Compounds and Methods of Use

Abstract

Compounds of formula (I): (I), and pharma- ceutically acceptable salts thereof, as well as pharmaceutical compositions, processes for preparation, and methods of treatment thereof, are provided, comprising ring A, ring B, X, R 1 , R 2 and n is as defined herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any of the embodiments described herein, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. JPEG2025503970000494.jpg35165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 303,451, filed January 26, 2022, which is incorporated by reference in its entirety and is hereby incorporated by reference 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 [Means for solving the problem]

[0006] In one embodiment, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X is -O- or -NR 7 - selected from the group consisting of Ring A is selected from the group consisting of optionally substituted fused bicyclic 8-10 membered heteroaryl ring systems containing at least one nitrogen atom, where 8-10 members refers to the total number of atoms in the fused system and the optionally substituted pyridin-3-yl; Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Each R 1 is independently absent or H, -D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)ORa1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 )R a1 , -NR a1 S(=O) 2 R a1 , and -S(=O) 2 N(R a1 ) selected from the group consisting of Each R 2 are independently H, -D, =O, 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 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 , -OC(=O)N(R a2 ) 2 , -CH 2 C(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NRa2 )R a2 , -NR a2 S(=O) 2 R a2 , and -S(=O) 2 N(R a2 ) 2 and two R 2 can be taken together with the atom(s) to which they are attached to form a 3-10 membered cycloalkyl or heterocyclyl ring (e.g., a ring which can be taken together with the morpholine or piperazine ring of structure I to form a bridged, fused, or spiro bicyclic heterocyclic ring); Each R 7 However, independently, H, -D, and -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, arylalkyl, heteroarylalkyl, -C(=O)R a7 , -C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a1 , R a2 , and R a7 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6Haloalkyl, C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, C 6 -C 10 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 5 Each R 5 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); n is 0, 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

[0007] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any of the embodiments described herein, 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 (I) 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 (I) 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 (I) 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 (I) 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 (I), or a pharma- ceutically acceptable salt thereof, as defined in any of the embodiments described herein, or a pharma- ceutical acceptable 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 adapted 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 (I), 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 (I), 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 Substance Definitions 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 may 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 may 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 instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a 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 a-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 which R 38 The groups may also be 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(C 3 -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 Each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 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 is substituted with an X group; - 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 and wherein the 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 comprises 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(Rbb ) 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 2R aa 、-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 case of C is independent. 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 can 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 (I), or a pharma- ceutically acceptable salt thereof. Unless the context otherwise requires, references throughout the specification to a "compound of formula (I)" or "compound(s) of formula (I)" include, for example, formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (I_1), formula (I_1a), formula (I_2), formula (I_2a), formula (I_3), formula (I_3a), formula (I_4), formula (I_4a ... ), formula (I_4), formula (I_4a), formula (I_5), formula (I_5a), formula (I_6), formula (I_6a), formula (I_7), formula (I_7a), formula (I_8), formula (I_8a), formula (I_9), formula (I_9a), formula (II_1), formula (II _1a), formula (II_2), formula (II_2a), formula (II_3), formula (II_3a), formula (II_4), formula (II_4a), formula (II_5), formula (II_5a), formula (II_6), formula (II_6a), formula (II_7), formula (II_7a) ), formula (II_8), formula (II_8a), formula (II_9), formula (II_9a), formula (III_1), formula (III_1a), formula (III_2), formula (III_2a), formula (III_3), formula (III_3a), formula (III_4), formula ( III_4a), Formula (III_5), Formula (III_5a), Formula (III_6), Formula (III_6a), Formula (III_7), Formula (III_7a), Formula (III_8), Formula (III_8a), Formula (III_9), Formula (III_9a), Formula ( IV), Formula (IVa), Formula (IV_1), Formula (IV_1a), Formula (IV_2), Formula (IV_2a), Formula (IV_3), Formula (IV_3a), Formula (IV_4), Formula (IV_4a), Formula (IV_5), Formula (IV_5a), Formula (V_1), Formula (V_1a), Formula (V_2), Formula (V_2a), Formula (VI), Formula (VIa), Formula (VI_1), Formula (VI_1a) (i.e., all embodiments of Formula (I), including compounds of Formula (I)-Formula (VI_1a), as well as the compounds of Table 1.

[0100] In one embodiment, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X is -O- or -NR 7 - selected from the group consisting of Ring A is selected from the group consisting of optionally substituted fused bicyclic 8-10 membered heteroaryl ring systems containing at least one nitrogen atom, where 8-10 members refers to the total number of atoms in the fused system and the optionally substituted pyridin-3-yl; Ring B is C 6 -C 10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted at any available position; Each R 1 is independently absent or H, -D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 )R a1 , -NR a1 S(=O) 2 R a1 , and -S(=O) 2 N(Ra1 ) selected from the group consisting of Each R 2 are independently H, -D, =O, 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 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 , -OC(=O)N(R a2 ) 2 , -CH 2 C(=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 and two R 2 can be taken together with the atom(s) to which they are attached to form a 3-10 membered cycloalkyl or heterocyclyl ring (e.g., a ring which can be taken together with the morpholine or piperazine ring of structure I to form a bridged, fused, or spiro bicyclic heterocyclic ring); Each R 7 However, independently, H, -D, and -C 1 -C6 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, arylalkyl, heteroarylalkyl, -C(=O)R a7 , -C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a1 , R a2 , and R a7 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, C 6 -C 10 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 5 Each R 5 Independently, =O, halo, -CN, -C1 -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); n is 0, 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

