R 1 , R 2 , R 3 , R 4 , and m are as defined in any of the embodiments described herein.

[0218] In some embodiments, the compound of formula (I) is a compound of formula (I_3a): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0219] In some embodiments, the compound of formula (I) is a compound of formula (I_4): [ka] wherein ring B, R 1 , R 2 , and m are as defined in any of the embodiments described herein.

[0220] In some embodiments, the compound of formula (I) is a compound of formula (I_4a): [ka] wherein ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0221] In some embodiments, the compound of formula (I) is a compound of formula (I_4b): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0222] In some embodiments, the compound of formula (I) is a compound of formula (I_5): [ka] wherein ring B, R 1 , R 2 , and m are as defined in any of the embodiments described herein.

[0223] In some embodiments, the compound of formula (I) is a compound of formula (I_5a): [ka] wherein ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0224] In some embodiments, the compound of formula (I) is a compound of formula (I_5b): [ka] wherein ring B, R 1 , and R 2 is as defined in any of the embodiments described herein.

[0225] In some embodiments, the compound of formula (I) is a compound of formula (I_5c): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0226] In some embodiments, the compound of formula (I) is a compound of formula (I_5d): [ka] wherein rings B and R 1 is as defined in any of the embodiments described herein.

[0227] As generally defined herein, each R 1 is independently -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10 Selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position.

[0228] In some embodiments, each R 1 is independently -C 1 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 10 Carbocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0229] In some embodiments, each R 1 is independently -C 2 -C 6 Alkyl, -C 2 -C 6 Heteroalkyl, -C 2 -C 6 Haloalkyl, -C 3 -C 9 Carbocyclyl, C 6 -C 10 and selected from the group consisting of aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 8 Each R 8 is as defined in any of the embodiments described herein).

[0230] In some embodiments, each R 1 is independently -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 ), -C 2 -C 6 Heteroalkyl (e.g., -CH 2 CH 2 OCH 3 ), -C 2 -C 6 Haloalkyl (e.g., -CH 2 CH 2 CF 3 ), -C 3 -C 10Carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl), 3- to 10-membered heterocyclyl (e.g., chromanyl), heteroarylalkyl (e.g., -CH 2 -pyridinyl, -CH(CH 3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, -CH 2 -pyrazolyl), arylalkyl (e.g., benzyl, -CH(CH 3 ) Phenyl, -CH 2 -Naphthalenyl, -CH 2 -chromanyl, -CH 2 CH 2 -phenyl), heterocyclylalkyl (e.g., CH 2 -tetrahydropyranyl), and cycloalkylalkyl (e.g., -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 )Cyclopropyl, -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0231] In some embodiments, R 1 -C 2 -C 6 Alkyl (e.g., -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 ), -C 2 -C 6 Heteroalkyl (e.g., -CH 2 CH 2 OCH3 ), -C 3 -C 9 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl), heteroarylalkyl (e.g., -CH 2 -pyridinyl, -CH(CH 3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl), arylalkyl (e.g., benzyl, -CH(CH 3 ) Phenyl, -CH 2 CH 2 -phenyl), and cycloalkylalkyl (e.g., -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 )Cyclopropyl, -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0232] In some embodiments, R 1 is independently -C 2 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 ), -C 2 -C 6 Heteroalkyl (e.g., -CH2 CH 2 OCH 3 ), -C 3 -C 9 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl), heteroarylalkyl (e.g., -CH 2 -pyridinyl, -CH(CH 3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl), arylalkyl (e.g., benzyl, -CH(CH 3 ) Phenyl, -CH 2 CH 2 -phenyl), and cycloalkylalkyl (e.g., -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 )Cyclopropyl, -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0233] In some embodiments, each R 1 is independently -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 ), -C 2 -C6 Heteroalkyl (e.g., -CH 2 CH 2 OCH 3 ), and arylalkyl (e.g., benzyl, -CH(CH 3 ) Phenyl, -CH 2 -Naphthalenyl, -CH 2 -chromanyl), each of which is selected from the group consisting of 0, 1, or 2 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0234] In some embodiments, each R 1 is independently -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 ), -C 2 -C 6 Heteroalkyl (e.g., -CH 2 CH 2 OCH 3 ), and arylalkyl (e.g., benzyl, -CH(CH 3 ) Phenyl, -CH 2 -Naphthalenyl, -CH 2 -chromanyl), where the alkyl and arylalkyl are not further substituted.

[0235] In some embodiments, each R 1 are independently -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2, -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl, chromanyl, -CH 2 -pyridinyl, -CH(CH 3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, -CH 2 -Pyrazolyl, benzyl, -CH(CH 3 ) Phenyl, -CH 2 CH 2 -Phenyl, CH 2 -Naphthyl, -CH 2 -chromanyl, -CH 2 -Tetrahydropyranyl, -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 ) cyclopropyl, and -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0236] In some embodiments, R 1 are independently -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2, -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl, -CH 2 -pyridinyl, -CH(CH 3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, benzyl, -CH(CH 3 ) Phenyl, -CH 2 CH 2 -phenyl, -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 ) cyclopropyl, and -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0237] In some embodiments, R 1 are independently -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl, -CH 2 -pyridinyl, -CH(CH3 )-Pyridinyl-CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, benzyl, -CH(CH 3 ) Phenyl, -CH 2 CH 2 -phenyl, -CH 2 -Cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -Cyclopentyl, -CH 2 -Cyclohexyl, -CH(CH 3 ) cyclopropyl, and -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0238] In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, chromanyl, -CH 2 -Cyclopropyl, -CH 2 -Cyclohexyl, -CH 2 CH 2 -Cyclopropyl, -CH 2 -Tetrahydropyranyl, -CH 2 -pyridinyl, -CH 2-pyrimidinyl, -CH 2 -Pyrazolyl, -BenzylCH 2 -chromanyl, CH2-naphthyl, and -CH 2 -cyclopropyl, each of which is selected from the group consisting of 0, 1 or 2 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0239] In some embodiments, R 1 are independently -Me, -Et, -Pr, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , cyclopentyl, 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, -CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, benzyl, and -CH 2 -cyclopropyl, each of which is selected from the group consisting of 0 or 1 R 8 at any available position, and each R 8 is as defined in any of the embodiments described herein.

[0240] In some embodiments, each R 1 are independently -Et, -Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , cyclopentyl, 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, -CH 2-pyrimidinyl, -CH(CH 3 )-pyrimidinyl, benzyl, and -CH 2 -cyclopropyl, each of which is selected from the group consisting of 0 or 1 R 8 at any available position, and each R 8 are independently -F, -Me, -OCHF 2 , -cyclopropyl, and -CH 2 OCH 3 is selected from the group consisting of:

[0241] In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 OCH 3、 [ka] [ka] is selected from the group consisting of:

[0242] In some embodiments, R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2CH 2 OCH 3、 [ka] is selected from the group consisting of:

[0243] In some embodiments, R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , [ka] is selected from the group consisting of:

[0244] In some embodiments, R 1 -Et, -Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , cyclopentyl, 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, -CH 2 -pyrimidinyl, -CH(CH 3 )-pyrimidinyl, benzyl, and -CH 2 -cyclopropyl, each of which is selected from the group consisting of 0 or 1 R 8 at any available position, and R 8 is as defined in any of the embodiments described herein. In some embodiments, R 8 -F, -Me, -OCHF 2 , -cyclopropyl, and -CH 2OCH 3 is selected from the group consisting of:

[0245] In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, chromanyl, -CH 2 -Cyclopropyl, -CH 2 -Cyclohexyl, -CH(CH 3 ) cyclopropyl, and -CH 2 CH 2 -cyclopropyl, each of which is selected from the group consisting of 0 or 1 R 8 at any available position, and each R 8 are independently -Me and -OCHF 2 is selected from the group consisting of:

[0246] In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CF 3, -CH 2 CH 2 OCH 3、 [ka] is selected from the group consisting of:

[0247] In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , and -CH 2 CH(CH 3 )CH 2 CH 3 is selected from the group consisting of:

[0248] In some embodiments, each R 1 are independently -Me, -Et, benzyl, -CH 2 -pyridinyl, and CH 2 -pyrimidinyl, benzyl, -CH 2 -pyridinyl, and CH 2 -pyrimidinyl is independently -Me, -F, -Cl, and -CF 3 and wherein the aryl group is substituted with 0, 1, or 2 substituents selected from:

[0249] In some embodiments, each R 1 are independently benzyl, -CH 2 -pyridinyl, and CH 2 -pyrimidinyl, benzyl, -CH 2 -pyridinyl, and -CH 2 -pyrimidinyl is independently -Me, -F, -Cl, and -CF 3 and wherein the aryl group is substituted with 0, 1, or 2 substituents selected from:

[0250] In some embodiments, each R1 is independently selected from the group consisting of -Me, -Et, and benzyl, and benzyl is independently selected from the group consisting of Me, -F, -Cl, and -CF 3 and wherein the aryl group is substituted with 0, 1, or 2 substituents selected from:

[0251] In some embodiments, each R 1 are independently -Me, -Et, -CH 2 -phenyl, and -CH(CH 3 ) phenyl, wherein phenyl is independently selected from the group consisting of Me, -F, -Cl, and -CF 3 and wherein the aryl group is substituted with 0, 1, or 2 substituents selected from:

[0252] In some embodiments, R 1 -C 2 -C 6 Alkyl (e.g., -Et, -Pr, - i Pr, -Bu, -sec-Bu, -iso-Bu, - t Bu, -pentyl, -iso-pentyl, -neo-pentyl, -CH(CH 3 )CH(CH 3 ) 2 ) with 0, 1, 2, or 3 R 8 (i.e., one or more hydrogens of the alkyl group are replaced by R 8 ), R 8 is as defined in any of the embodiments described herein. In some embodiments, each R 1 are independently -Me, -Et, - i Pr, -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , and [ka] In some embodiments, each R 1 is independently selected from the group consisting of -Me, and -Et. 1 In some embodiments, R 1 is -Et. In some embodiments, R 1 In some embodiments, R 1 teeth,- i In some embodiments, R 1 is -Bu. In some embodiments, R 1 is -sec-Bu. In some embodiments, R 1 In some embodiments, R 1 teeth,- t In some embodiments, R 1 is -pentyl. In some embodiments, R 1 In some embodiments, R 1 is -neo-pentyl. In some embodiments, R 1 is -CH(CH 3 )CH(CH 3 ) 2 In some embodiments, R 1 is -CH 2 CH(CH 3 )CH 2 CH 3 In some embodiments, R 1 is -CH 2 CH(CH 3 ) 2 In some embodiments, -C 2 -C 6 The alkyl is unsubstituted. In some embodiments, -C 2 -C 6 Alkyl is one R 8 In some embodiments, -C 2 -C 6 Alkyl is a group consisting of two R 8 In some embodiments, -C2 -C 6 Alkyl is a group consisting of three R 8 In some embodiments, R 1 is substituted with cyclopropyl -CH 2 CH(CH 3 ) 2 In some embodiments, R 1 teeth, [ka] It is.

[0253] In some embodiments, R 1 -C 2 -C 6 Heteroalkyl and 0, 1, 2, or 3 R 8 (i.e., one or more hydrogens of the alkyl group are replaced by R 8 ), R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is an alkoxymethyl group (e.g., -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 In some embodiments, R 1 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 1 is -CH 2 CH 2 OCH 3 In some embodiments, R 1 is aminomethyl (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 In some embodiments, -C 2 -C 6 Heteroalkyl is a group consisting of one R 8 In some embodiments, -C 2 -C 6Heteroalkyl is a group consisting of two R 8 In some embodiments, -C 2 -C 6 Heteroalkyl is a group consisting of three R 8 In some embodiments, R 1 is substituted with cyclopropyl -CH 2 CH 2 OCH 3 In some embodiments, R 1 teeth, [ka] It is.

[0254] In some embodiments, R 1 -C 2 -C 6 Haloalkyl (e.g., -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CHF 2 , -CH 2 CH 2 CF 3 ) with 0, 1, 2, or 3 R 8 (i.e., one or more hydrogens of the alkyl group are replaced by R 8 ), R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is -CH 2 CH 2 CF 3 It is.

[0255] In some embodiments, R 1 is C 3 -C 10 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl) and 0, 1, 2, or 3 R 8 is replaced by R 8is as defined in any of the embodiments described herein. In some embodiments, R 1 is C 3 -C 7 Monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C 4 -C 10 Bicyclic cycloalkyl, C 5 -C 7 Monocyclic cycloalkenyl, C 6 -C 10 Bicyclic cycloalkenyl, and C fused to a phenyl ring 8 -C 10 C forming partially aromatic carbocyclyls (e.g., 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl) 4 -C 6 cycloalkenyl.

[0256] In some embodiments, R 1 is C 3 -C 7 Monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), and C fused to a phenyl ring 8 -C 10 C forming partially aromatic carbocyclyls (e.g., 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthalenyl) 4 -C 6 cycloalkenyl.

[0257] In some embodiments, R 1 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl (e.g., 2,3-dihydro-1H-inden-1-yl), and 1,2,3,4 tetrahydronaphthalenyl (e.g., 1,2,3,4 tetrahydronaphthalen-1-yl). 1is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-1H-indenyl (e.g., 2,3-dihydro-1H-inden-1-yl), and 1,2,3,4 tetrahydronaphthalenyl (e.g., 1,2,3,4 tetrahydronaphthalen-1-yl). 1 is selected from the group consisting of cyclopentyl, 2,3-dihydro-1H-indenyl (eg, 2,3-dihydro-1H-inden-1-yl), and 1,2,3,4 tetrahydronaphthalenyl (eg, 1,2,3,4 tetrahydronaphthalen-1-yl). In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl. In some embodiments, R 1 is 2,3-dihydro-1H-indenyl (e.g., 2,3-dihydro-1H-inden-1-yl). In some embodiments, R 1 is 1,2,3,4 tetrahydronaphthalenyl (e.g., 1,2,3,4 tetrahydronaphthalen-1-yl). In some embodiments, C 3 -C 10 The carbocyclyl is unsubstituted. In some embodiments, C 3 -C 10 Carbocyclyl is a group that has one R 8 In some embodiments, C 3 -C 10 Carbocyclyl is a group that has two R 8 In some embodiments, C 3 -C 10 Carbocyclyl is a group that has three R 8 In some embodiments, R 1is selected from the group consisting of 2,3-dihydro-1H-inden-1-yl, 4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl, and 2-(difluoromethoxy)cyclopentyl. 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is.

[0258] In some embodiments, R 1 is a 3- to 10-membered heterocyclyl and has 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is 3-6 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, chromanyl). 1 is oxetanyl (e.g., oxetan-3-yl). In some embodiments, R 1 is tetrahydropyranyl. In some embodiments, R 1 is tetrahydrofuranyl. In some embodiments, R 1 is azetidinyl. In some embodiments, R 1 is pyrrolidinyl. In some embodiments, R1 is piperidinyl. In some embodiments, R 1 is piperazinyl. In some embodiments, R 1 is morpholinyl. In some embodiments, R 1 is azepanyl. In some embodiments, R 1 is chromanyl. In some embodiments, R 1 teeth, [ka] It is.