[0101] In one embodiment, provided is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, X is -O- or -NR 7 - selected from the group consisting of Ring A is selected from the group consisting of optionally substituted fused bicyclic 8-10 membered heteroaryl ring systems containing at least one nitrogen atom, where 8-10 members refers to the total number of atoms in the fused system and the pyridin-3-yl, and the 8-10 membered heteroaryl and pyridin-3-yl are selected from the group consisting of 0, 1, 2, 3, or 4 R 4 in any available position, 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 3 in any available position, Each R 1 is independently absent or H, -D, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(Ra1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 )R a1 , -NR a1 S(=O) 2 R a1 , and -S(=O) 2 N(R a1 ) 2 is selected from the group consisting of Each R 2 are independently H, -D, =O, 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 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 , -OC(=O)N(R a2 ) 2 , -CH 2 C(=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 and two R 2 can be taken together with the atom(s) to which they are attached to form a 3-10 membered cycloalkyl or heterocyclyl ring (e.g., a ring which can be taken together with the morpholine or piperazine ring of structure I to form a bridged, fused, or spiro bicyclic heterocyclic ring); Each R 7 However, independently, H, -D, and -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, arylalkyl, heteroarylalkyl, -C(=O)R a7 , -C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroarylalkyl, arylalkyl, and heteroarylalkyl is selected from the group consisting of 0, 1, 2, or 3 -OH, -OCH 3 , -CN, halo (e.g., -Cl, -F), -NH 2 , -C 1 -C 6 Alkyl (e.g., -Me, -Et), -C 1 -C 6 Haloalkyl (e.g., -CF 3 , -CHF 2 ), or combinations thereof, substituted at any available position; Each R 3Independently, -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 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)R a3 , -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 3 Each alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl may have 0, 1, 2, or 3 -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof substituted at any available position; Each R 4 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 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 , -C(=O)N(OR a4 )(R a4 ), -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 a1 , R a2 , R a3 , R a4 , and R a7 However, independently, H, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, C 3 -C 9Cycloalkyl, 3-10 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, C 6 -C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl, arylalkyl, and heteroarylalkyl, each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl being selected from the group consisting of 0, 1, 2, or 3 R 5 at any available position, and each R 5 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(Rb ) 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., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); n is 0, 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, R 1 is non-existent (e.g., two R 2 The spiro ring formed by the R 1 (when bonding with an atom carrying

[0103] In certain embodiments, R 1 is not absent or H, and rings B and R 1 In another embodiment, R 1 is not absent or H, and rings B and R 1 is in the cis relative configuration.

[0104] In some embodiments, in formula (I), [ka] The part represented as [ka] wherein X, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0105] In certain embodiments, [ka] The part represented as [ka] wherein X, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0106] In another embodiment, [ka] The part represented as [ka] wherein X, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0107] In some embodiments, the compound of formula (I) is a compound of formula (Ia) [ka] and In the formula, X, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0108] In some embodiments, the compound of formula (I) is a compound of formula (Ib) [ka] and In the formula, X, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0109] In some embodiments, the compound of formula (I) is a compound of formula (Ic) [ka] and In the formula, X, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0110] In some embodiments, the compound of formula (I) is a compound of formula (Id) [ka] and In the formula, X, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0111] As generally defined herein, X is -O-, -NR 7 - is selected from the group consisting of

[0112] In some embodiments, X is --O--.

[0113] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] and In the formula, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0114] In some embodiments, the compound of formula (I) is a compound of formula (IIa): [ka] and In the formula, ring A, ring B, R 1 , R 2, and n is as defined in any of the embodiments described herein.

[0115] In some embodiments, the compound of formula (I) is a compound of formula (IIb): [ka] and In the formula, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0116] In some embodiments, the compound of formula (I) is a compound of formula (IIc): [ka] and In the formula, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0117] In some embodiments, the compound of formula (I) is a compound of formula (IId): [ka] and In the formula, ring A, ring B, R 1 , R 2 , and n is as defined in any of the embodiments described herein.

[0118] In some embodiments, the compound is a compound of Formula (IIa) or Formula (IIb).

[0119] In some embodiments, the compound is a compound of Formula (IIc) or Formula (IId).

[0120] In some embodiments, X is -NR 7 -, wherein R 7is as defined in any of the embodiments described herein.

[0121] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] and In the formula, ring A, ring B, R 1 , R 2 , R 7 , and n is as defined in any of the embodiments described herein.

[0122] In some embodiments, the compound of formula (I) is a compound of formula (IIIa): [ka] and In the formula, ring A, ring B, R 1 , R 2 , R 7 , and n is as defined in any of the embodiments described herein.

[0123] In some embodiments, the compound of formula (I) is a compound of formula (IIIb): [ka] and In the formula, ring A, ring B, R 1 , R 2 , R 7 , and n is as defined in any of the embodiments described herein.

[0124] In some embodiments, the compound of formula (I) is a compound of formula (IIIc): [ka] and In the formula, ring A, ring B, R 1 , R 2 , R 7, and n is as defined in any of the embodiments described herein.

[0125] In some embodiments, the compound of formula (I) is a compound of formula (IIId): [ka] and In the formula, ring A, ring B, R 1 , R 2 , R 7 , and n is as defined in any of the embodiments described herein.

[0126] In some embodiments, the compound is a compound of Formula (IIIa) or Formula (IIIb).

[0127] In some embodiments, the compound is a compound of Formula (IIIc) or Formula (IIId).

[0128] As generally defined herein, Ring A is an optionally substituted fused bicyclic 8-10 membered heteroaryl ring system containing at least one nitrogen atom, where 8-10 members refers to the total number of atoms in the fused system or pyridin-3-yl.

[0129] In some embodiments, Ring A is a fused bicyclic 8-10 membered heteroaryl ring containing at least one nitrogen atom, where 8-10 members refers to the total number of atoms in the fused system or pyridin-3-yl, and Ring A is selected from the group consisting of 0, 1, 2, 3, or 4 R 4 at any available position, and R 4 is as defined herein.

[0130] In some embodiments, Ring A is an optionally substituted fused bicyclic 8-10 membered heteroaryl ring system containing at least one nitrogen atom and 0, 1, 2, or 3 additional heteroatoms selected from the group consisting of N, O, and S, or oxidized forms thereof, where 8-10 members refers to the total number of atoms in the fused system. In some embodiments, Ring A is an optionally substituted fused bicyclic 8-10 membered heteroaryl ring system containing 0, 1, 2, or 3 R4 at any available position, and R 4 is as defined herein.

[0131] In some embodiments, Ring A comprises a 5-6 membered monocyclic heteroaryl ring containing at least one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from the group consisting of N, O, or S, or oxidized forms thereof (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl), fused to a carbocyclyl or heterocyclyl ring, the total number of atoms in the fused system being 8-10, and the system containing a total of 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, or oxidized forms thereof. The point of attachment is on the heteroaryl ring.