[0259] In some embodiments, R 1 is a 5-10 membered heteroaryl (e.g., a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S), and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R 1 is a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). 1 is a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, the heteroaryl is selected from the group consisting of 0, 1, 2, or 3 -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or a combination thereof.

[0260] In some embodiments, R 1 is a 6-10 membered monocyclic or bicyclic aryl, and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is phenyl and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein.

[0261] In some embodiments, R 1 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, -CH 2 CH(CH 3 ) cyclopropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl) with 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is cyclopropylmethyl (-CH 2 In some embodiments, R 1 is cyclopropylethyl (-CH 2 CH 2 In some embodiments, R 1 is cyclopropylpropyl (-CH 2 CH 2 CH 2 In some embodiments, R 1 -CH 2CH(CH 3 ) cyclopropyl. In some embodiments, R 1 is cyclobutylmethyl (-CH 2 In some embodiments, R 1 is cyclobutylethyl (-CH 2 CH 2 In some embodiments, R 1 is cyclopentylmethyl (-CH 2 cyclopentyl). In some embodiments, R 1 is cyclopentylethyl (-CH 2 CH 2 cyclopentyl). In some embodiments, R 1 is cyclohexylmethyl (-CH 2 cyclohexyl). In some embodiments, R 1 is cyclohexylethyl (-CH 2 CH 2 cyclohexyl). In some embodiments, R 1 is cycloheptylmethyl (-CH 2 cycloheptyl). In some embodiments, R 1 is cycloheptylethyl (-CH 2 CH 2 cycloheptyl).

[0262] In some embodiments, cycloalkylalkyl is unsubstituted. In some embodiments, cycloalkylalkyl is one R 8 In some embodiments, the cycloalkylalkyl is substituted with two R 8 In some embodiments, the cycloalkylalkyl is substituted with 3 R 8 In some embodiments, R 1 is -CH 2 OCH 3 Substituted with -CH 2 It is cyclopropyl.

[0263] In some embodiments, R 1is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is tetrahydropyranylmethyl. In some embodiments, R 1 teeth, [ka] It is.

[0264] In some embodiments, R 1 is arylalkyl (e.g., benzyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is benzyl. In some embodiments, the arylalkyl (e.g., benzyl) is unsubstituted. In some embodiments, the arylalkyl (e.g., benzyl) is a arylalkyl having one R 8 In some embodiments, arylalkyl (e.g., benzyl) is substituted with two R 8 In some embodiments, an arylalkyl (e.g., benzyl) is substituted with three R 8 In some embodiments, R 1 is benzyl and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 are independently Me, -F, -Cl, and -CF 3 and wherein the aryl group is benzyl substituted at any available position with 0, 1, or 2 substituents selected from:

[0265] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0266] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0267] 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] 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] It is.

[0268] In some embodiments, R 1is heteroarylalkyl (e.g., pyridinylmethyl, pyridinylethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl, pyrimidinylmethyl, pyrimidinylethyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyridinylmethyl (-CH 2 pyridinyl), pyridinylethyl (-CH 2 CH 2 Pyridinyl, -CH(CH 3 )pyridinyl), thiazolylmethyl (-CH 2 thiazolyl), triazolylethyl (-CH 2 CH 2 triazolyl), pyrazolylmethyl (-CH 2 pyrazolyl), pyrimidinylmethyl (-CH 2 pyrimidinyl), and pyrimidinylethyl (-CH 2 CH 2 Pyrimidinyl, -CH(CH 3 ) pyrimidinyl)) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyridinylmethyl (-CH 2 pyridinyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyridinylethyl (-CH 2 CH 2 Pyridinyl, -CH(CH 3 ) pyridinyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is thiazolylmethyl (-CH 2thiazolyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is triazolylethyl (-CH 2 CH 2 triazolyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyrazolylmethyl (-CH 2 pyrazolyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyrimidinylmethyl (-CH 2 pyrimidinyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein. In some embodiments, R 1 is pyrimidinylethyl (-CH 2 CH 2 Pyrimidinyl, -CH(CH 3 ) pyrimidinyl) and 0, 1, 2, or 3 R 8 is replaced by R 8 is as defined in any of the embodiments described herein.

[0269] In some embodiments, each R 1 are independently -Me, -F, -Cl, and -CF 3 -CH 2 -pyridinyl.

[0270] In some embodiments, each R 1 are independently -Me, -F, -Cl, and -CF 3CH substituted at any available position with 0, 1, or 2 substituents selected from 2 -pyrimidinyl.

[0271] In some embodiments, the heteroarylalkyl is unsubstituted. In some embodiments, the heteroarylalkyl is a heteroaryl having one R 8 In some embodiments, the heteroarylalkyl is substituted with two R 8 In some embodiments, the heteroarylalkyl is substituted with 3 R 8 In some embodiments, R 1 are independently -F, -Cl, and -CF 3 -CH 2 -pyridin-2-yl, -CH 2 -pyrimidin-2-yl, and -CH(CH 3 In some embodiments, R 1 -CH 2 -pyrimidin-2-yl, and -CH(CH 3 )-pyrimidin-2-yl.

[0272] In some embodiments, R is [ka] is selected from the group consisting of: In some embodiments, R 1 teeth, [ka] is selected from the group consisting of: 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] In some embodiments, R 1 teeth, [ka] It is.

[0273] As generally defined herein, each R 2 are independently -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 R a2 is as defined in any of the embodiments described herein.

[0274] In some embodiments, each R 2 are independently -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2, -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), and -OC(=O)N(R a2 ), R a2 is as defined in any of the embodiments described herein.

[0275] In some embodiments, each R 2 are independently halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), and -OC(=O)N(R a2 ) 2 R a2 is as defined in any of the embodiments described herein. In some embodiments, each R 2 are independently: =O, -C 1 -C 6 Alkyl, 3-10 membered heterocyclyl, -OR a2 , -C(=O)N(R a2 ) 2 , and -N(R a2 ) 2R a2 is as defined in any of the embodiments described herein. In some embodiments, each R 2 are independently: =O, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, -OR a2 , and -N(R a2 ) 2 is selected from the group consisting of:

[0276] In some embodiments, each R a2 are independently H and C 1 -C 6 In some embodiments, each R a2 is independently selected from the group consisting of H and -Me. In some embodiments, each R a2 is H.

[0277] In some embodiments, each R 2 are independently: =O, -C 1 -C 6 Alkyl, and -N(R a2 ) 2 R a2 is as defined in any of the embodiments described herein.

[0278] In some embodiments, each R 2 are independently -D, =O, -Me, -Et, - i Pr, - t Bu, -NH 2 , -NHCH 3 , and -NH(CH 3 ) 2 is selected from the group consisting of:

[0279] In some embodiments, each R 2 are independently: =O, -Me, -Et, - i Pr, - tBu, -NH 2 , -NHCH 3 , and -NH(CH 3 ) 2 is selected from the group consisting of:

[0280] In some embodiments, R 2 are independently -D, -NH 2 -Me, and -Me.

[0281] In some embodiments, R 2 are independently -NH 2 -Me, and -Me.

[0282] In some embodiments, R 2 is -D.

[0283] In some embodiments, R 2 is =O.

[0284] In certain embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 2 is -Cl. In some embodiments, R 2 is -F. In some embodiments, R 2 In some embodiments, R 2 is -I.

[0285] In some embodiments, R 2 is -CN.

[0286] In certain embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 In some embodiments, R 2 is -Et. In some embodiments, R 2 is -Pr or -iPr.

[0287] In some embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 2 is hydroxymethyl (-CH 2 In some embodiments, R 2 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0288] In some embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 is trifluoromethyl (-CF 3 In another embodiment, R 2 is difluoromethyl (-CHF 2 ).

[0289] In some embodiments, R 2 is C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl.

[0290] In some embodiments, R 2 is 3-10 membered heterocyclyl. In some embodiments, R 2is 3-6 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 2 is oxetanyl (e.g., oxetan-3-yl). In some embodiments, R 2 is tetrahydropyranyl. In some embodiments, R 2 is tetrahydrofuranyl. In some embodiments, R 2 is azetidinyl. In some embodiments, R 2 is pyrrolidinyl. In some embodiments, R 2 is piperidinyl. In some embodiments, R 2 is piperazinyl. In some embodiments, R 2 is morpholinyl. In some embodiments, R 2 is azepanil.

[0291] In some embodiments, R 2 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0292] In some embodiments, R 2 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0293] In some embodiments, R 2 is arylalkyl. In some embodiments, R 2 is benzyl.

[0294] In some embodiments, R 2is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0295] In some embodiments, R 2 -OR a2 and R a2 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 2 is hydroxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is isopropoxy. In some embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 is trifluoromethoxy (-OCF 3 ) and in other embodiments, R 2 is difluoromethoxy (-OCHF 2 ).

[0296] In some embodiments, R 2 is -N(R a2 ) 2 and R a2 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a2 , -N(CH 3 )R a2 In some embodiments, R 2 is -NH 2 In some embodiments, R 2 -NHR a2 (For example, -NHCH 3 , -NHCH 2 CH 3, -NHPr, -NH i In some embodiments, R 2 is -N(CH 3 )R a2 (For example, -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 3 )CH 2 CH 2 CH 3 , -N(CH 3 ) i Pr, -N(CH 3 )cyclopropyl, -N(CH 3 )cyclobutyl).

[0297] In some embodiments, R 2 is -C(=O)R a2 , or -C(=O)OR a2 and R a2 is as defined in any of the embodiments described herein. In some embodiments, R 2 is -C(=O)R a2 and R a2 is as defined in any of the embodiments described herein. In some embodiments, R 2 is —C(═O)alkyl. In some embodiments, R 2 is -C(=O)CH 3 , -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O) t Bu, -C(=O) i Pr, -C(=O)CH 2 CH 2 CH 3 , or -C(=O)OCH 3 In some embodiments, R 2 is acetyl (-C(=O)CH 3 In some embodiments, R 2 is -C(=O)OR a2 In some embodiments, R 2is -COOH. In some embodiments, R 2 COOCH 3 It is.

[0298] In some embodiments, R 2 -NR a2 C(=O)R a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -NHC(=O)R a2 (For example, -NHC(=O)CH 3 , -NHC(=O)CH 2 CH 3 , -NHC(=O)CH 2 CH 2 CH 3 , -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 2 is -N(CH 3 )C(=O)R a2 (For example, -N(CH 3 )C(=O)CH 3 , -N(CH 3 )C(=O)CH 2 CH 3 , -N(CH 3 )C(=O)CH 2 CH 2 CH 3 , -N(CH 3 )C(=O) i Pr, -N(CH 3 )C(=O)Bu, -N(CH 3 )C(=O) t Bu, -N(CH 3 )C(=O)cyclopropyl, -N(CH 3 )C(=O)cyclobutyl).

[0299] In some embodiments, R 2 -NR a2 C(=O)OR a2 and Ra2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -NHC(=O)OR a2 (For example, -NHC(=O)OCH 3 , -NHC(=O)OCH 2 CH 3 , -NHC(=O)OCH 2 CH 2 CH 3 , -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t In some embodiments, R 2 is -N(CH 3 )C(=O)OR a2 (For example, -N(CH 3 )C(=O)OCH 3 , -N(CH 3 )C(=O)OCH 2 CH 3 , -N(CH 3 )C(=O)OCH 2 CH 2 CH 3 , -N(CH 3 )C(=O)O i Pr, -N(CH 3 )C(=O)OBu, -N(CH 3 )C(=O)O t Bu, -N(CH 3 )C(=O)Ocyclopropyl, -N(CH 3 )C(=O)Ocyclobutyl).

[0300] In some embodiments, R 2 is -C(=O)N(R a2 ) 2 and R a2 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a2 , -C(=O)N(CH 3 )R a2 In some embodiments, R 2is -C(=O)NH 2 In certain embodiments, R 2 is -C(=O)NHR a2 (For example, -C(=O)NHCH 3 , -C(=O)NHCH 2 CH 3 , -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t In certain embodiments, R 2 is -C(=O)N(CH 3 )R a2 (For example, -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 3 )CH 2 CH 3 , -C(=O)N(CH 3 )CH 2 CH 2 CH 3 , -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N(CH 3 ) cyclopropyl, -C(=O)N(CH 3 )cyclobutyl). In some embodiments, R 2 is -C(=O)N(OR a2 )(R a2 In certain embodiments, R 2 is -C(=O)NH(OR a2 ) (e.g., -C(=O)NHOH, -C(=O)NHOCH 3 In some embodiments, R 2 is -C(=O)NHOH.

[0301] In some embodiments, R 2 is -OC(=O)N(R a2 ) 2 and Ra2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -OC(=O)NHR a2 (For example, -OC(=O)NHCH 3 , -OC(=O)NHCH 2 CH 3 , -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, -OC(=O)NHcyclopropyl, -OC(=O)NHcyclobutyl). In certain embodiments, R 2 is -OC(=O)N(CH 3 )R a2 (For example, -OC(=O)N(CH 3 ) 2 , -OC(=O)N(CH 3 )CH 2 CH 3 , -OC(=O)N(CH 3 )CH 2 CH 2 CH 3 , -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N(CH 3 ) cyclopropyl, -OC(=O)N(CH 3 )cyclobutyl).