[0132] In some embodiments, ring A is selected from the group consisting of 0, 1, 2, or 3 R 4 at any available position, and R 4 is as defined herein.

[0133] In some embodiments, Ring A comprises a 5-6 membered monocyclic heteroaryl ring containing at least one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from the group consisting of N, O, or S, or oxidized forms thereof (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl), fused to a carbocyclyl ring, and the total number of atoms in the fused system is 8-10. 4 at any available position, and R 4 is as defined herein.

[0134] In some embodiments, ring A comprises a 5-6 membered monocyclic heteroaryl ring containing at least one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from the group consisting of N, O, or S, or oxidized forms thereof (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl), fused to a heterocyclyl ring, the total number of atoms in the fused system being 8-10, and the system containing a total of 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, or oxidized forms thereof. In some embodiments, ring A comprises 0, 1, 2, or 3 R 4 at any available position, and R 4 is as defined herein.

[0135] In some embodiments, ring A comprises a phenyl ring fused to a 5-6 membered monocyclic heteroaryl ring containing at least one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from the group consisting of N, O, or S, or oxidized forms thereof (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl), and the point of attachment is on either the phenyl ring or the heteroaryl ring. In some embodiments, ring A comprises 0, 1, 2, or 3 R 4 at any available position, and R 4 is as defined herein.

[0136] In some embodiments, Ring A is optionally substituted pyridin-3-yl. In some embodiments, Ring A is pyridin-3-yl and has 0, 1, 2, 3, or 4 R 4 at any available position, and R 4 is as defined herein.

[0137] In some embodiments, ring A is [ka] is selected from the group consisting of During the ceremony, Ring A 1 , A 2 , and A 4 each is independently 4- to 6-membered carbocyclyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or phenyl; Each ring A 3 is independently 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, the heterocyclyl and heteroaryl containing at least one nitrogen atom; Each ring A 5 is independently a 5- to 6-membered heteroaryl, the heteroaryl containing at least one nitrogen atom; Each R 4 and m is as defined in any of the embodiments described herein.

[0138] In one embodiment, Ring A 1 , A 2 , and A 4 are each independently a 4- to 6-membered carbocyclyl, a 4- 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.

[0139] In one embodiment, each ring A 3 is independently a 4- 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.

[0140] In one embodiment, each ring A 5 is independently a 5-6 membered heteroaryl, the heteroaryl containing 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.

[0141] In one embodiment, ring A is [ka] In the formula, A 1 , R 4 , and m are as defined herein.

[0142] In one embodiment, ring A is [ka] In the formula, A 2 , R 4 , and m are as defined herein.

[0143] In one embodiment, ring A is [ka] In the formula, A 3 , R 4 , and m are as defined herein.

[0144] In one embodiment, ring A is [ka] In the formula, A 4 , R 4 , and m are as defined herein.

[0145] In one embodiment, ring A is [ka] In the formula, A 5 , R 4 , and m are as defined herein.

[0146] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0147] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0148] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0149] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0150] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0151] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0152] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0153] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , R 11 and m are as defined herein. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1.

[0154] In some embodiments, ring A is [ka] wherein R 4 and m is as defined herein.

[0155] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , R 11 and m are as defined herein. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1.

[0156] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0157] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0158] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0159] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0160] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0161] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0162] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0163] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0164] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0165] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0166] In some embodiments, ring A is [ka] where R 4 and m is as defined herein.

[0167] In one embodiment, ring A is [ka] where R 4 and m is as defined herein.

[0168] In some embodiments, ring A is [ka] where R 8 , R 9 , R 10 is as defined herein.

[0169] As generally defined herein, m is 0, 1, 2, 3, or 4.

[0170] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2.

[0171] In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2.

[0172] In some embodiments, m is 0.

[0173] In some embodiments, m is 1.

[0174] In some embodiments, m is 2.

[0175] In some embodiments, m is 3.

[0176] In some embodiments, m is 4.

[0177] In some embodiments, ring A is

[0178] [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0179] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0180] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0181] In some embodiments, ring A is [ka] wherein R 4 , R 8 , and R 9 is as defined in any of the embodiments described herein.

[0182] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0183] In some embodiments, ring A is [ka] wherein R 4 , R8 , and R 9 is as defined in any of the embodiments described herein.

[0184] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0185] In some embodiments, ring A is [ka] wherein R 4 , R 8 , and R 9 is as defined in any of the embodiments described herein.

[0186] In some embodiments, ring A is [ka] wherein R 4 , R 8 , R 9 , R 10 , and R 11 is as defined in any of the embodiments described herein.

[0187] In some embodiments, ring A is [ka] wherein R 4 is as defined in any of the embodiments described herein.

[0188] In some embodiments, ring A is [ka] is

[0189] In some embodiments, ring A is [ka] where R 4 is as defined in any of the embodiments described herein.

[0190] In some embodiments, ring A is [ka] where R 4 is as defined in any of the embodiments described herein.

[0191] In some embodiments, ring A is [ka] where R 4 is as defined in any of the embodiments described herein.

[0192] In some embodiments, ring A is [ka] where R 4 is as defined in any of the embodiments described herein.

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

[0194] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0195] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0196] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0197] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0198] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0199] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0200] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0201] In certain embodiments, ring A is [ka] is selected from the group consisting of: 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] 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] It is.

[0202] In some embodiments, ring A is [ka] It is.

[0203] In some embodiments, the compound of formula (I) is a compound of formula (I_1): [ka] wherein X, ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0204] In some embodiments, the compound is a compound of formula (I_1a): [ka] wherein X, ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0205] In some embodiments, the compound of formula (I) is a compound of formula (I_2): [ka] wherein X, ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0206] In some embodiments, the compound is a compound of formula (I_2a): [ka] wherein X, ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0207] In some embodiments, the compound of formula (I) is a compound of formula (I_3): [ka] wherein X, ring B, R 1 , R 2 , and n are as defined herein.

[0208] In some embodiments, the compound is a compound of formula (I_3a): [ka] wherein X, ring B, R1 , R 2 , and n are as defined herein.

[0209] In some embodiments, the compound of formula (I) is a compound of formula (I_4): [ka] wherein X, ring B, R 1 , R 2 , and n are as defined herein.

[0210] In some embodiments, the compound is a compound of formula (I_4a): [ka] wherein X, ring B, R 1 , R 2 , and n are as defined herein.

[0211] In some embodiments, the compound of formula (I) is a compound of formula (I_5): [ka] wherein X, ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0212] In some embodiments, the compound is a compound of formula (I_5a): [ka] wherein X, ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0213] In some embodiments, the compound of formula (I) is a compound of formula (I_6): [ka] wherein X, ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0214] In some embodiments, the compound is a compound of formula (I_6a): [ka] wherein X, ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0215] In some embodiments, the compound of formula (I) is a compound of formula (I_7): [ka] wherein X, ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0216] In some embodiments, the compound is a compound of formula (I_7a): [ka] wherein X, ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0217] In some embodiments, the compound of formula (I) is a compound of formula (I_8): [ka] wherein X, ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0218] In some embodiments, the compound is a compound of formula (I_8a): [ka] wherein X, ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0219] In some embodiments, the compound of formula (I) is a compound of formula (I_9): [ka] wherein X, ring B, R 1 , R 2 , and n are as defined herein.

[0220] In some embodiments, the compound is a compound of formula (I_9a): [ka] wherein X, ring B, R 1 , R 2 , and n are as defined herein.

[0221] In some embodiments, the compound of formula (I) is a compound of formula (II_1): [ka] wherein ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0222] In some embodiments, the compound is a compound of formula (II_1a): [ka] wherein ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0223] In some embodiments, the compound of formula (I) is a compound of formula (II_2): [ka] wherein ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0224] In some embodiments, the compound is a compound of formula (II_2a): [ka] wherein ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0225] In some embodiments, the compound of formula (I) is a compound of formula (II_3): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0226] In some embodiments, the compound is a compound of formula (II_3a): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0227] In some embodiments, the compound of formula (I) is a compound of formula (II_4): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0228] In some embodiments, the compound is a compound of formula (II_4a): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0229] In some embodiments, the compound of formula (I) is a compound of formula (II_5): [ka] wherein ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0230] In some embodiments, the compound is a compound of formula (II_5a): [ka] wherein ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0231] In some embodiments, the compound of formula (I) is a compound of formula (II_6): [ka] wherein ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0232] In some embodiments, the compound is a compound of formula (II_6a): [ka] wherein ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0233] In some embodiments, the compound of formula (I) is a compound of formula (II_7): [ka] wherein ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0234] In some embodiments, the compound is a compound of formula (II_7a): [ka] wherein ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0235] In some embodiments, the compound of formula (I) is a compound of formula (II_8): [ka] wherein ring B, R 1 , R 2 , R 4, and n are as defined herein.

[0236] In some embodiments, the compound is a compound of formula (II_8a): [ka] wherein ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0237] In some embodiments, the compound of formula (I) is a compound of formula (II_9): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0238] In some embodiments, the compound is a compound of formula (II_9a): [ka] wherein ring B, R 1 , R 2 , and n are as defined herein.

[0239] In some embodiments, the compound of formula (I) is a compound of formula (III_1): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0240] In some embodiments, the compound is a compound of formula (III_1a): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0241] In some embodiments, the compound of formula (I) is a compound of formula (III_2): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0242] In some embodiments, the compound is a compound of formula (III_2a): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0243] In some embodiments, the compound of formula (I) is a compound of formula (III_3): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0244] In some embodiments, the compound is a compound of formula (III_3a): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0245] In some embodiments, the compound of formula (I) is a compound of formula (III_4): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0246] In some embodiments, the compound is a compound of formula (III_4a): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0247] In some embodiments, the compound of formula (I) is a compound of formula (III_5): [ka] where R 7 , ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0248] In some embodiments, the compound is a compound of formula (III_5a): [ka] where R 7 , ring B, R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , and n are as defined herein.

[0249] In some embodiments, the compound of formula (I) is a compound of formula (III_6): [ka] where R 7 , ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0250] In some embodiments, the compound is a compound of formula (III_6a): [ka] where R 7 , ring B, R 1 , R 2 , R 8 , R 9 , and n are as defined herein.

[0251] In some embodiments, the compound of formula (I) is a compound of formula (III_7): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0252] In some embodiments, the compound is a compound of formula (III_7a): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , m, and n are as defined herein.

[0253] In some embodiments, the compound of formula (I) is a compound of formula (III_8): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0254] In some embodiments, the compound is a compound of formula (III_8a): [ka] where R 7 , ring B, R 1 , R 2 , R 4 , and n are as defined herein.

[0255] In some embodiments, the compound of formula (I) is a compound of formula (III_9): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0256] In some embodiments, the compound is a compound of formula (III_9a): [ka] where R 7 , ring B, R 1 , R 2 , and n are as defined herein.

[0257] As generally described herein, each R 4 are independently -D, halo, =O, -CN, -C 1 -C 6 Alkyl, -C 1 -C6 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 , -C(=O)N(OR a4 )(R a4 ), -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 herein.

[0258] In some embodiments, each R 4 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, 3-10 membered heterocyclyl, -OR a4 , -N(R a4 ) 2 , -C(=O)Ra4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -C(=O)N(OR a4 )(R a4 ), and -OC(=O)N(R a4 ) 2 wherein R a4 is as defined herein.

[0259] In some embodiments, each R 4 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, 3-10 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 , -C(=O)N(OR a4 )(R a4 ), and -OC(=O)N(R a4 ) 2 wherein R a4 is as defined herein.

[0260] In some embodiments, each R 4 are independently -D, =O, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C3 -C 9 Cycloalkyl, -OR a4 , and -N(R a4 ) 2 is selected from the group consisting of:

[0261] In some embodiments, each R 4 are independently -D, =O, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, -OR a4 , and -N(R a4 ) 2 is selected from the group consisting of:

[0262] In some embodiments, each R 4 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 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 , -C(=O)N(OR a4 )(R a4 ), and -OC(=O)N(R a4 ) 2 wherein R a4 is as defined herein.

[0263] In certain embodiments, each R 4 are independently: =O, -C 1-C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, -C(=O)N(R a4 ) 2 , -OR a4 , and -N(R a4 ) 2 wherein R a4 is as defined herein.