[0302] In some embodiments, R 2 is -S(=O)R a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -S(=O)alkyl (e.g., -S(=O)CH 3 , -S(=O)CH 2 CH 3 , -S(=O)CH 2 CH 2 CH 3 , -S(=O) iIn certain embodiments, R 2 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0303] In some embodiments, R 2 is -S(=O) 2 R a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -S(=O) 2 Alkyl (e.g., -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , -S(=O) 2 Pr, -S(=O) 2 i In certain embodiments, R 2 is -S(=O) 2 Cycloalkyl (e.g., -S(=O) 2 Cyclopropyl, -S(=O) 2 Cyclobutyl, -S(=O) 2 Cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 2 is S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0304] In some embodiments, R 2 -SR a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -S alkyl (e.g., -SCH 3 , -SCH 2 CH 3 , -SPr, -S i In certain embodiments, R 2is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 2 is -Saryl (e.g., -Sphenyl). In some embodiments, R 2 is -S(=O)(=NR a2 )R a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -S(=O)(=NH)R a2 (For example, -S(=O)(=NH)CH 3 , -S(=O)(=NH)CH 2 CH 3 , -S(=O)(=NH)CH 2 CH 2 CH 3 , -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 2 is -S(=O)(=NCH 3 )R a2 (For example, -S(=O)(=NCH 3 )CH 3 , -S(=O)(=NCH 3 )CH 2 CH 3 , -S(=O)(=NCH 3 )CH 2 CH 2 CH 3 , -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) t Bu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0305] In some embodiments, R2 -NR a2 S(=O) 2 R a2 and R a2 is as defined in any of the embodiments described herein. In certain embodiments, R 2 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 CH 3 , -NHS(=O) 2 CH 2 CH 3 , -NHS(=O) 2 Pr, -NHS(=O) 2 i In certain embodiments, R 2 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 2 is -N(CH 3 )S(=O) 2 Alkyl (e.g., -N(CH 3 )S(=O) 2 CH 3 , -N(CH 3 )S(=O) 2 CH 2 CH 3 , -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i In certain embodiments, R 2 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH 3 )S(=O) 2 Cyclopropyl, -N(CH 3 )S(=O) 2 Cyclobutyl, -N(CH 3 )S(=O) 2Cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

[0306] In some embodiments, R 2 is -S(=O) 2 N(R a2 ) 2 and R a2 is as defined in any of the embodiments described herein. (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a2 , -S(=O) 2 N(CH 3 )R a2 In some embodiments, R 2 is -S(=O) 2 NH 2 In some embodiments, R 2 is -S(=O) 2 NHR a2 (For example, -S(=O) 2 NHCH 3 , -S(=O) 2 NHCH 2 CH 3 , -S(=O) 2 NHPr, -S(=O) 2 NH i Pr, -S(=O) 2 NHcyclopropyl, -S(=O) 2 NHcyclobutyl). In some embodiments, R 2 is -S(=O) 2 N(CH 3 )R a2 (For example, -S(=O) 2 N(CH 3 ) 2 , -S(=O) 2 N(CH 3 )CH 2 CH 3 , -S(=O) 2 N(CH 3 )CH 2 CH 2 CH 3 , -S(=O) 2N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0307] As generally defined herein, each R 3 are independently H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 , and -S(=O) 2 N(R a3 ) 2 R a3 is as defined in any of the embodiments described herein.

[0308] In some embodiments, R 3H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , and -OC(=O)N(R a3 ) 2 R a3 is as defined in any of the embodiments described herein.

[0309] In certain embodiments, R 3 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -OR a3 , and -N(R a3 ) 2 R a3 is as defined in any of the embodiments described herein.

[0310] In some embodiments, each R 3 -H, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -OR a3 , and -N(R a3 ) 2 R a3 is as defined in any of the embodiments described herein.

[0311] In some embodiments, each R 3 OR a3 , and -N(R a3 ) 2 R a3 is as defined in any of the embodiments described herein.

[0312] In some embodiments, each R a3 are independently H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -nBu, - t Bu, -sec-Bu, -iso-Bu), and -C 1 -C 6 Haloalkyl (e.g., -CHF 2 , -CF 3 ).

[0313] In some embodiments, R 3 -H, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), -C 1 -C 6 Alkyl (e.g., -CF 3 , -CHF 2 ), -OH, -O-(C 1 -C 6 alkyl) (e.g., -OCH 3 , -OEt), -O-(C 1 -C 6 haloalkyl) (e.g., -OCF 3 , -OCHF 2 ), -NH 2 , -NH-(C 1 -C 6 alkyl) (e.g., -NHCH 3 ), and -N-(C 1 -C 6 Alkyl) 2 (For example, -N(CH 3 ) 2 ).

[0314] In certain embodiments, R 3 -H, -Me, -Et, -CHF 2 , -OCH 3 , -OEt, -OCHF 2 , -OCF 3 , -OH, and -NH 2 In some embodiments, R 3 -H, -Et, -OCH 3 , -OEt, -OCHF 2 , -OCF 3 and -OH.

[0315] In certain embodiments, R 3 -H, -Me, -CHF 2 , -OCH 3 , and -NH 2 Selected from the group consisting of 。

[0316] In other embodiments, R 3 -H, -Me, -CHF 2 , and -NH 2 In some embodiments, R 3 -Me and -NH 2 is selected from the group consisting of:

[0317] In some embodiments, R 3 -H, -NH 2 , and -OCH 3 is selected from the group consisting of:

[0318] In some embodiments, R 3 is -NH 2 , and -OCH 3 is selected from the group consisting of:

[0319] In some embodiments, R 3 is H. In some embodiments, R 3 is -D.

[0320] In certain embodiments, R 3 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 3 is -Cl. In some embodiments, R 3 is -F. In some embodiments, R 3 In some embodiments, R 3 is -I.

[0321] In some embodiments, R 3 is -CN.

[0322] In certain embodiments, R 3 -C 1 -C 6 In some embodiments, R 3 In some embodiments, R 3 is -Et. In some embodiments, R 3 is -Pr or -iPr.

[0323] In some embodiments, R 3 -C 1 -C 6 In some embodiments, R 3 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 3 is hydroxymethyl (-CH 2 In some embodiments, R 3 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is. In some embodiments, R 3 -C 1 -C 6 In some embodiments, R 3is trifluoromethyl (-CF 3 In another embodiment, R 3 is difluoromethyl (-CHF 2 ).

[0324] In some embodiments, R 3 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.

[0325] In some embodiments, R 3 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 3 is oxetanyl. In some embodiments, R 3 is tetrahydropyranyl. In some embodiments, R 3 is tetrahydrofuranyl. In some embodiments, R 3 is azetidinyl. In some embodiments, R 3 is pyrrolidinyl. In some embodiments, R 3 is piperidinyl. In some embodiments, R 3 is piperazinyl. In some embodiments, R 3 is morpholinyl. In some embodiments, R 3 is azepanil.

[0326] In some embodiments, R 3is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 3 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0327] In some embodiments, R 3 is arylalkyl. In some embodiments, R 3 is benzyl. In some embodiments, R 3 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0328] In some embodiments, R 3 -OR a3 and R a3 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 3 is hydroxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is isopropoxy. In some embodiments, R 3 is difluoromethoxy (-OCHF 2 In some embodiments, R 3 is trifluoromethoxy (-OCF 3 ).

[0329] In some embodiments, R 3 is -N(R a3 ) 2 and R a3 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a3 , -N(CH 3 )R a3 In some embodiments, R 3 is -NH 2 In some embodiments, R 3 -NHR a3 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 3 is -N(CH 3 )R a3 (For example, -N(CH 3 ) 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, -N(CH 3 )cyclopropyl, -N(CH 3 )cyclobutyl). In some embodiments, R 3 is -C(=O)R a3 OR -C(=O)OR a3 In some embodiments, R 3 is -C(=O)R a3 and R a3 is as defined in any of the embodiments described herein. In some embodiments, R 3 is —C(═O)alkyl. In some embodiments, R 3 is -C(=O)CH 3 , -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O) t Bu, -C(=O) i Pr, -C(=O)Pr, or -C(=O)OCH3 In some embodiments, R 3 is acetyl (-C(=O)Me). In some embodiments, R 3 is -C(=O)OR a3 In some embodiments, R 3 is -COOH. In some embodiments, R 3 COOCH 3 It is.

[0330] In some embodiments, R 3 -NR a3 C(=O)R a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -NHC(=O)R a3 (For example, -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 3 is -N(CH 3 )C(=O)R a3 (For example, -N(CH 3 )C(=O)Me, -N(CH 3 )C(=O)Et, -N(CH 3 )C(=O)Pr, -N(CH 3 )C(=O) i Pr, -N(CH 3 )C(=O)Bu, -N(CH 3 )C(=O) t Bu, -N(CH 3 )C(=O)cyclopropyl, -N(CH 3 )C(=O)cyclobutyl. In some embodiments, R 3 -NR a3 C(=O)OR a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R3 is -NHC(=O)OR a3 (For example, -NHC(=O)OCH 3 , -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t In some embodiments, R 3 is -N(CH 3 )C(=O)OR a3 (For example, -N(CH 3 )C(=O)OCH 3 , -N(CH 3 )C(=O)OEt, -N(CH 3 )C(=O)OPr, -N(CH 3 )C(=O)O i Pr, -N(CH 3 )C(=O)OBu, -N(CH 3 )C(=O)O t Bu, -N(CH 3 )C(=O)Ocyclopropyl, -N(CH 3 )C(=O)Ocyclobutyl).

[0331] In some embodiments, R 3 is -C(=O)N(R a3 ) 2 and R a3 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a3 , -C(=O)N(CH 3 )R a3 In some embodiments, R 3 is -C(=O)NH 2 In certain embodiments, R 3 is -C(=O)NHR a3 (For example, -C(=O)NHCH 3 , -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH tIn certain embodiments, R 3 is -C(=O)N(CH 3 )R a3 (For example, -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 3 )Et, -C(=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N(CH 3 ) cyclopropyl, -C(=O)N(CH 3 )cyclobutyl). In some embodiments, R 3 is -OC(=O)N(R a3 ) 2 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -OC(=O)NHR a3 (For example, -OC(=O)NHCH 3 , -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, -OC(=O)NHcyclopropyl, -OC(=O)NHcyclobutyl). In certain embodiments, R 3 is -OC(=O)N(CH 3 )R a3 (For example, -OC(=O)N(CH 3 ) 2 , -OC(=O)N(CH 3 )Et, -OC(=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N(CH3 ) cyclopropyl, -OC(=O)N(CH 3 )cyclobutyl).

[0332] In some embodiments, R 3 is -S(=O)R a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 3 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0333] In some embodiments, R 3 is -S(=O) 2 R a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -S(=O) 2 Alkyl (e.g., -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, -S(=O) 2 i In certain embodiments, R 3 is -S(=O) 2 Cycloalkyl (e.g., -S(=O) 2 Cyclopropyl, -S(=O) 2 Cyclobutyl, -S(=O) 2 Cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 3 is S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0334] In some embodiments, R 3 -SR a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 3 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 3 is -Saryl (e.g., -Sphenyl). In some embodiments, R 3 is -S(=O)(=NR a3 )R a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -S(=O)(=NH)R a3 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 3 is -S(=O)(=NCH 3 )R a3 (For example, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et, -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) t Bu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0335] In some embodiments, R 3 -NR a3 S(=O) 2 R a3 and R a3 is as defined in any of the embodiments described herein. In certain embodiments, R 3 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 i In certain embodiments, R 3 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 3 is -N(CH 3 )S(=O) 2 Alkyl (e.g., -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(=O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i In certain embodiments, R 3 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH 3 )S(=O) 2 Cyclopropyl, -N(CH 3 )S(=O) 2 Cyclobutyl, -N(CH 3 )S(=O) 2 Cyclopentyl, -N(CH 3 )S(=O) 2 Cyclohexyl).

[0336] In some embodiments, R 3 is -S(=O) 2 N(R a3 ) 2 and R a3 is as defined in any of the embodiments described herein. (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a3 , -S(=O) 2 N(CH 3 )R a3 ) In some embodiments, R 3 is -S(=O) 2 NH 2 In some embodiments, R 3 is -S(=O) 2 NHR a3 (For example, -S(=O) 2 NHCH 3 , -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S(=O) 2 NH i Pr, -S(=O) 2 NHcyclopropyl, -S(=O) 2 NHcyclobutyl). In some embodiments, R 3 is -S(=O) 2 N(CH 3 )R a3 (For example, -S(=O) 2 N(CH 3 ) 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0337] As generally described herein, each R 4 are independently -D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 , and -S(=O) 2 N(R a4 ) 2 R a4 is as defined in any of the embodiments described herein.

[0338] In some embodiments, R 4 is halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9Cycloalkyl (e.g., cyclopropyl), 3- to 10-membered heterocyclyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 R a4 is as defined in any of the embodiments described herein.

[0339] In certain embodiments, R 4 is halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 haloalkyl, 3-10 membered heterocyclyl (e.g., oxetanyl), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , and -C(=O)N(R a4 ) 2 R a4 is as defined in any of the embodiments described herein.

[0340] In some embodiments, R 4 ,Halo,-C 1 -C 6 Alkyl, -C 1 -C 6 haloalkyl, 3-10 membered heterocyclyl (e.g., oxetanyl), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), -OR a4 , -C(=O)R a4 , and -C(=O)N(R a4 )2 R a4 is as defined in any of the embodiments described herein.

[0341] In some embodiments, R 4 -C 1 -C 6 Alkyl, 3-10 membered heterocyclyl (e.g., oxetanyl), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), and -C(=O)N(R a4 ) 2 and each R a4 is as defined in any of the embodiments described herein. In some embodiments, each R a4 are independently H and -C 1 -C 6 and alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu).

[0342] In some embodiments, R 4 -Cl, -Me, -Et, - i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 , cyclopropyl, -OCH 3 , oxetan-3-yl, tetrahydrofuran-3-yl, -C(=O)NHOH, -C(=O)H, and -C(=O)NH 2 is selected from the group consisting of:

[0343] In certain embodiments, R 4 -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), 3- to 10-membered heterocyclyl (e.g., oxetan-3-yl), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), and -C(=O)NH 2is selected from the group consisting of:

[0344] In some embodiments, R 4 -Cl, -Me, -Et, - i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 In some embodiments, R 4 is selected from the group consisting of cyclopropyl, -Me, and -Et.

[0345] In some embodiments, R 4 is -Me, -Et, oxetan-3-yl, cyclopropyl, and -C(=O)NH 2 is selected from the group consisting of:

[0346] In some embodiments, R 4 is -Me, -Et, cyclopropyl, and -C(=O)NH 2 is selected from the group consisting of:

[0347] In some embodiments, R 4 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl.

[0348] In some embodiments, R 4 is selected from the group consisting of -Me, -Et, and cyclopropyl.

[0349] In some embodiments, R 4 is D.

[0350] In certain embodiments, R 4 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -F. In some embodiments, R 4 In some embodiments, R4 is -I.

[0351] In some embodiments, R 4 is -CN.

[0352] In certain embodiments, R 4 -C 1 -C 6 In some embodiments, R 4 In some embodiments, R 4 is -Et. In some embodiments, R 4 is -Pr or -iPr. In some embodiments, R 4 -C 1 -C 6 In some embodiments, R 4 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 4 is hydroxymethyl (-CH 2 In some embodiments, R 4 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0353] In some embodiments, R 4 -C 1 -C 6 In some embodiments, R 4 is trifluoromethyl (-CF 3 In another embodiment, R 4 is difluoromethyl (-CHF 2 ).

[0354] In some embodiments, R 4 -C 3 -C 9cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is cyclohexyl.

[0355] In some embodiments, R 4 is 3-6 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 4 is oxetanyl (e.g., oxetan-3-yl). In some embodiments, R 4 is tetrahydropyranyl. In some embodiments, R 4 is tetrahydrofuranyl. In some embodiments, R 4 is azetidinyl. In some embodiments, R 4 is pyrrolidinyl. In some embodiments, R 4 is piperidinyl. In some embodiments, R 4 is piperazinyl. In some embodiments, R 4 is morpholinyl. In some embodiments, R 4 is azepanil.

[0356] In some embodiments, R 4 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 4is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0357] In some embodiments, R 4 is arylalkyl. In some embodiments, R 4 is benzyl.

[0358] In some embodiments, R 4 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0359] In some embodiments, R 4 -OR a4 and R a4 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 4 is hydroxy. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is isopropoxy. In some embodiments, R 4 -C 1 -C 6 In some embodiments, R 4 is trifluoromethoxy (-OCF 3 ) and in other embodiments, R 4 is difluoromethoxy (-OCHF 2 ).

[0360] In some embodiments, R 4 is -N(Ra4 ) 2 and R a4 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a4 , -N(CH 3 )R a4 In some embodiments, R 4 is -NH 2 In some embodiments, R 4 -NHR a4 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 4 is -N(CH 3 )R a4 (For example, -N(CH 3 ) 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, -N(CH 3 )cyclopropyl, -N(CH 3 )cyclobutyl). In some embodiments, R 4 is -C(=O)R a4 OR -C(=O)OR a4 and R a4 is as defined in any of the embodiments described herein. In some embodiments, R 4 is -C(=O)R a4 and R a4 is as defined in any of the embodiments described herein. In some embodiments, R 4 is —C(═O)alkyl. In some embodiments, R 4 is -C(=O)CH 3 , -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O) t Bu, -C(=O) i Pr, -C(=O)Pr, or -C(=O)OCH 3 In some embodiments, R4 is acetyl (-C(=O)Me). In some embodiments, R 4 is -C(=O)OR a4 In some embodiments, R 4 is -COOH. In some embodiments, R 4 COOCH 3 It is.

[0361] In some embodiments, R 4 -NR a4 C(=O)R a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -NHC(=O)R a4 (e.g. -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 4 is -N(CH 3 )C(=O)R a4 (For example, -N(CH 3 )C(=O)Me, -N(CH 3 )C(=O)Et, -N(CH 3 )C(=O)Pr, -N(CH 3 )C(=O) i Pr, -N(CH 3 )C(=O)Bu, -N(CH 3 )C(=O) t Bu, -N(CH 3 )C(=O)cyclopropyl, -N(CH 3 )C(=O)cyclobutyl.

[0362] In some embodiments, R 4 -NR a4 C(=O)OR a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R4 is -NHC(=O)OR a4 (For example, -NHC(=O)OCH 3 , -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t In some embodiments, R 4 is -N(CH 3 )C(=O)OR a4 (For example, -N(CH 3 )C(=O)OCH 3 , -N(CH 3 )C(=O)OEt, -N(CH 3 )C(=O)OPr, -N(CH 3 )C(=O)O i Pr, -N(CH 3 )C(=O)OBu, -N(CH 3 )C(=O)O t Bu, -N(CH 3 )C(=O)Ocyclopropyl, -N(CH 3 )C(=O)Ocyclobutyl).

[0363] In some embodiments, R 4 is -C(=O)N(R a4 ) 2 and R a4 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a4 , -C(=O)N(CH 3 )R a4 In some embodiments, R 4 is -C(=O)NH 2 In certain embodiments, R 4 is -C(=O)NHR a4 (For example, -C(=O)NHCH 3 , -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH tIn certain embodiments, R 4 is -C(=O)N(CH 3 )R a4 (For example, -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 3 )Et, -C(=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N(CH 3 ) cyclopropyl, -C(=O)N(CH 3 )cyclobutyl).

[0364] In some embodiments, R 4 is -C(=O)N(OR a4 )(R a4 ) and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -C(=O)NH(OR a4 ) (e.g., -C(=O)NHOH, -C(=O)NHOCH 3 In some embodiments, R 4 is -C(=O)NHOH.

[0365] In some embodiments, R 4 is -OC(=O)N(R a4 ) 2 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -OC(=O)NHR a4 (For example, -OC(=O)NHCH 3 , -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH tBu, -OC(=O)NHcyclopropyl, -OC(=O)NHcyclobutyl). In certain embodiments, R 4 is -OC(=O)N(CH 3 )R a4 (For example, -OC(=O)N(CH 3 ) 2 , -OC(=O)N(CH 3 )Et, -OC(=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N(CH 3 ) cyclopropyl, -OC(=O)N(CH 3 )cyclobutyl).

[0366] In some embodiments, R 4 is -S(=O)R a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 4 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0367] In some embodiments, R 4 is -S(=O) 2 R a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -S(=O) 2 Alkyl (e.g., -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, -S(=O)2 i In certain embodiments, R 4 is -S(=O) 2 Cycloalkyl (e.g., -S(=O) 2 Cyclopropyl, -S(=O) 2 Cyclobutyl, -S(=O) 2 Cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 4 is S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0368] In some embodiments, R 4 -SR a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 4 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 4 is -Saryl (e.g., -Sphenyl).

[0369] In some embodiments, R 4 is -S(=O)(=NR a4 )R a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -S(=O)(=NH)R a4 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) tIn some embodiments, R 4 is -S(=O)(=NCH 3 )R a4 (For example, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et, -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) t Bu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0370] In some embodiments, R 4 -NR a4 S(=O) 2 R a4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 i In certain embodiments, R 4 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 4 is -N(CH 3 )S(=O) 2 Alkyl (e.g., -N(CH 3 )S(=O)2 Me, -N(CH 3 )S(=O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i In certain embodiments, R 4 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH 3 )S(=O) 2 Cyclopropyl, -N(CH 3 )S(=O) 2 Cyclobutyl, -N(CH 3 )S(=O) 2 Cyclopentyl, -N(CH 3 )S(=O) 2 Cyclohexyl).

[0371] In some embodiments, R 4 is -S(=O) 2 N(R a4 ) 2 and R a4 is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a4 , -S(=O) 2 N(CH 3 )R a4 In some embodiments, R 4 is -S(=O) 2 NH 2 In some embodiments, R 4 is -S(=O) 2 NHR a4 (For example, -S(=O) 2 NHCH 3 , -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S(=O) 2 NH i Pr, -S(=O) 2 NHcyclopropyl, -S(=O)2 NHcyclobutyl). In some embodiments, R 4 is -S(=O) 2 N(CH 3 )R a4 (For example, -S(=O) 2 N(CH 3 ) 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0372] Some embodiments include R 3 and R 4 In one embodiment, R 3 -H, -OCH 3 , -OEt, -OCF 3 , -OCHF 2 , -CHF 2 , -Me, -Et, -OH, and -NH 2 R 4 -Cl, -Me, -Et, - i Pr, -CF 3 , -CHF 2 , -OCHF 2 , cyclopropyl, and -C(=O)NH 2 In one embodiment, R 3 -H, -CHF 2 , -Me, and -NH 2 R 4 -Cl, -Me, -Et, -CF 3 , -CHF 2 , -OCHF 2 In a further embodiment, R is selected from the group consisting of oxetan-3-yl, and cyclopropyl. 3 is -NH2 -Me; and -Me; 4 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl. In one embodiment, R 3 is -NH 2 and R 4 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl. 3 is -NH 2 and R 4 is selected from the group consisting of -Me, -Et, and cyclopropyl.

[0373] In another embodiment, R 3 -H, -OCH 3 , -OEt, -OCF 3 , -OCHF 2 , -Et, and -OH; R 4 is -C(=O)NH 2 In some embodiments, R 3 -H, and -OCH 3 R 4 is -C(=O)NH 2 In some embodiments, R 3 -OCH 3 and R 4 is -C(=O)NH 2 It is.

[0374] As generally defined herein, each R 5 are independently H, -D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(Ra5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , -OC(=O)N(R a5 ) 2 , -S(=O)R a5 , -S(=O) 2 R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O) 2 R a5 , and -S(=O) 2 N(R a5 ) 2 R a5 is as defined in any of the embodiments described herein.

[0375] In some embodiments, R 5 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, -OR a5 , -N(R a5 ) 2 , -C(=O)R a5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 ) 2 , and -OC(=O)N(R a5 ), R a5is as defined in any of the embodiments described herein.

[0376] In certain embodiments, R 5 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, and -N(R a5 ) 2 R a5 is as defined in any of the embodiments described herein. In some embodiments, R a5 -H, and -C 1 -C 6 In some embodiments, R is selected from the group consisting of alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu). 5 -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), -OH, -O-(C 1 -C 6 alkyl) (e.g., -OCH 3 ), -NH 2 , -NH-(C 1 -C 6 alkyl) (e.g., -NHCH 3 ), and -N-(C 1 -C 6 Alkyl) 2 (For example, -N(CH 3 ) 2 In some embodiments, R 5 is H, -Me, and -NH 2 In certain embodiments, R 5 is selected from the group consisting of H and -Me.

[0377] In some embodiments, R 5 is H. In some embodiments, R 5 is -D. In certain embodiments, R 5 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 5 is -Cl. In some embodiments, R 5 is -F. In some embodiments, R 5 In some embodiments, R 5 is -I.

[0378] In some embodiments, R 5 is -CN.

[0379] In certain embodiments, R 5 -C 1 -C 6 In some embodiments, R 5 In some embodiments, R 5 is -Et. In some embodiments, R 5 is -Pr or -iPr. In some embodiments, R 5 -C 1 -C 6 In some embodiments, R 5 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 5 is hydroxymethyl (-CH 2 In some embodiments, R 5 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0380] In some embodiments, R 5 -C 1 -C 6 In some embodiments, R 5is trifluoromethyl (-CF 3 In another embodiment, R 5 is difluoromethyl (-CHF 2 ).

[0381] In some embodiments, R 5 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is cyclobutyl. In some embodiments, R 5 is cyclopentyl. In some embodiments, R 5 is cyclohexyl.

[0382] In some embodiments, R 5 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 5 is oxetanyl. In some embodiments, R 5 is tetrahydropyranyl. In some embodiments, R 5 is tetrahydrofuranyl. In some embodiments, R 5 is azetidinyl. In some embodiments, R 5 is pyrrolidinyl. In some embodiments, R 5 is piperidinyl. In some embodiments, R 5 is piperazinyl. In some embodiments, R 5 is morpholinyl. In some embodiments, R 5 is azepanil.

[0383] In some embodiments, R 5is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 5 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0384] In some embodiments, R 5 is arylalkyl. In some embodiments, R 5 is benzyl. In some embodiments, R 5 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0385] In some embodiments, R 5 -OR a5 and R a5 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 5 is hydroxy. In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is isopropoxy. In some embodiments, R 5 is difluoromethoxy (-OCHF 2 In some embodiments, R 5 is trifluoromethoxy (-OCF 3 ).

[0386] In some embodiments, R 5 is -N(R a5 ) 2 and R a5 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a5 , -N(CH 3 )R a5 In some embodiments, R 5 is -NH 2 In some embodiments, R 5 -NHR a5 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 5 is -N(CH 3 )R a5 (For example, -N(CH 3 ) 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, -N(CH 3 )cyclopropyl, -N(CH 3 )cyclobutyl).

[0387] In some embodiments, R 5 is -C(=O)R a5 OR -C(=O)OR a5 and R a5 is as defined in any of the embodiments described herein. In some embodiments, R 5 is -C(=O)R a5 and R a5 is as defined in any of the embodiments described herein. In some embodiments, R 5 is —C(═O)alkyl. In some embodiments, R 5 is -C(=O)CH 3, -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O) t Bu, -C(=O) i Pr, -C(=O)Pr, or -C(=O)OCH 3 In some embodiments, R 5 is acetyl (-C(=O)Me). In some embodiments, R 5 is -C(=O)OR a5 In some embodiments, R 5 is -COOH. In some embodiments, R 5 COOCH 3 It is.

[0388] In some embodiments, R 5 -NR a5 C(=O)R a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -NHC(=O)R a5 (For example, -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 5 is -N(CH 3 )C(=O)R a5 (For example, -N(CH 3 )C(=O)Me, -N(CH 3 )C(=O)Et, -N(CH 3 )C(=O)Pr, -N(CH 3 )C(=O) i Pr, -N(CH 3 )C(=O)Bu, -N(CH 3 )C(=O) t Bu, -N(CH 3 )C(=O)cyclopropyl, -N(CH 3 )C(=O)cyclobutyl.

[0389] In some embodiments, R 5 -NR a5 C(=O)OR a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -NHC(=O)OR a5 (For example, -NHC(=O)OCH 3 , -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t In some embodiments, R 5 is -N(CH 3 )C(=O)OR a5 (For example, -N(CH 3 )C(=O)OCH 3 , -N(CH 3 )C(=O)OEt, -N(CH 3 )C(=O)OPr, -N(CH 3 )C(=O)O i Pr, -N(CH 3 )C(=O)OBu, -N(CH 3 )C(=O)O t Bu, -N(CH 3 )C(=O)Ocyclopropyl, -N(CH 3 )C(=O)Ocyclobutyl).

[0390] In some embodiments, R 5 is -C(=O)N(R a5 ) 2 and R a5 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a5 , -C(=O)N(CH 3 )R a5 In some embodiments, R 5 is -C(=O)NH 2 In certain embodiments, R 5 is -C(=O)NHRa5 (For example, -C(=O)NHCH 3 , -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t In certain embodiments, R 5 is -C(=O)N(CH 3 )R a5 (For example, -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 3 )Et, -C(=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N(CH 3 ) cyclopropyl, -C(=O)N(CH 3 )cyclobutyl).

[0391] In some embodiments, R 5 is -OC(=O)N(R a5 ) 2 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -OC(=O)NHR a5 (For example, -OC(=O)NHCH 3 , -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, -OC(=O)NHcyclopropyl, -OC(=O)NHcyclobutyl). In certain embodiments, R 5 is -OC(=O)N(CH 3 )R a5 (For example, -OC(=O)N(CH 3 ) 2 , -OC(=O)N(CH 3 )Et, -OC(=O)N(CH3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N(CH 3 ) cyclopropyl, -OC(=O)N(CH 3 )cyclobutyl).

[0392] In some embodiments, R 5 is -S(=O)R a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 5 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0393] In some embodiments, R 5 is -S(=O) 2 R a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -S(=O) 2 Alkyl (e.g., -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, -S(=O) 2 i In certain embodiments, R 5 is -S(=O) 2 Cycloalkyl (e.g., -S(=O) 2 Cyclopropyl, -S(=O) 2 Cyclobutyl, -S(=O) 2 Cyclopentyl, -S(=O) 2cyclohexyl). In some embodiments, R 5 is S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0394] In some embodiments, R 5 -SR a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 5 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 5 is -Saryl (e.g., -Sphenyl).