[0264] In some embodiments, each R 4 are independently -D, =O, -C 1 -C 6 Alkyl, and -N(R a4 ) 2 is selected from the group consisting of:

[0265] In certain embodiments, each R 4 are independently: =O, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, -OR a4 , and -N(R a4 ) 2 wherein R a4 is as defined herein.

[0266] In some embodiments, each R 4 are independently: =O, -C 1 -C 6 Alkyl, 3-10 membered heterocyclyl, -OR a4 , -C(=O)N(R a4 ) 2 , and -N(R a4 ) 2 wherein R a4 is as defined herein. In some embodiments, each R a4 is independently selected from the group consisting of H and -Me.

[0267] In some embodiments, each R 4 are independently: =O, -C 1 -C 6 Alkyl, and -N(R a4 ) 2 wherein R a4 is as defined herein.

[0268] In some embodiments, each R 4 are independently: =O, -Me, -Et, - i Pr, - t Bu, cyclopropyl, oxetanyl (e.g., oxetan-3-yl), -OCH 3 , -C(=O)NH 2 , -NH 2 , -NHCH 3 , and -NH(CH 3 ) 2 is selected from the group consisting of:

[0269] In some embodiments, each R 4 are independently: =O, -Me, -Et, - i Pr, - t Bu, -NH 2 , -NHCH 3 , and -NH(CH 3 ) 2 is selected from the group consisting of:

[0270] In some embodiments, R 4 is cyclopropyl, oxetanyl (e.g., oxetan-3-yl), -C(=O)NH 2 , -NHCH 3 , -NH 2 , -OCH 3 , -Et, or -Me.

[0271] In some embodiments, R 4 -NHCH 3 , -NH 2 or -Me.

[0272] In some embodiments, R 4 is -NH 2 or -Me.

[0273] In some embodiments, R 4 is -NH 2 or -Me.

[0274] In some embodiments, R 4 is =O.

[0275] In some embodiments, R 4 is D.

[0276] 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, R 4 is -I.

[0277] In some embodiments, R 4 is -CN.

[0278] 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.

[0279] In some embodiments, R 4 -C 1 -C 6 In some embodiments, R 4is 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.

[0280] 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 ).

[0281] In some embodiments, R 4 is C 3 -C 9 cycloalkyl (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.

[0282] In some embodiments, R 4 is 3-10 membered heterocyclyl. 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.

[0283] In some embodiments, R 4 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0284] In some embodiments, R 4 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0285] In some embodiments, R 4 is arylalkyl. In some embodiments, R 4 is benzyl.

[0286] In some embodiments, R 4 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0287] In some embodiments, R 4 -OR a4and 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 ).

[0288] In some embodiments, R 4 is -N(R a4 ) 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 , -NHCH 2 CH 3 , -NHPr, -NH i In some embodiments, R 4 is -N(CH 3 )R a4 (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).

[0289] 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)CH 2 CH 2 CH 3 , or -C(=O)OCH 3 In some embodiments, R 4 is acetyl (-C(=O)CH 3 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.

[0290] In some embodiments, R 4 -NR a4 C(=O)Ra4 and R a4 is as defined in any of the embodiments described herein. In certain embodiments, R 4 is -NHC(=O)R a4 (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 4 is -N(CH 3 )C(=O)R a4 (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).

[0291] 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, R 4 is -NHC(=O)OR a4 (For example, -NHC(=O)OCH 3 , -NHC(=O)OCH 2 CH3 , -NHC(=O)OCH 2 CH 2 CH 3 , -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)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).

[0292] 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)NHCH 2 CH 3, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t In 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 )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 4 is -C(=O)N(OR a4 )(R a4 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.

[0293] 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)NHCH 2 CH3 , -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 4 is -OC(=O)N(CH 3 )R a4 (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).

[0294] 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)CH 3 , -S(=O)CH 2 CH 3 , -S(=O)CH 2 CH 2 CH 3 , -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).

[0295] 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 CH 3 , -S(=O) 2 CH 2 CH 3 , -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).

[0296] 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., -SCH 3 , -SCH 2 CH 3 , -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). In some embodiments, R 4 is -S(=O)(=NRa4 )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)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 4 is -S(=O)(=NCH 3 )R a4 (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).

[0297] 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) 2Alkyl (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 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 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 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).

[0298] 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 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 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 )CH 2 CH 3 , -S(=O) 2 N(CH 3 )CH 2 CH 2 CH 3 , -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0299] As generally defined herein, each R 8 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 a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -C(=O)N(R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 , and -S(=O) 2 N(R a8 ) 2 wherein R a8 is as defined herein.

[0300] In some embodiments, R 8 H, 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, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -C(=O)N(R a8 ) 2 , and -OC(=O)N(R a8 ) 2 wherein R a8 is as defined herein.

[0301] In certain embodiments, R 8 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -OR a8 , and -N(R a8 ) 2 wherein R a8 is as defined herein.

[0302] In some embodiments, R 8 -H, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -OR a8 , and -N(R a8 ) 2 wherein R a8 is as defined herein.

[0303] In some embodiments, R 8 OR a8 , and -N(R a8 ) 2 wherein R a8 is as defined herein.

[0304] In some embodiments, each R a8 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 ).

[0305] In some embodiments, R 8 -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 ).

[0306] In certain embodiments, R 8 -H, -Me, -Et, -CHF 2 , -OCH 3 , -OEt, -OCHF 2 , -OCF 3 , -OH, and -NH 2 Selected from the group consisting of 。In some embodiments, R 8 -H, -Et, -OCH 3 , -OEt, -OCHF 2 , -OCF 3 and -OH.

[0307] In certain embodiments, R 8 -H, -Me, -CHF 2 , -OCH 3 , and -NH 2 Selected from the group consisting of 。

[0308] In other embodiments, R 8 -H, -Me, -CHF 2 , and -NH 2 In some embodiments, R 8 -Me and -NH 2 is selected from the group consisting of:

[0309] In some embodiments, R 8 is -NH 2 , and -OCH 3 is selected from the group consisting of:

[0310] In some embodiments, R 8 is H. In some embodiments, R 8 is -D.

[0311] In certain embodiments, R 8 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 8 is -Cl. In some embodiments, R 8 is -F. In some embodiments, R 8 In some embodiments, R 8 is -I.