[0395] In some embodiments, R 5 is -S(=O)(=NR a5 )R a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -S(=O)(=NH)R a5 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 5 is -S(=O)(=NCH 3 )R a5 (For example, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et, -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) iPr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) t Bu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0396] In some embodiments, R 5 -NR a5 S(=O) 2 R a5 and R a5 is as defined in any of the embodiments described herein. In certain embodiments, R 5 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 i In certain embodiments, R 5 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 5 is -N(CH 3 )S(=O) 2 Alkyl (e.g., -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(=O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i In certain embodiments, R 5 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH 3)S(=O) 2 Cyclopropyl, -N(CH 3 )S(=O) 2 Cyclobutyl, -N(CH 3 )S(=O) 2 Cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

[0397] In some embodiments, R 5 is -S(=O) 2 N(R a5 ) 2 and R a5 is as defined in any of the embodiments described herein. (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a5 , -S(=O) 2 N(CH 3 )R a5 In some embodiments, R 5 is -S(=O) 2 NH 2 In some embodiments, R 5 is -S(=O) 2 NHR a5 (For example, -S(=O) 2 NHCH 3 , -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S(=O) 2 NH i Pr, -S(=O) 2 NHcyclopropyl, -S(=O) 2 NHcyclobutyl). In some embodiments, R 5 is -S(=O) 2 N(CH 3 )R a5 (For example, -S(=O) 2 N(CH 3 ) 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O)2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0398] As generally defined herein, each R 6 are independently H, D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 , and -S(=O) 2 N(R a6 ) 2 and each R a6 is as defined in any of the embodiments described herein.

[0399] In certain embodiments, R6 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, and -OC(=O)N(R a6 ) 2 and each R a6 is as defined in any of the embodiments described herein.

[0400] In some embodiments, R 6 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, and -N(R a6 ) 2 and each R a6 is as defined in any of the embodiments described herein. In some embodiments, each R a6 are independently H and -C 1 -C 6 In some embodiments, R is selected from the group consisting of alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu). 6 -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), -OH, -O-(C 1 -C 6 alkyl) (e.g., -OCH3 ), -NH 2 , -NH-(C 1 -C 6 alkyl) (e.g., -NHCH 3 ), and -N-(C 1 -C 6 Alkyl) 2 (For example, -N(CH 3 ) 2 ).

[0401] In some embodiments, R 6 is H. In some embodiments, R 6 is -D.

[0402] In certain embodiments, R 6 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -F. In some embodiments, R 6 In some embodiments, R 6 is -I.

[0403] In some embodiments, R 6 is -CN. In certain embodiments, R 6 -C 1 -C 6 In some embodiments, R 6 In some embodiments, R 6 is -Et. In some embodiments, R 6 is -Pr or -iPr.

[0404] In some embodiments, R 6 -C 1 -C 6 In some embodiments, R 6 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R6 is hydroxymethyl (-CH 2 In some embodiments, R 6 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0405] In some embodiments, R 6 -C 1 -C 6 In some embodiments, R 6 is trifluoromethyl (-CF 3 In another embodiment, R 6 is difluoromethyl (-CHF 2 ). In some embodiments, R 6 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 is cyclohexyl. In some embodiments, R 6 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 6 is oxetanyl. In some embodiments, R 6 is tetrahydropyranyl. In some embodiments, R 6 is tetrahydrofuranyl. In some embodiments, R 6 is azetidinyl. In some embodiments, R6 is pyrrolidinyl. In some embodiments, R 6 is piperidinyl. In some embodiments, R 6 is piperazinyl. In some embodiments, R 6 is morpholinyl. In some embodiments, R 6 is azepanil.

[0406] In some embodiments, R 6 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 6 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, R 6 is arylalkyl. In some embodiments, R 6 is benzyl. In some embodiments, R 6 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0407] In some embodiments, R 6 -OR a6 and R a6 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 6 is hydroxy. In some embodiments, R 6 is methoxy. In some embodiments, R 6is ethoxy. In some embodiments, R 6 is propoxy. In some embodiments, R 6 is isopropoxy. In some embodiments, R 6 is difluoromethoxy (-OCHF 2 In some embodiments, R 6 is trifluoromethoxy (-OCF 3 ).

[0408] In some embodiments, R 6 is -N(R a6 ) 2 and R a6 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a6 , -N(CH 3 )R a6 In some embodiments, R 6 is -NH 2 In some embodiments, R 6 -NHR a6 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 6 is -N(CH 3 )R a6 (For example, -N(CH 3 ) 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, -N(CH 3 )cyclopropyl, -N(CH 3 )cyclobutyl).

[0409] In some embodiments, R 6 is -C(=O)R a6 OR -C(=O)OR a6 and R a6is as defined in any of the embodiments described herein. In some embodiments, R 6 is -C(=O)R a6 and R a6 is as defined in any of the embodiments described herein. In some embodiments, R 6 is —C(═O)alkyl. In some embodiments, R 6 is -C(=O)CH 3 , -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O) t Bu, -C(=O) i Pr, -C(=O)Pr, or -C(=O)OCH 3 In some embodiments, R 6 is acetyl (-C(=O)Me). In some embodiments, R 6 is -C(=O)OR a6 In some embodiments, R 6 is -COOH. In some embodiments, R 6 COOCH 3 It is.

[0410] In some embodiments, R 6 -NR a6 C(=O)R a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -NHC(=O)R a6 (e.g. -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 6 is -N(CH 3 )C(=O)R a6 (For example, -N(CH 3 )C(=O)Me, -N(CH 3 )C(=O)Et, -N(CH 3)C(=O)Pr, -N(CH 3 )C(=O) i Pr, -N(CH 3 )C(=O)Bu, -N(CH 3 )C(=O) t Bu, -N(CH 3 )C(=O)cyclopropyl, -N(CH 3 )C(=O)cyclobutyl.

[0411] In some embodiments, R 6 -NR a6 C(=O)OR a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -NHC(=O)OR a6 (For example, -NHC(=O)OCH 3 , -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t In some embodiments, R 6 is -N(CH 3 )C(=O)OR a6 (For example, -N(CH 3 )C(=O)OCH 3 , -N(CH 3 )C(=O)OEt, -N(CH 3 )C(=O)OPr, -N(CH 3 )C(=O)O i Pr, -N(CH 3 )C(=O)OBu, -N(CH 3 )C(=O)O t Bu, -N(CH 3 )C(=O)Ocyclopropyl, -N(CH 3 )C(=O)Ocyclobutyl).

[0412] In some embodiments, R 6 is -C(=O)N(R a6 ) 2 and Ra6 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a6 , -C(=O)N(CH 3 )R a6 In some embodiments, R 6 is -C(=O)NH 2 In certain embodiments, R 6 is -C(=O)NHR a6 (For example, -C(=O)NHCH 3 , -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t In certain embodiments, R 6 is -C(=O)N(CH 3 )R a6 (For example, -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 3 )Et, -C(=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N(CH 3 ) cyclopropyl, -C(=O)N(CH 3 )cyclobutyl).

[0413] In some embodiments, R 6 is -OC(=O)N(R a6 ) 2 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -OC(=O)NHR a6 (For example, -OC(=O)NHCH 3 , -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH iPr, -OC(=O)NHBu, -OC(=O)NH t Bu, -OC(=O)NHcyclopropyl, -OC(=O)NHcyclobutyl). In certain embodiments, R 6 is -OC(=O)N(CH 3 )R a6 (For example, -OC(=O)N(CH 3 ) 2 , -OC(=O)N(CH 3 )Et, -OC(=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N(CH 3 ) cyclopropyl, -OC(=O)N(CH 3 )cyclobutyl).

[0414] In some embodiments, R 6 is -S(=O)R a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 6 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0415] In some embodiments, R 6 is -S(=O) 2 R a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -S(=O) 2 Alkyl (e.g., -S(=O) 2 Me, -S(=O)2 Et, -S(=O) 2 Pr, -S(=O) 2 i In certain embodiments, R 6 is -S(=O) 2 Cycloalkyl (e.g., -S(=O) 2 Cyclopropyl, -S(=O) 2 Cyclobutyl, -S(=O) 2 Cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 6 is S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0416] In some embodiments, R 6 -SR a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 6 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 6 is -Saryl (e.g., -Sphenyl).

[0417] In some embodiments, R 6 is -S(=O)(=NR a6 )R a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -S(=O)(=NH)R a6 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) tIn some embodiments, R 6 is -S(=O)(=NCH 3 )R a6 (For example, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et, -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) t Bu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0418] In some embodiments, R 6 -NR a6 S(=O) 2 R a6 and R a6 is as defined in any of the embodiments described herein. In certain embodiments, R 6 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 i In certain embodiments, R 6 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl).

[0419] In certain embodiments, R 6 is -N(CH 3 )S(=O) 2is alkyl, R a6 is as defined in any of the embodiments described herein (e.g., -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(=O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i In certain embodiments, R 6 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH 3 )S(=O) 2 Cyclopropyl, -N(CH 3 )S(=O) 2 Cyclobutyl, -N(CH 3 )S(=O) 2 Cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

[0420] In some embodiments, R 6 is -S(=O) 2 N(R a6 ) 2 and R a6 is as defined in any of the embodiments described herein. (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a6 , -S(=O) 2 N(CH 3 )R a6 In some embodiments, R 6 is -S(=O) 2 NH 2 In some embodiments, R 6 is -S(=O) 2 NHR a6 (For example, -S(=O) 2 NHCH 3 , -S(=O) 2 NHEt, -S(=O) 2NHPr, -S(=O) 2 NH i Pr, -S(=O) 2 NHcyclopropyl, -S(=O) 2 NHcyclobutyl). In some embodiments, R 6 is -S(=O) 2 N(CH 3 )R a6 (For example, -S(=O) 2 N(CH 3 ) 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0421] As generally defined herein, ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position.

[0422] In some embodiments, each aryl and heteroaryl in ring B is selected from 0, 1, 2, or 3 R 7 at any available position, and each R 7 is as defined in any of the embodiments described herein. In some embodiments, ring B is selected from the group consisting of 0, 1, or 2 R 7 In some embodiments, ring B is substituted with 0 or 1 R 7 In some embodiments, ring B is substituted with one or two R 7 In some embodiments, ring B is unsubstituted. In some embodiments, ring B is substituted with one R 7 In some embodiments, ring B is substituted with two R 7In some embodiments, ring B is substituted with 3 R 7 is replaced by.

[0423] In some embodiments, ring B is independently -C 6 -C 10 Monocyclic or bicyclic aryl (e.g., phenyl, fully aromatic 9-10 membered bicyclic aryl, C 5 -C 6 bicyclic aryls comprising a phenyl ring fused to a carbocycle, a 5-6 membered heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or oxidized forms thereof; 5-6 membered monocyclic heteroaryls (e.g., comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S); and 8-10 membered bicyclic heteroaryls (e.g., comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S), each aryl and heteroaryl being optionally substituted (e.g., comprising 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0424] In some embodiments, ring B is C 6 -C 10Monocyclic or bicyclic aryl (e.g., phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydroquinolinyl, 1,2 dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl, chromanyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-benzo[b][1, 4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, 2,3-dihydro-1H-benzo[d]imidazolyl), 5-6 membered monocyclic heteroaryl (e.g., thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl), 8-10 membered bicyclic heteroaryl (e.g., benzo[d]isothiazolyl, indolyl, benzofuranyl, ranyl, 1H-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazolyl [1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl), each aryl and heteroaryl is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0425] In some embodiments, Ring B is thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoxa ... and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R are optionally substituted). 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0426] In some embodiments, Ring B is thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0427] In some embodiments, Ring B is selected from the group consisting of pyridinyl, pyrimidinyl, isoquinolinyl, pyrazolyl, chromanyl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0428] In some embodiments, Ring B is selected from the group consisting of pyridinyl, pyrimidinyl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0429] In some embodiments, Ring B is pyrazol-5-yl, pyrazol-1-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, pyridin-3-yl, pyridin-4-yl, phenyl, naphthalen-1-yl, naphthalen-2-yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1H-indazol-5-yl, 1H-indazol- 4-yl, 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-3-yl, isoquinolin-6-yl, isoquinolin-1-yl, benzo[d]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d ]thiazol-4-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrazolo[3,4-b]pyridin- 5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5-yl, chroman-5-yl, and thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0430] In some embodiments, Ring B is pyrazol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, pyridin-3-yl, pyridin-4-yl, phenyl, naphthalen-1-yl, naphthalen-2-yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1H-indazol-5-yl, 1H-indazol ...phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-3-yl, isoquinolin-6-yl, benzo[d]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazole- 4-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrazolo[3,4-b]pyridine -5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5-yl, and thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0431] In some embodiments, Ring B is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrazol-5-yl, pyrazol-1-yl, isoquinolin-1-yl, chroman-5-yl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0432] In some embodiments, ring B is independently -C 6 -C 10 Monocyclic or bicyclic aryl (e.g., phenyl, fully aromatic 9-10 membered bicyclic aryl, C 5 -C 6 and 8-10 membered bicyclic heteroaryl (e.g., containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S), each aryl and heteroaryl being optionally substituted (e.g., containing 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0433] In some embodiments, ring B is independently -C 6 -C 10 Monocyclic or bicyclic aryl (e.g., phenyl, fully aromatic 9-10 membered bicyclic aryl, C 5 -C 6and 5-6 membered monocyclic heteroaryl (e.g., containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S), each aryl and heteroaryl being optionally substituted (e.g., containing 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0434] In some embodiments, Ring B is independently selected from the group consisting of phenyl and 5-6 membered monocyclic heteroaryl (e.g., containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S), where phenyl and heteroaryl are optionally substituted (e.g., containing 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0435] In some embodiments, Ring B is selected from the group consisting of pyridinyl, pyrimidinyl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0436] In some embodiments, Ring B is selected from the group consisting of pyridinyl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0437] In some embodiments, Ring B is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0438] In some embodiments, Ring B is selected from the group consisting of pyridin-2-yl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein).

[0439] In some embodiments, ring B is unsubstituted. In some embodiments, ring B is unsubstituted. 7 In some embodiments, ring B is substituted with two R 7 In some embodiments, ring B is substituted with 3 R 7 is replaced by.

[0440] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0441] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0442] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0443] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0444] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0445] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein.

[0446] In some embodiments, ring B is [ka] and each R 7 is as defined in any of the embodiments described herein. In some embodiments, Ring B is an optionally substituted 6-10 membered monocyclic or bicyclic aryl. In some embodiments, Ring B is 0, 1, 2, or 3 R 7 is replaced by R 7is as defined in any of the embodiments described herein. In some embodiments, Ring B is naphthalenyl or phenyl, each of which is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 7 So, R 7 is as defined in any of the embodiments described herein).

[0447] In some embodiments, Ring B is an optionally substituted phenyl. In some embodiments, Ring B is 0, 1, 2, or 3 R 7 and each R 7 are independently as defined in any of the embodiments described herein. In some embodiments, the phenyl is unsubstituted. In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with two R 7 In some embodiments, the phenyl is substituted with three R 7 is replaced by.

[0448] In some embodiments, ring B is [ka] wherein each R 7 is as defined in any of the embodiments described herein.

[0449] In some embodiments, ring B is [ka] wherein each R 7is as defined in any of the embodiments described herein.

[0450] In some embodiments, ring B is [ka] wherein each R 7 is as defined in any of the embodiments described herein.

[0451] In some embodiments, ring B is [ka] wherein each R 7 is as defined in any of the embodiments described herein.

[0452] In some embodiments, ring B is [ka] wherein each R 7 is as defined in any of the embodiments described herein.