[0312] In some embodiments, R 8 is -CN.

[0313] In certain embodiments, R 8 -C 1 -C 6 In some embodiments, R 8 In some embodiments, R 8 is -Et. In some embodiments, R 8 is -Pr or -iPr.

[0314] In some embodiments, R 8 -C 1 -C 6 In some embodiments, R 8 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 8 is hydroxymethyl (-CH 2 In some embodiments, R 8 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is. In some embodiments, R 8 -C 1 -C 6 In some embodiments, R 8 is trifluoromethyl (-CF 3 In another embodiment, R 8 is difluoromethyl (-CHF 2 ).

[0315] In some embodiments, R 8 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8is cyclobutyl. In some embodiments, R 8 is cyclopentyl. In some embodiments, R 8 is cyclohexyl.

[0316] In some embodiments, R 8 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 8 is oxetanyl. In some embodiments, R 8 is tetrahydropyranyl. In some embodiments, R 8 is tetrahydrofuranyl. In some embodiments, R 8 is azetidinyl. In some embodiments, R 8 is pyrrolidinyl. In some embodiments, R 8 is piperidinyl. In some embodiments, R 8 is piperazinyl. In some embodiments, R 8 is morpholinyl. In some embodiments, R 8 is azepanil.

[0317] In some embodiments, R 8 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 8 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0318] In some embodiments, R 8 is arylalkyl. In some embodiments, R 8 is benzyl. In some embodiments, R 8 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0319] In some embodiments, R 8 -OR a8 where R a8 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 8 is hydroxy. In some embodiments, R 8 is methoxy. In some embodiments, R 8 is ethoxy. In some embodiments, R 8 is propoxy. In some embodiments, R 8 is isopropoxy. In some embodiments, R 8 is difluoromethoxy (-OCHF 2 In some embodiments, R 8 is trifluoromethoxy (-OCF 3 ).

[0320] In some embodiments, R 8 is -N(R a8 ) 2 where R a8 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a8 , -N(CH 3 )R a8 In some embodiments, R 8 is -NH 2 In some embodiments, R 8 -NHR a8 (For example, -NHCH 3, -NHEt, -NHPr, -NH i In some embodiments, R 8 is -N(CH 3 )R a8 (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 8 is -C(=O)R a8 , or -C(=O)OR a8 In some embodiments, R 8 is -C(=O)R a8 and R a8 is as defined in any of the embodiments described herein. In some embodiments, R 8 is —C(═O)alkyl. In some embodiments, R 8 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 8 is acetyl (-C(=O)Me). In some embodiments, R 8 is -C(=O)OR a8 In some embodiments, R 8 is -COOH. In some embodiments, R 8 COOCH 3 It is.

[0321] In some embodiments, R 8 -NR a8 C(=O)R a8 where R a8is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -NHC(=O)R a8 (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 8 is -N(CH 3 )C(=O)R a8 (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 8 -NR a8 C(=O)OR a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -NHC(=O)OR a8 (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 8 is -N(CH 3 )C(=O)OR a8 (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).

[0322] In some embodiments, R 8 is -C(=O)N(R a8 ) 2 where R a8 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a8 , -C(=O)N(CH 3 )R a8 In some embodiments, R 8 is -C(=O)NH 2 In certain embodiments, R 8 is -C(=O)NHR a8 (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 8 is -C(=O)N(CH 3 )R a8 (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 8 is -OC(=O)N(R a8 ) 2 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -OC(=O)NHR a8 (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 8 is -OC(=O)N(CH 3 )R a8 (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).

[0323] In some embodiments, R 8 is -S(=O)R a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 8is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0324] In some embodiments, R 8 is -S(=O) 2 R a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 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 8 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 8 is -S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0325] In some embodiments, R 8 -SR a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 8 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 8 is -Saryl (e.g., -Sphenyl). In some embodiments, R 8 is -S(=O)(=NR a8 )R a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -S(=O)(=NH)R a8 (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 8 is -S(=O)(=NCH 3 )R a8 (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).

[0326] In some embodiments, R 8 -NR a8 S(=O) 2 R a8 where R a8 is as defined in any of the embodiments described herein. In certain embodiments, R 8 is -NHS(=O) 2 Alkyl (e.g., -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2i In certain embodiments, R 8 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 8 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 8 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).

[0327] In some embodiments, R 8 is -S(=O) 2 N(R a8 ) 2 where R a8 is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a8 , -S(=O) 2 N(CH 3 )R a8In some embodiments, R 8 is -S(=O) 2 NH 2 In some embodiments, R 8 is -S(=O) 2 NHR a8 (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 8 is -S(=O) 2 N(CH 3 )R a8 (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).

[0328] As generally defined herein, each R 9 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 a9 , -N(Ra9 ) 2 , -C(=O)R a9 , -C(=O)OR a9 , -NR a9 C(=O)R a9 , -NR a9 C(=O)OR a9 , -C(=O)N(R a9 ) 2 , -OC(=O)N(R a9 ) 2 , -S(=O)R a9 , -S(=O) 2 R a9 , -SR a9 , -S(=O)(=NR a9 )R a9 , -NR a9 S(=O) 2 R a9 , and -S(=O) 2 N(R a9 ) 2 wherein R a9 is as defined herein.

[0329] In some embodiments, R 9 is halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), 3- to 10-membered heterocyclyl, -OR a9 , -N(R a9 ) 2 , -C(=O)R a9 , -C(=O)OR a9 , -NR a9 C(=O)R a9 , -NR a9 C(=O)OR a9 , -C(=O)N(R a9 ) 2 , -OC(=O)N(R a9 ) 2 wherein R a9is as defined herein.

[0330] In certain embodiments, R 9 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 a9 , -N(R a9 ) 2 , -C(=O)R a9 , and -C(=O)N(R a9 ) 2 wherein R a9 is as defined herein.

[0331] In some embodiments, R 9 ,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 a9 , -C(=O)R a9 , and -C(=O)N(R a9 ) 2 wherein R a9 is as defined herein.

[0332] In some embodiments, R 9 -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 a9 ) 2 wherein each R a9is as defined in any of the embodiments described herein. In some embodiments, each R a9 are independently H and -C 1 -C 6 and alkyl (e.g., -Me, -Et, -Pr, -iPr, -nBu, -tBu, -sec-Bu, -iso-Bu).

[0333] In some embodiments, R 9 -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:

[0334] In certain embodiments, R 9 -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 is selected from the group consisting of:

[0335] In some embodiments, R 9 -Cl, -Me, -Et, - i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 In some embodiments, R 9 is selected from the group consisting of cyclopropyl, -Me, and -Et.

[0336] In some embodiments, R 9 is -Me, -Et, oxetan-3-yl, cyclopropyl, and -C(=O)NH 2 is selected from the group consisting of:

[0337] In some embodiments, R 9 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl.

[0338] In some embodiments, R 9 is H. In some embodiments, R 9 is D.

[0339] In certain embodiments, R 9 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 9 is -Cl. In some embodiments, R 9 is -F. In some embodiments, R 9 In some embodiments, R 9 is -I.

[0340] In some embodiments, R 9 is -CN.

[0341] In certain embodiments, R 9 -C 1 -C 6 In some embodiments, R 9 In some embodiments, R 9 is -Et. In some embodiments, R 9 is -Pr or -iPr. In some embodiments, R 9 -C 1 -C 6 In some embodiments, R 9 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R9 is hydroxymethyl (-CH 2 In some embodiments, R 9 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0342] In some embodiments, R 9 -C 1 -C 6 In some embodiments, R 9 is trifluoromethyl (-CF 3 In another embodiment, R 9 is difluoromethyl (-CHF 2 ).

[0343] In some embodiments, R 9 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 9 is cyclopropyl. In some embodiments, R 9 is cyclobutyl. In some embodiments, R 9 is cyclopentyl. In some embodiments, R 9 is cyclohexyl.

[0344] In some embodiments, R 9 is 3-6 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 9 is oxetanyl (e.g., oxetan-3-yl). In some embodiments, R 9 is tetrahydropyranyl. In some embodiments, R 9is tetrahydrofuranyl. In some embodiments, R 9 is azetidinyl. In some embodiments, R 9 is pyrrolidinyl. In some embodiments, R 9 is piperidinyl. In some embodiments, R 9 is piperazinyl. In some embodiments, R 9 is morpholinyl. In some embodiments, R 9 is azepanil.

[0345] In some embodiments, R 9 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 9 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0346] In some embodiments, R 9 is arylalkyl. In some embodiments, R 9 is benzyl.

[0347] In some embodiments, R 9 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0348] In some embodiments, R 9 -OR a9 where R a9 is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 9is hydroxy. In some embodiments, R 9 is methoxy. In some embodiments, R 9 is ethoxy. In some embodiments, R 9 is propoxy. In some embodiments, R 9 is isopropoxy. In some embodiments, R 9 -C 1 -C 6 In some embodiments, R 9 is trifluoromethoxy (-OCF 3 ) and in other embodiments, R 9 is difluoromethoxy (-OCHF 2 ).

[0349] In some embodiments, R 9 is -N(R a9 ) 2 where R a9 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a9 , -N(CH 3 )R a9 In some embodiments, R 9 is -NH 2 In some embodiments, R 9 -NHR a9 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 9 is -N(CH 3 )R a9 (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 9 is -C(=O)R a9 OR -C(=O)OR a9 where R a9 is as defined in any of the embodiments described herein. In some embodiments, R 9 is -C(=O)R a9 where R a9 is as defined in any of the embodiments described herein. In some embodiments, R 9 is —C(═O)alkyl. In some embodiments, R 9 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 9 is acetyl (-C(=O)Me). In some embodiments, R 9 is -C(=O)OR a9 In some embodiments, R 9 is -COOH. In some embodiments, R 9 COOCH 3 It is.

[0350] In some embodiments, R 9 -NR a9 C(=O)R a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -NHC(=O)R a9 (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 9 is -N(CH 3 )C(=O)Ra9 (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.

[0351] In some embodiments, R 9 -NR a9 C(=O)OR a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -NHC(=O)OR a9 (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 9 is -N(CH 3 )C(=O)OR a9 (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).

[0352] In some embodiments, R 9 is -C(=O)N(R a9 ) 2 where R a9 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a9 , -C(=O)N(CH 3 )R a9 In some embodiments, R 9 is -C(=O)NH 2 In certain embodiments, R 9 is -C(=O)NHR a9 (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 9 is -C(=O)N(CH 3 )R a9 (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).

[0353] In some embodiments, R 9 is -C(=O)N(OR a9 )(R a9 ) in which R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -C(=O)NH(ORa9 ) (e.g., -C(=O)NHOH, -C(=O)NHOCH 3 In some embodiments, R 9 is -C(=O)NHOH.

[0354] In some embodiments, R 9 is -OC(=O)N(R a9 ) 2 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -OC(=O)NHR a9 (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 9 is -OC(=O)N(CH 3 )R a9 (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).

[0355] In some embodiments, R 9 is -S(=O)R a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 9 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0356] In some embodiments, R 9 is -S(=O) 2 R a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 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 9 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 9 is -S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0357] In some embodiments, R 9 -SR a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 9is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 9 is -Saryl (e.g., -Sphenyl).

[0358] In some embodiments, R 9 is -S(=O)(=NR a9 )R a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9 is -S(=O)(=NH)R a9 (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 9 is -S(=O)(=NCH 3 )R a9 (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).

[0359] In some embodiments, R 9 -NR a9 S(=O) 2 R a9 where R a9 is as defined in any of the embodiments described herein. In certain embodiments, R 9is -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 9 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 9 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 9 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).

[0360] In some embodiments, R 9 is -S(=O) 2 N(R a9 ) 2 where R a9is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a9 , -S(=O) 2 N(CH 3 )R a9 In some embodiments, R 9 is -S(=O) 2 NH 2 In some embodiments, R 9 is -S(=O) 2 NHR a9 (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 9 is -S(=O) 2 N(CH 3 )R a9 (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).