[0453] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0454] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0455] In some embodiments, ring B is [ka] It is.

[0456] In some embodiments, ring B is [ka] It is.

[0457] In some embodiments, ring B is [ka] It is.

[0458] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0459] In some embodiments, ring B is [ka] It is.

[0460] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0461] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0462] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0463] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein. In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0464] In some embodiments, ring B is [ka] It is.

[0465] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0466] In some embodiments, ring B is [ka] It is.

[0467] In some embodiments, ring B is [ka] It is.

[0468] In some embodiments, ring B is [ka] It is.

[0469] In some embodiments, ring B is [ka] It is.

[0470] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0471] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0472] In some embodiments, ring B is [ka] where each R 7 is as defined in any of the embodiments described herein.

[0473] In some embodiments, ring B is [ka] is selected from. In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] It is.

[0474] In some embodiments, the compound of formula (A) is a compound of formula (A-II): [ka] where R a , R a’ , ring A, and R 1 is as defined in any of the embodiments described herein, and phenyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the compound of formula (I) is substituted with a compound of formula (II): [ka] wherein ring A and R 1is as defined in any of the embodiments described herein, and phenyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the phenyl is unsubstituted. In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with one R 7 In some embodiments, the phenyl is substituted with one R meta to the point of attachment to the piperidine. 7 In some embodiments, the phenyl is substituted with two R 7 In some embodiments, the phenyl is substituted with three R 7 is replaced by.

[0475] In some embodiments, the compound of formula (A) is a compound of formula (A-II_1): [ka] where R a , R a’ , ring A, R 1 , and R 7 is as defined in any of the embodiments described herein. In some further embodiments, the compound of formula (I) is a compound of formula (II_1): [ka] wherein ring A, R 1 , and R 7 is as defined in any of the embodiments described herein.

[0476] In some embodiments, the compound of formula (A) is a compound of formula (A-II_2): [ka] where R a , R a’ , ring A, R 1 , and R 7is as defined in any of the embodiments described herein.

[0477] In another embodiment, the compound of formula (I) is a compound of formula (II_2): [ka] wherein ring A, R 1 , and R 7 is as defined in any of the embodiments described herein.

[0478] In some embodiments, Ring B is halo (e.g., fluoro, chloro, bromo), -C 1 -C 6 Alkyl (e.g., -Me), -C 1 -C 6 Haloalkyl (e.g., -CF 3 ), -C 1 -C 6 Heteroalkoxy (e.g., -OCH 2 CH 2 N(CH 3 ) 2 ), or phenyl substituted with 3-10 membered heterocyclyl (e.g., piperazinyl (e.g., N-Me piperazinyl)). In some embodiments, Ring B is -F, -Cl, -Me, -CF 3 , -OCH 2 CH 2 N(CH 3 ) 2 ), or N-Mepiperazinyl. In some embodiments, Ring B is phenyl substituted with halo (e.g., -F, -Cl, -Br). In some embodiments, Ring B is phenyl substituted with -Me. In some embodiments, Ring B is -CF 3 is phenyl substituted with

[0479] In some embodiments, ring B is an optionally substituted 9-10 membered bicyclic aryl (e.g., naphthalenyl). In some embodiments, ring B is naphthalenyl (e.g., naphthalen-1-yl, naphthalen-2-yl). In some embodiments, ring B is naphthalen-2-yl. In some embodiments, ring B is C 5 -C 6 In some embodiments, ring B is an optionally substituted bicyclic aryl containing a phenyl ring fused to a carbocycle (e.g., tetrahydronaphthyl, dihydroindenyl). In some embodiments, ring B is 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, ring B is 2,3-dihydro-1H-indenyl. In some embodiments, ring B is an optionally substituted bicyclic aryl containing a phenyl ring fused to a 5-6 membered heterocycle containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or an oxidized form thereof (e.g., tetrahydronaphthalenyl, dihydroindenyl, 1,2,3,4 tetrahydroquinolinyl, 1,2-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, tetrahydroisoquinolinyl, chromanyl, indolinyl, isoindolinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzodioxolyl, dihydrobenzimidazolyl).

[0480] In some embodiments, the bicyclic aryl is unsubstituted. In some embodiments, ring B is unsubstituted naphthalenyl (e.g., naphthalen-1-yl, naphthalen-2-yl). In some embodiments, ring B is unsubstituted naphthalen-2-yl. In some embodiments, the bicyclic aryl has 0, 1, 2, or 3 R 7 Each R 7 is as defined in any of the embodiments described herein. In some embodiments, the bicyclic aryl is selected from the group consisting of one R 7 In some embodiments, the bicyclic aryl is substituted with one R 7 is replaced by R 7 is selected from the group consisting of halo (e.g., -F, -Cl, -Br), -Me, ═O.

[0481] In some embodiments, Ring B is an optionally substituted 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms).

[0482] In some embodiments, the 5-6 membered monocyclic heteroaryl is unsubstituted. In some embodiments, the 5-6 membered monocyclic heteroaryl has 0, 1, 2, or 3 R 7 Each R 7 is as defined in any of the embodiments described herein. In some embodiments, the 5-6 membered monocyclic heteroaryl is selected from one R 7 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with two R 7 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with two R 7 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with three R 7 is replaced by.

[0483] In some embodiments, Ring B is selected from the group consisting of thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is selected from the group consisting of pyrazol-5-yl, pyrazol-1-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyrimidin-2-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0484] In some embodiments, Ring B is selected from the group consisting of pyrazol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyrimidin-2-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0485] In some embodiments, Ring B is a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl), each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0486] In some embodiments, Ring B is selected from the group consisting of thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, and triazolyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is selected from the group consisting of pyrazol-5-yl, pyrazol-1-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, and thiazol-5-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0487] In some embodiments, Ring B is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl). In some embodiments, Ring B is pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl). In some embodiments, Ring B is thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, Ring B is furyl (e.g., fur-2-yl, fur-3-yl). In some embodiments, Ring B is thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, Ring B is isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl). In some embodiments, Ring B is oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl). In some embodiments, Ring B is soxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl). In some embodiments, Ring B is imidazolyl (e.g., imidazol-2-yl, imidazol-4-yl). In some embodiments, Ring B is triazolyl. In some embodiments, Ring B is thiadiazolyl. In some embodiments, Ring B is oxadiazolyl. In certain embodiments, the 5-membered monocyclic heteroaryl is unsubstituted. In some embodiments, the 5-membered monocyclic heteroaryl has one R 7 In some embodiments, the 5-membered monocyclic heteroaryl is substituted with two R 7 In some embodiments, the 5-membered monocyclic heteroaryl is substituted with 3 R 7 is replaced by.

[0488] In some embodiments, Ring B is a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, the 6-membered monocyclic heteroaryl is unsubstituted. In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 0, 1, 2, or 3 R 7In some embodiments, the 6-membered monocyclic heteroaryl is substituted with one R 7 In some embodiments, the 6-membered monocyclic heteroaryl is substituted with two R 7 In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 3 R 7 In some embodiments, Ring B is selected from the group consisting of pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), and pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyrimidin-2-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is selected from the group consisting of pyridin-2-yl, and pyrimidin-2-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl) and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyridin-2-yl and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyridin-3-yl and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyridin-4-yl and is optionally substituted (e.g., 0, 1, 2, or 3 R 7In some embodiments, Ring B is pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl) and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyrimidin-2-yl and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is pyrimidin-4-yl. In some embodiments, Ring B is pyrimidin-5-yl and is optionally substituted (e.g., 0, 1, 2, or 3 R 7 is substituted at any available position.

[0489] In one embodiment, Ring B is [ka] where R 7 is as defined in any of the embodiments described herein. In one embodiment, Ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] It is.

[0490] In some embodiments, the compound of formula (A) is a compound of formula (A-III): [ka] where Ra , R a’ , ring A, and R 1 is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 is replaced by.

[0491] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] wherein ring A and R 1 is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the pyridinyl is unsubstituted. In some embodiments, the pyridinyl is substituted with one R 7 In some embodiments, the pyridinyl is substituted with one R 7 In some embodiments, pyridinyl is substituted with two R 7 In some embodiments, pyridinyl is substituted with three R 7 is replaced by.

[0492] In some embodiments, the compound of formula (A) is a compound of formula (A-III_1): [ka] where R a , R a’ , ring A, R 1 , and R 7 is as defined in any of the embodiments described herein.

[0493] In some embodiments, the compound of formula (I) is a compound of formula (III_1): [ka] wherein ring A, R 1 , and R 7 is as defined in any of the embodiments described herein.

[0494] In some embodiments, the compound of formula (A) is a compound of formula (A-IV): [ka] where R a , R a’ , ring A, and R 1 is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 is replaced by.

[0495] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] wherein ring A and R 1 is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the pyridinyl is unsubstituted. In some embodiments, the pyridinyl is substituted with one R 7 In some embodiments, pyridinyl is substituted with two R 7 In some embodiments, pyridinyl is substituted with three R 7 is replaced by.

[0496] In some embodiments, the compound of formula (A) is a compound of formula (AV): [ka] where R a , R a’ , ring A, and R 1is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 is replaced by.

[0497] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] wherein ring A and R 1 is as defined in any of the embodiments described herein, and pyridinyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the pyridinyl is unsubstituted. In some embodiments, the pyridinyl is substituted with one R 7 In some embodiments, pyridinyl is substituted with two R 7 In some embodiments, pyridinyl is substituted with three R 7 is replaced by.

[0498] In some embodiments, the compound of formula (A) is a compound of formula (A-VI): [ka] where R a , R a’ , ring A, and R 1 is as defined in any of the embodiments described herein, and pyrimidinyl is selected from 0, 1, 2, or 3 R 7 is replaced by.

[0499] In some embodiments, the compound of formula (I) is a compound of formula (VI): [ka] wherein ring A and R 1is as defined in any of the embodiments described herein, and pyrimidinyl is selected from 0, 1, 2, or 3 R 7 In some embodiments, the pyrimidinyl is unsubstituted. In some embodiments, the pyrimidinyl is substituted with one R 7 In some embodiments, the pyrimidinyl is substituted with two R 7 In some embodiments, the pyrimidinyl is substituted with three R 7 is replaced by.

[0500] In some embodiments, ring B is an 8-10 membered bicyclic heteroaryl, the bicyclic heteroaryl being optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7 is as defined in any of the embodiments described herein. In certain embodiments, Ring B is an 8-10 membered bicyclic heteroaryl (e.g., 5,5 bicyclic heteroaryl (e.g., 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl), 5,6 bicyclic heteroaryl (e.g., indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[d]isothiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a ]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, thiazolo[5,4-b]pyridinyl), or 6,6 bicyclic heteroaryl (e.g., quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl), each bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, each bicyclic heteroaryl being optionally substituted (e.g., 0, 1, 2, or 3 R 7 is replaced by R 7is as defined in any of the embodiments described herein. In some embodiments, Ring B is a 5,6 bicyclic heteroaryl (e.g., indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[d]isothiazolyl, imidazo[1,2-a]pyridinyl, imidazo [1,2-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, thiazolo[5,4-b]pyridinyl), or 6,6 bicyclic heteroaryl (e.g., quinolinyl, isoquinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl).

[0501] In some embodiments, Ring B is a 5,6 bicyclic heteroaryl (e.g., indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[d]isothiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, thiazolo[5,4-b]pyridinyl).

[0502] In some embodiments, Ring B is a 6,6 bicyclic heteroaryl (eg, quinolinyl, isoquinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl).

[0503] In some embodiments, a bicyclic heteroaryl (e.g., 5,5 bicyclic heteroaryl, 5,6 bicyclic heteroaryl, 6,6 bicyclic heteroaryl) contains 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, a bicyclic heteroaryl contains 1 or 2 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, a bicyclic heteroaryl contains 1 heteroatom selected from the group consisting of O, N, and S. In some embodiments, a bicyclic heteroaryl contains 2 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, a bicyclic heteroaryl contains 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, a bicyclic heteroaryl contains 4 heteroatoms selected from the group consisting of O, N, and S.

[0504] In some embodiments, Ring B is indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxophenyl ... and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0505] In some embodiments, Ring B is indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d ]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 (Replaced by ).

[0506] In certain embodiments, Ring B is selected from the group consisting of 2H-indazolyl, quinolinyl, isoquinolinyl, and benzo[d]thiazolyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is an optionally substituted 2H-indazolyl (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is an optionally substituted quinolinyl (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is an optionally substituted isoquinolinyl (e.g., 0, 1, 2, or 3 R 7 In some embodiments, Ring B is an optionally substituted benzo[d]thiazolyl (e.g., 0, 1, 2, or 3 R 7 (replaced by ).

[0507] In some embodiments, Ring B is selected from the group consisting of isoquinolinyl, and chromanyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 7 in any available position).

[0508] In some embodiments, Ring B is indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1H-indazol-5-yl, 1H-indazol-4-yl, 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-3-yl, isoquinolin-1-yl, isoquinolin-6-yl, benzo[d]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-4-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]ox...

Claims

1. A compound of formula (A), or a pharmaceutically acceptable salt thereof: During the ceremony, 【Chem.721】 Ring A is 【Chemical 722】 is selected from the group consisting of Ring B is C ６ -C １０ aryl, and 5- to 10-membered heteroaryl, each of which is optionally substituted at any available position; Ring A １ and A ２ each is independently a 5- to 6-membered carbocyclyl, a 5- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A ３ is independently a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein said heterocyclyl and heteroaryl contain at least one nitrogen atom; Each R １ But independently, -C １ -C ６ Alkyl, —C ２ -C ６ Heteroalkyl, —C ２ -C ６ Haloalkyl, —C ３ -C １０ Carbocyclyl, C ６ -C １０ selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is optionally substituted at any available position; Each R ２ are independently -D, halo, ═O, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ２ , -N(R ａ２ ) ２ , -C(=O)R ａ２ , -C(=O)OR ａ２ , -NR ａ２ C(=O)R ａ２ , -NR ａ２ C(=O)OR ａ２ , -C(=O)N(R ａ２ ) ２ , -C(=O)N(OR ａ２ ) (R ａ２ ), -OC(=O)N(R ａ２ ) ２ , -S(=O)R ａ２ , -S(=O) ２ R ａ２ , -SR ａ２ , -S(=O)(=NR ａ２ ) R ａ２ , -NR ａ２ S (= O) ２ R ａ２ , and -S(=O) ２ N (R ａ２ ) ２ is selected from the group consisting of Each R ３ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ３ , -N(R ａ３ ) ２ , -C(=O)R ａ３ , -C(=O)OR ａ３ , -NR ａ３ C(=O)R ａ３ , -NR ａ３ C(=O)OR ａ３ , -C(=O)N(R ａ３ ) ２ , -OC(=O)N(R ａ３ ) ２ , -S(=O)R ａ３ , -S(=O) ２ R ａ３ , -SR ａ３ , -S(=O)(=NR ａ３ ) R ａ３ , -NR ａ３ S (= O) ２ R ａ３ , and -S(=O) ２ N (R ａ３ ) ２ is selected from the group consisting of Each R ４ are independently D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ４ , -N(R ａ４ ) ２ , -C(=O)R ａ４ , -C(=O)OR ａ４ , -NR ａ４ C(=O)R ａ４ , -NR ａ４ C(=O)OR ａ４ , -C(=O)N(R ａ４ ) ２ , -OC(=O)N(R ａ４ ) ２ , -S(=O)R ａ４ , -S(=O) ２ R ａ４ , -SR ａ４ , -S(=O)(=NR ａ４ ) R ａ４ , -NR ａ４ S (= O) ２ R ａ４ , and -S(=O) ２ N (R ａ４ ) ２ is selected from the group consisting of Each R ５ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ５ , -N(R ａ５ ) ２ , -C(=O)R ａ５ , -C(=O)OR ａ５ , -NR ａ５ C(=O)R ａ５ , -NR ａ５ C(=O)OR ａ５ , -C(=O)N(R ａ５ ) ２ , -OC(=O)N(R ａ５ ) ２ , -S(=O)R ａ５ , -S(=O) ２ R ａ５ , -SR ａ５ , -S(=O)(=NR ａ５ ) R ａ５ , -NR ａ５ S (= O) ２ R ａ５ , and -S(=O) ２ N (R ａ５ ) ２ is selected from the group consisting of Each R ６ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ６ , -N(R ａ６ ) ２ , -C(=O)R ａ６ , -C(=O)OR ａ６ , -NR ａ６ C(=O)R ａ６ , -NR ａ６ C(=O)OR ａ６ , -C(=O)N(R ａ６ ) ２ , -OC(=O)N(R ａ６ ) ２ , -S(=O)R ａ６ , -S(=O) ２ R ａ６ , -SR ａ６ , -S(=O)(=NR ａ６ ) R ａ６ , -NR ａ６ S (= O) ２ R ａ６ , and -S(=O) ２ N (R ａ６ ) ２ is selected from the group consisting of Each R ａ and R ａ ' are independently H and C １ -C ６ alkyl, Each R ａ２ , R ａ３ , R ａ４ , R ａ５ , and R ａ６ are independently H, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, C ３ -C ９ and each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R ９ and each R ９ are independently ═O, halo, —CN, —C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Hydroxyalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR ｂ , -N(R ｂ ) ２ , -C(=O)R ｂ , -C(=O)OR ｂ , -NR ｂ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -C(=O)N(R ｂ ) ２ , -OC(=O)N(R ｂ ) ２ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -SR ｂ , -S(=O)(=NR ｂ ) R ｂ , -NR ｂ S (= O) ２ R ｂ , and -S(=O) ２ N (R ｂ ) ２ and each R ｂ are independently H, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu), and C ３ -C ９ cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); m is 0, 1, 2, or 3; (i) R ４ But -CH ３ If R ３ But it's not H, (ii) The compound is selected from the group consisting of compounds a) to k): a) N1-benzyl-N2-(8-fluoroquinolin-3-yl)-N1-(2-(2-methoxyethoxy)ethyl)oxalamide: 【Chemical 723】 b) N1-(8-fluoroquinolin-3-yl)-N2-phenethyl-N2-(pyridin-4-ylmethyl)oxalamide: 【Chemical 724】 c) N1-(6-amino-5,6,7,8-tetrahydroquinolin-3-yl)-N2-(3-fluoro-4-(pyridin-3-yl)benzyl)-N2-methyloxalamide: 【Chemical 725】 d) N1-cyclopentyl-N1-(3-fluorobenzyl)-N2-(8-fluoroquinolin-3-yl)oxalamide: 【Chemical Formula 726】 e) N1-(4-carbamoylbenzyl)-N2-(8-fluoroquinolin-3-yl)-N1-methyloxalamide: 【Chemical 727】 f) N1-benzyl-N1-methyl-N2-(quinolin-3-yl)oxalamide: 【Chemical 728】 g) N1-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-N2-(5-((dimethylamino)methyl)pyridin-3-yl)-N1-methyloxalamide 【Chemical 729】 h) N1-(4-bromo-2-(3-chlorophenoxy)benzyl)-N2-(5-bromo-2-(4-methylpiperazin-1-yl)pyridin-3-yl)-N1-methyloxalamide 【Chemical 730】 i) Methyl 4-((N-methyl-2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)acetamido)methyl)benzoate 【Chemistry 731】 j) N1-methyl-N1-(2-methylbenzyl)-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: 【Chemical 732】 k) N1-(furan-2-ylmethyl)-N1-methyl-N2-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxalamide: 【Chemical 733】 or a pharmaceutically acceptable salt thereof, which is not one of:

2. R ａ and R ａ 2. The compound of claim 1, wherein each of R, ...

3. The compound is a compound of formula (I): 【Chemistry 734】 2. The compound of claim 1, wherein:

4. Ring A is 【Chemical 735】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. Ring A is 【Chemical 736】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

6. The compound is a compound of formula (A_1): 【Chemical 737】 2. The compound of claim 1, wherein:

7. The compound is a compound of formula (A_4): 【Chemical 738】 2. The compound of claim 1, wherein:

8. Ring A is 【Chemical 739】 wherein: Each R ２ are independently -D, halo, ═O, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ２ , -N(R ａ２ ) ２ , -C(=O)R ａ２ , -C(=O)OR ａ２ , -NR ａ２ C(=O)R ａ２ , -NR ａ２ C(=O)OR ａ２ , -C(=O)N(R ａ２ ) ２ , -C(=O)N(OR ａ２ ) (R ａ２ ), -OC(=O)N(R ａ２ ) ２ , -S(=O)R ａ２ , -S(=O) ２ R ａ２ , -SR ａ２ , -S(=O)(=NR ａ２ ) R ａ２ , -NR ａ２ S (= O) ２ R ａ２ , and -S(=O) ２ N (R ａ２ ) ２ is selected from the group consisting of Each R ３ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ３ , -N(R ａ３ ) ２ , -C(=O)R ａ３ , -C(=O)OR ａ３ , -NR ａ３ C(=O)R ａ３ , -NR ａ３ C(=O)OR ａ３ , -C(=O)N(R ａ３ ) ２ , -OC(=O)N(R ａ３ ) ２ , -S(=O)R ａ３ , -S(=O) ２ R ａ３ , -SR ａ３ , -S(=O)(=NR ａ３ ) R ａ３ , -NR ａ３ S (= O) ２ R ａ３ , and -S(=O) ２ N (R ａ３ ) ２ is selected from the group consisting of Each R ４ are independently D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ４ , -N(R ａ４ ) ２ , -C(=O)R ａ４ , -C(=O)OR ａ４ , -NR ａ４ C(=O)R ａ４ , -NR ａ４ C(=O)OR ａ４ , -C(=O)N(R ａ４ ) ２ , -OC(=O)N(R ａ４ ) ２ , -S(=O)R ａ４ , -S(=O) ２ R ａ４ , -SR ａ４ , -S(=O)(=NR ａ４ ) R ａ４ , -NR ａ４ S (= O) ２ R ａ４ , and -S(=O) ２ N (R ａ４ ) ２ is selected from the group consisting of Each R ５ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ５ , -N(R ａ５ ) ２ , -C(=O)R ａ５ , -C(=O)OR ａ５ , -NR ａ５ C(=O)R ａ５ , -NR ａ５ C(=O)OR ａ５ , -C(=O)N(R ａ５ ) ２ , -OC(=O)N(R ａ５ ) ２ , -S(=O)R ａ５ , -S(=O) ２ R ａ５ , -SR ａ５ , -S(=O)(=NR ａ５ ) R ａ５ , -NR ａ５ S (= O) ２ R ａ５ , and -S(=O) ２ N (R ａ５ ) ２ is selected from the group consisting of Each R ６ are independently H, D, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ６ , -N(R ａ６ ) ２ , -C(=O)R ａ６ , -C(=O)OR ａ６ , -NR ａ６ C(=O)R ａ６ , -NR ａ６ C(=O)OR ａ６ , -C(=O)N(R ａ６ ) ２ , -OC(=O)N(R ａ６ ) ２ , -S(=O)R ａ６ , -S(=O) ２ R ａ６ , -SR ａ６ , -S(=O)(=NR ａ６ ) R ａ６ , -NR ａ６ S (= O) ２ R ａ６ , and -S(=O) ２ N (R ａ６ ) ２ is selected from the group consisting of Each R ａ２ , R ａ３ , R ａ４ , R ａ５ , and R ａ６ are independently H, -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, C ３ -C ９ and each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R ９ and each R ９ are independently ═O, halo, —CN, —C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Hydroxyalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR ｂ , -N(R ｂ ) ２ , -C(=O)R ｂ , -C(=O)OR ｂ , -NR ｂ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -C(=O)N(R ｂ ) ２ , -OC(=O)N(R ｂ ) ２ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -SR ｂ , -S(=O)(=NR ｂ ) R ｂ , -NR ｂ S (= O) ２ R ｂ , and -S(=O) ２ N (R ｂ ) ２ and each R ｂ are independently H, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu), and C ３ -C ９ 2. A cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. Ring A is 【Chemical 740】 9. The compound of claim 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

10. Each R ２ are independently -D, ═O, -C １ -C ６ Alkyl, and —N(R ａ２ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. Each R ａ２ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

12. Each R ２ are independently -NH ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

13. Each R ２ But -NH ２ 2. The compound of claim 1, wherein:

14. Ring A is 【Chemistry 741】 9. The compound of claim 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

15. Ring A is 【Chemistry 742】 9. The compound of claim 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. Ring A is 【Chemical 743】 2. The compound of claim 1, wherein:

17. R ５ H, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, and —N(R ａ５ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. R ａ５ But H, and C １ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu).

19. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of H and -Me.

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

21. R ６ H, halo, -CN, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, and —N(R ａ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

22. Each R ａ６ are independently H and -C １ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu).

23. R ６ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

24. Ring A is 【Chemical 744】 2. The compound of claim 1, wherein:

25. The compound is a compound of formula (A_2a): 【Chem.745】 2. The compound of claim 1, wherein:

26. R ３ But H, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ａ３ , and −N(R ａ３ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. R ３ But H, -OR ａ３ , and −N(R ａ３ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

28. Each R ａ３ are independently H, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -nBu, - ｔ Bu, -sec-Bu, -iso-Bu), and -C １ -C ６ Haloalkyl (e.g., —CHF ２ , -CF ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

29. R ３ But H, -C １ -C ６ alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), -C １ -C ６ Alkyl (e.g., —CF ３ , -CHF ２ ), -OH, -O-(C １ -C ６ alkyl) (e.g., —OCH ３ , -OEt), -O-(C １ -C ６ haloalkyl) (e.g., —OCF ３ , -OCHF ２ ), -NH ２ , —NH—(C １ -C ６ alkyl) (e.g., —NHCH ３ ), and -N-(C １ -C ６ alkyl) ２ (For example, -N(CH ３ ) ２ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

30. R ３ H, -Me, -CHF ２ , -OCH ３ , and —NH ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

31. R ３ H, -NH ２ , and -OCH ３ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

32. R ４ But, -C １ -C ６ alkyl, 3- to 10-membered heterocyclyl (e.g., oxetanyl), —C ３ -C ９ Cycloalkyl (e.g., cyclopropyl), and —C(═O)N(R ａ４ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. Each R ａ４ are independently H and -C １ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu).

34. R ４ But, -C １ -C ６ alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu), 3- to 10-membered heterocyclyl (e.g., oxetan-3-yl), -C ３ -C ９ Cycloalkyl (e.g., cyclopropyl), and —C(═O)NH ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

35. R ４ -Me, -Et, oxetan-3-yl, cyclopropyl, and -C(=O)NH ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

36. R ４ is -Me, -Et, cyclopropyl, and -C(=O)NH ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

37. R ４ is -C(=O)NH ２ 2. The compound of claim 1, wherein:

38. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of -Me, -Et, and cyclopropyl.

39. R ３ But, -OCH ３ and R ４ is -C(=O)NH ２ 2. The compound of claim 1, wherein:

40. R ３ But -NH ２ and R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of -Me, -Et, and cyclopropyl.

41. Ring A is 【Chemical 746】 9. The compound of claim 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42. Ring B is C ６ -C １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of aryl (e.g., phenyl, naphthalenyl), 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl, each optionally substituted at any available position.

43. Ring B is thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoquinolinyl, benzo[d]i 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of: midazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, chromanyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, each of which is optionally substituted.

44. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of pyridinyl, pyrimidinyl, and phenyl, each of which is optionally substituted.

45. Each ring B may contain 0, 1, 2, or 3 R ７ at any available position, wherein Each R ７ are independently -D, ═O, -CN, halo, -SF ５ , -C １ -C ６ Alkyl, —C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR ａ７ , -N(R ａ７ ) ２ , -C(=O)R ａ７ , -C(=O)OR ａ７ , -NR ａ７ C(=O)R ａ７ , -NR ａ７ C(=O)OR ａ７ , -C(=O)N(R ａ７ ) ２ , —OC(═O)R ａ７ , -OC(=O)N(R ａ７ ) ２ , -S(=O)R ａ７ , -S(=O) ２ R ａ７ , -SR ａ７ , -S(=O)(=NR ａ７ ) R ａ７ , -NR ａ７ S (= O) ２ R ａ７ , and -S(=O) ２ N (R ａ７ ) ２ and R ７ Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., contains 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH ３ , -C(=O)NHCH ３ , -NH ２ , -NHC(=O)CH ３ , or a combination thereof), Each R ａ７ are independently H, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —C substituted with 0 or 1 =O １ -C ６ Heteroalkyl, C ３ -C ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl or a 3- to 10-membered heterocyclyl substituted with 0 or 1 =0, -Me, or a combination thereof.

46. Ring B is C ６ -C １０ aryl, and 5-6 membered monocyclic heteroaryl, wherein said aryl and heteroaryl are selected from the group consisting of 0, 1, 2, or 3 R ７ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, substituted at any available position with

47. Ring B is thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, isoxazolyl, benzo[b]pyridin ...benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b]pyridinyl, benzo[b] thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, chromanyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl), each of which is selected from the group consisting of 0, 1, 2, or 3 R ７ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, substituted at any available position with

48. Ring B is selected from the group consisting of pyridinyl, pyrimidinyl, and phenyl, each of which contains 0, 1, 2, or 3 R ７ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, substituted at any available position with

49. Ring B is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, and phenyl, each of which contains 0, 1, 2, or 3 R ７ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, substituted at any available position with

50. Ring B is 【Chemical 747】 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

51. Ring B is 【Chemical 748】 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

52. Each R ７ are independently -D, ═O, -SF ５ , halo (e.g., —F, —Cl, —Br), —CN, —C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu), -C １ -C ６ Heteroalkyl (e.g., —CH ２ OH, -CH(OH)(CH ３ ), -C(OH)(CH ３ ) ２ , -CH ２ NH ２ ), -C １ -C ６ Haloalkyl (e.g., —CHF ２ , -CH ２ CF ３ , -CF ３ , -CF ２ CF ３ ), -C ３ -C ９ Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl), phenyl, 5- to 10-membered heteroaryl (e.g., pyrazolyl, thiazolyl, thiophenyl, pyridinyl), cycloalkylalkyl (e.g., —CH ２ -cyclopropyl), heterocyclylalkyl (e.g., —CH ２ -morpholinyl), heteroarylalkyl (e.g., —CH ２ -triazolyl, -CH ２ -imidazolyl, -CH ２ -pyrazolyl), -OR ａ７ (e.g., —OH, —OCH ３ , —O-tetrahydrofuranyl, —O-tetrahydropyran-4-yl, —OCF ３ , -OCHF ２ ), -N(R ａ７ ) ２ (For example, -NH ２ , -NHR ａ７ , -NHCH ３ , -N(CH ３ ) ２ ), -NR ａ７ C(=O)R ａ７ (For example, —NHC(═O)CH ３ ), -C(=O)N(R ａ７ ) ２ (For example, —C(═O)NH ２ , -C(=O)NHCH ３ ), -OC(=O)R ａ７ (For example, —OC(═O)CH ３ ), -S(=O)R ａ７ (For example, -SO ２ CH ３ ), -NR ａ７ S (= O) ２ R ａ７ (e.g., -NHSO ２ CH ３ ), and -S(=O) ２ N (R ａ７ ) ２ (For example, -SO ２ NH ２ , -SO ２ NHCH ３ ), wherein each alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., contains 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH ３ , -NHC(=O)CH ３ , or a combination thereof), Each R ａ７ are independently H, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu), -C １ -C ６ Haloalkyl (e.g., —CF ３ , -CHF ２ , -CF ２ CF ３ , -CH ２ CF ３ ), -C substituted with 0 or 1 =O １ -C ６ Heteroalkyl (e.g., —CH ２ CH ２ N (CH ３ ) ２ , -CH ２ C(=O)N(CH ３ ) ２ , -CH(CH ３ ) CH ２ N (CH ３ ) ２ , -CH(CH ３ )C(=O)N(CH ３ ) ２ ), C ３ -C ９ Cycloalkyl and 3- to 10-membered heterocyclyl substituted with 0 or 1 =O, -Me, or combinations thereof (e.g., tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxetan-3-yl, N-CH ３ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

53. Each R ７ are independently -D, halo (e.g., -F, -Cl, Br), -SF ５ , -CN, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu), -C １ -C ６ Haloalkyl (e.g., —CHF ２ , -CH ２ CF ３ , -CF ３ ), -N(R ａ７ ) ２ (For example, -NH ２ , -NHR ａ７ , -NHCH ３ , -N(CH ３ ) ２ ), -NR ａ７ C(=O)R ａ７ (For example, —NHC(═O)CH ３ ), and —C(═O)N(R ａ７ ) ２ (For example, —C(═O)NH ２ , -C(=O)NHCH ３ and each R ａ７ are independently H and -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

54. Each R ７ are independently halo (e.g., —F, —Cl, Br), and —C １ -C ６ Haloalkyl (e.g., —CHF ２ , -CH ２ CF ３ , -CF ２ CF ３ , -CF ３ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

55. Each R ａ７ are independently H, -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu, -CF ３ , -CHF ２ , and -CH ２ CF ３ 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

56. Each R ａ７ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein is independently selected from the group consisting of H and -Me.

57. Each R ７ are independently -D, -F, -Cl, Br, -CN, or -SF ５ , -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu, -CHF ２ , -CH ２ CF ３ , -CF ２ CF ３ , -CF ３ , -CH ２ OH, -CH(OH)(CH ３ ), -C(OH)(CH ３ ) ２ , -CH ２ NH ２ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidin-1-yl, piperidin-4-yl, piperazin-4-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thiophen-2-yl, -CH ２ -cyclopropyl, -CH ２ -morpholin-4-yl, -CH ２ -1,2,4-triazol-1-yl, -CH ２ -imidazol-1-yl, -CH ２ -pyrazol-1-yl, -OH, -OCH ３ , -OCF ３ , -OCHF ２ , —O-tetrahydrofuran-3-yl, —O-tetrahydropyran-4-yl, —O—(N—CH ３ -2-oxo-pyrrolidin-3-yl), -OCF ３ , -OCHF ２ , -NH ２ , -NHCH ３ , -NHCH ２ CF ３ , —NH-oxetan-3-yl, —NH—(N—CH ３ -2-oxo-pyrrolidin-3-yl), -N(CH ３ ) ２ , -NHC(=O)CH ３ , -NHCH ２ C(=O)N(CH ３ ) ２ , -NHCH(CH ３ )C(=O)N(CH ３ ) ２ , —C(═O)NH ２ , -C(=O)NHCH ３ , -OC(=O)CH ３ , -SO ２ CH ３ , -NHSO ２ CH ３ , -SO ２ NH ２ , and -SO ２ NHCH ３ each selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidin-1-yl, piperidin-4-yl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiophen-2-yl, -CH ２ -cyclopropyl, -CH ２ -morpholin-4-yl, -CH ２ -1,2,4-triazol-1-yl-CH ２ -imidazol-1-yl, and -CH ２ -pyrazol-1-yl is independently selected from 0, 1, 2, or 3 -Me, -OH, -C(=O)CH ３ , -NHC(=O)CH ３ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, which may be substituted with:

58. Each R ７ are independently -D, ═O, -F, -Cl, -Me, - ｉ Pr, -CHF ２ , -CF ２ CF ３ , -CF ３ , -CN, -SF ５ , cyclopropyl, piperidin-4-yl, piperazin-4-yl, phenyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, —OH, —OCH ３ , -OCF ３ , -OCHF ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHC(O)CH ３ , -CONH ２ and each cyclopropyl, phenyl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl independently contains 0, 1, 2, or 3 -Me, -OH, -C(=O)CH ３ , -NHC(=O)CH ３ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, which may be substituted with:

59. Each R ７ are independently —F, —Cl, —Me, — ｉ Pr, -CF ２ CF ３ , -CF ３ , -CN, -SF ５ , phenyl, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHC(O)CH ３ , and -CONH ２ 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

60. Each R ７ are independently —F, —Cl, —Me, —CF ２ CF ３ , and -CF ３ 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

61. Each R ７ are independently —F, —Cl, and —CF ３ 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

62. Each R ７ are independently —F and —CF ３ 46. ​​The compound of claim 45, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

63. Ring B is 【Chemical 749】 2. The compound of claim 1, selected from:

64. Each R １ But independently, -C １ -C ６ Alkyl, —C ２ -C ６ Heteroalkyl, —C ２ -C ６ Haloalkyl, —C ３ -C １０ Carbocyclyl, C ６ -C １０ selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, and cycloalkylalkyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R ８ at any available position, and each R ８ are independently halo, ═O, —CN, —OH, —NH ２ , -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —O(C １ -C ６ alkyl), —O(C １ -C ６ haloalkyl), -NH(C １ -C ６ alkyl), -NH(C １ -C ６ haloalkyl), -N(C １ -C ６ alkyl) ２ , -N(C １ -C ６ haloalkyl) ２ , —C(O)NH ２ , -NHC(O)(C １ -C ６ alkyl), C ３ -C ９ Cycloalkyl, and C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of heteroalkyl.

65. Each R １ But independently, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu, -CH(CH ３ ) CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , -CH ２ CH (CH ３ ) CH ２ CH ３ ), -C ２ -C ６ Heteroalkyl (e.g., —CH ２ CH ２ OCH ３ ), -C ２ -C ６ Haloalkyl (e.g., —CH ２ CH ２ CF ３ ), -C ３ -C １０ carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl), 3- to 10-membered heterocyclyl (e.g., chromanyl), heteroarylalkyl (e.g., —CH ２ -pyridinyl, -CH(CH ３ )-pyridinyl-CH ２ -pyrimidinyl, -CH(CH ３ )-pyrimidinyl, —CH ２ -pyrazolyl), arylalkyl (e.g., benzyl, —CH(CH ３ ) phenyl, —CH ２ -naphthalenyl, -CH ２ -chromanyl, -CH ２ CH ２ -phenyl), heterocyclylalkyl (e.g., CH ２ -tetrahydropyranyl), and cycloalkylalkyl (e.g., —CH ２ -cyclopropyl, -CH ２ -cyclobutyl, -CH ２ -cyclopentyl, -CH ２ -cyclohexyl, -CH(CH ３ ) cyclopropyl, —CH ２ CH ２ -cyclopropyl), each of which is selected from the group consisting of 0, 1, 2, or 3 R ８ at any available position, and each R ８ are independently halo (e.g., —F, —Cl), ═O, —CN, —OH, —NH ２ , -C １ -C ６ Alkyl (e.g., -Me, -Et-, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu), -C １ -C ６ Haloalkyl (e.g., —CF ３ ), -O(C １ -C ６ alkyl) (e.g., —OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ ), -O(C １ -C ６ haloalkyl) (e.g., —OCF ３ , -OCHF ２ , -OCH ２ CF ３ ), C ３ -C ９ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), and C １ -C ６ Heteroalkyl (e.g., —CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NHCH ３ , -CH ２ CH ２ NHCH ３ , -CH ２ N (CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) ２ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

66. Each R １ But independently, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr, -sec-Bu, - ｔ Bu, -CH(CH ３ ) CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , -CH ２ CH (CH ３ ) CH ２ CH ３ ), -C ２ -C ６ Heteroalkyl (e.g., —CH ２ CH ２ OCH ３ ), and arylalkyl (e.g., benzyl, —CH(CH ３ ) phenyl, —CH ２ -naphthalenyl, -CH ２ -chromanyl), each of which is selected from the group consisting of 0, 1, or 2 R ８ at any available position, and each R ８ are independently halo (e.g., —F, —Cl), and —C １ -C ６ Alkyl (e.g., -Me, -Et-, -Pr, - ｉ Pr, -sec-Bu, - ｔ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

67. Each R １ are independently -Me, -Et, - ｉ Pr, -CH(CH ３ ) CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , -CH ２ CH (CH ３ ) CH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, chromanyl, -CH ２ -cyclopropyl, -CH ２ -cyclohexyl, -CH ２ CH ２ -cyclopropyl, -CH ２ -tetrahydropyranyl, -CH ２ -pyridinyl, -CH ２ -pyrimidinyl, -CH ２ -pyrazolyl, -benzyl CH ２ -chromanyl, CH2-naphthyl, and -CH ２ -cyclopropyl, each of which is selected from the group consisting of 0, 1, or 2 R ８ at any available position, and each R ８ are independently —F, —Cl, —Me, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHC(O)CH ３ , —C(O)NH ２ , -CF ３ , -OCHF ２ , -cyclopropyl, and -CH ２ OCH ３ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

68. Each R １ is independently, -Me, -Et, - ｉ Pr, -CH(CH ３ )CH(CH ３ ) ２ , -CH ２ CH(CH ３ ) ２ , -CH ２ CH(CH ３ )CH ２ CH ３ , -CH ２ CH ２ CF ３ , -CH ２ CH ２ OCH ３、 【Chemical 750-1】 【Chemical 750-2】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

69. Each R １ are independently -Me, -Et, - ｉ Pr, -CH(CH ３ ) CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , -CH ２ CH (CH ３ ) CH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, chromanyl, -CH ２ -cyclopropyl, -CH ２ -cyclohexyl, -CH(CH ３ ) cyclopropyl, and —CH ２ CH ２ -cyclopropyl, each of which is selected from the group consisting of 0 or 1 R ８ at any available position, and each R ８ are independently -Me and -OCHF ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

70. Each R １ is independently, -Me, -Et, - ｉ Pr, -CH(CH ３ ), CH(CH ３ ), ２ , -CH ２ CH(CH ３ ), ２ , -CH ２ CH(CH ３ ), CH ２ CH ３ , -CH ２ CH ２ CF ３ , -CH ２ CH ２ OCH ３ , 【Chemistry 751】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

71. Each R １ are independently -Me, -Et, benzyl, -CH ２ -pyridinyl, and CH ２ -pyrimidinyl, benzyl, -CH ２ -pyridinyl, and CH ２ -pyrimidinyl is independently -Me, -F, -Cl, and -CF ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted at any available position with 0, 1, or 2 substituents selected from:

72. Each R １ are independently benzyl, —CH ２ -pyridinyl, and CH ２ -pyrimidinyl, benzyl, -CH ２ -pyridinyl, and CH ２ -pyrimidinyl is independently -Me, -F, -Cl, and -CF ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted at any available position with 0, 1, or 2 substituents selected from:

73. Each R １ is independently selected from the group consisting of -Me and -Et, or a pharmaceutically acceptable salt thereof.

74. The compound is 【Chemistry 752-1】 【Chemistry 752-2】 【Chemistry 752-3】 【Chemistry 752-4】 【Chemistry 752-5】 【Chemistry 752-6】 【Chemistry 752-7】 【Chemistry 752-8】 【Chemistry 752-9】 【Chemistry 752-10】 【Chemistry 752-11】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

75. The compound, 【Chemical 753】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

76. The compound, 【Chem.754】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

77. The compound, 【Chemical 755】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

78. The compound, 【Chemical 756】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

79. The compound, 【Chemical 757】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

80. The compound, 【Chemical 758】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

81. The compound of claim 80, 【Chemical 759】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

82. The compound of claim 82, 【Chemical 760】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

83. The compound, 【Chemistry 761】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

84. The compound, 【Chemical 762】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

85. The compound, 【Chemical 763】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

86. The compound, 【Chemical 764】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

87. The compound, 【Chemical 765】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

88. The compound, 【Chemical 766】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

89. The compound, 【Chemical 767】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

90. The compound, 【Chemical 768】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

91. The compound of claim 91, 【Chemical 769】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

92. The compound, 【Chemical 770】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

93. The compound, 【Chemistry 771】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

94. The compound, 【Chemical 772】 75. The compound of claim 74, which is: or a pharmaceutically acceptable salt thereof.

95. 95. A pharmaceutical composition comprising a compound according to any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

96. 96. The pharmaceutical composition of claim 95, further comprising a second therapeutic agent.

97. A composition comprising a compound according to any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in treating an MTAP deficiency and / or an MTA accumulation disease in a subject in need thereof.

98. 98. The composition or pharmaceutical composition of claim 97, wherein the compound, or a pharmaceutically acceptable salt thereof, or the composition is adapted to be administered in combination with a second therapeutic agent.

99. 97. The pharmaceutical composition of claim 96 for use in treating an MTAP deficiency and / or MTA storage disorder in a subject in need thereof.

100. 98. The composition or pharmaceutical composition for use according to claim 97, wherein the disease is a proliferative disease.

101. 101. The composition or pharmaceutical composition for use of claim 100, wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

102. 102. The composition or pharmaceutical composition for use of claim 101, wherein the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and colon, or sarcoma.

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