[0361] Some embodiments include R 8 and R 9 In one embodiment, R 8 -H, -OCH 3 , -OEt, -OCF 3, -OCHF 2 , -CHF 2 , -Me, -Et, -OH, and -NH 2 R 9 -Cl, -Me, -Et, - i Pr, -CF 3 , -CHF 2 , -OCHF 2 , cyclopropyl, and -C(=O)NH 2 In one embodiment, R 8 -H, -CHF 2 , -Me, and -NH 2 R 9 -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. 8 is -NH 2 -Me; and R 9 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl.

[0362] In one embodiment, R 8 is -NH 2 and R 9 is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl.

[0363] In another embodiment, R 8 -H, -OCH 3 , -OEt, -OCF 3 , -OCHF 2 , -Et, and -OH; R 9 is -C(=O)NH 2 In some embodiments, R 8 -H, and -OCH 3 R 9 is -C(=O)NH 2 In some embodiments, R 8 -OCH3 and R 9 is -C(=O)NH 2 It is.

[0364] As generally described herein, each R 10 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 a10 , -N(R a10 ) 2 , -C(=O)R a10 , -C(=O)OR a10 , -NR a10 C(=O)R a10 , -NR a10 C(=O)OR a10 , -C(=O)N(R a10 ) 2 , -OC(=O)N(R a10 ) 2 , -S(=O)R a10 , -S(=O) 2 R a10 , -SR a10 , -S(=O)(=NR a10 )R a10 , -NR a10 S(=O) 2 R a10 , and -S(=O) 2 N(R a10 ) 2 wherein R a10 is as defined in any of the embodiments described herein.

[0365] In some embodiments, R 10 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, -OR a10 , -N(R a10 ) 2 , -C(=O)R a10 , -C(=O)OR a10 , -NR a10 C(=O)R a10 , -NR a10 C(=O)OR a10 , -C(=O)N(R a10 ) 2 , and -OC(=O)N(R a10 ) wherein R a10 is as defined in any of the embodiments described herein.

[0366] In certain embodiments, R 10 H, halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, and -N(R a10 ) 2 wherein R a10 is as defined in any of the embodiments described herein. In some embodiments, R a10 -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). 10 -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 6alkyl) (e.g., -NHCH 3 ), and -N-(C 1 -C 6 Alkyl) 2 (For example, -N(CH 3 ) 2 In some embodiments, R 10 is H, -Me, and -NH 2 In certain embodiments, R 10 is selected from the group consisting of H and -Me 。

[0367] In some embodiments, R 10 is H. In some embodiments, R 10 is -D. In certain embodiments, R 10 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 10 is -Cl. In some embodiments, R 10 is -F. In some embodiments, R 10 In some embodiments, R 10 is -I.

[0368] In some embodiments, R 10 is -CN.

[0369] In certain embodiments, R 10 -C 1 -C 6 In some embodiments, R 10 In some embodiments, R 10 is -Et. In some embodiments, R 10 is -Pr or -iPr. In some embodiments, R 10 -C 1 -C 6 In some embodiments, R 10 is methoxymethyl (-CH 2 OCH3 In some embodiments, R 10 is hydroxymethyl (-CH 2 In some embodiments, R 10 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0370] In some embodiments, R 10 -C 1 -C 6 In some embodiments, R 10 is trifluoromethyl (-CF 3 In another embodiment, R 10 is difluoromethyl (-CHF 2 ).

[0371] In some embodiments, R 10 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 10 is cyclopropyl. In some embodiments, R 10 is cyclobutyl. In some embodiments, R 10 is cyclopentyl. In some embodiments, R 10 is cyclohexyl.

[0372] In some embodiments, R 10 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 10 is oxetanyl. In some embodiments, R 10is tetrahydropyranyl. In some embodiments, R 10 is tetrahydrofuranyl. In some embodiments, R 10 is azetidinyl. In some embodiments, R 10 is pyrrolidinyl. In some embodiments, R 10 is piperidinyl. In some embodiments, R 10 is piperazinyl. In some embodiments, R 10 is morpholinyl. In some embodiments, R 10 is azepanil.

[0373] In some embodiments, R 10 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 10 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0374] In some embodiments, R 10 is arylalkyl. In some embodiments, R 10 is benzyl. In some embodiments, R 10 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0375] In some embodiments, R 10 -OR a10 where R a10 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 10 is hydroxy. In some embodiments, R 10 is methoxy. In some embodiments, R 10 is ethoxy. In some embodiments, R 10 is propoxy. In some embodiments, R 10 is isopropoxy. In some embodiments, R 10 is difluoromethoxy (-OCHF 2 In some embodiments, R 10 is trifluoromethoxy (-OCF 3 ).

[0376] In some embodiments, R 10 is -N(R a10 ) 2 where R a10 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a10 , -N(CH 3 )R a10 In some embodiments, R 10 is -NH 2 In some embodiments, R 10 -NHR a10 (For example, -NHCH 3 , -NHEt, -NHPr, -NH i In some embodiments, R 10 is -N(CH 3 )R a10 (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).

[0377] In some embodiments, R 10 is -C(=O)R a10 OR -C(=O)OR a10 where R a10 is as defined in any of the embodiments described herein. In some embodiments, R 10 is -C(=O)R a10 where R a10 is as defined in any of the embodiments described herein. In some embodiments, R 10 is —C(═O)alkyl. In some embodiments, R 10 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 10 is acetyl (-C(=O)Me). In some embodiments, R 10 is -C(=O)OR a10 In some embodiments, R 10 is -COOH. In some embodiments, R 10 COOCH 3 It is.

[0378] In some embodiments, R 10 -NR a10 C(=O)R a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -NHC(=O)R a10 (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 10is -N(CH 3 )C(=O)R a10 (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.

[0379] In some embodiments, R 10 -NR a10 C(=O)OR a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -NHC(=O)OR a10 (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 10 is -N(CH 3 )C(=O)OR a10 (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).

[0380] In some embodiments, R 10 is -C(=O)N(R a10 ) 2 where R a10 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a10 , -C(=O)N(CH 3 )R a10 In some embodiments, R 10 is -C(=O)NH 2 In certain embodiments, R 10 is -C(=O)NHR a10 (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 10 is -C(=O)N(CH 3 )R a10 (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).

[0381] In some embodiments, R 10 is -OC(=O)N(R a10 ) 2 where R a10is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -OC(=O)NHR a10 (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 10 is -OC(=O)N(CH 3 )R a10 (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).

[0382] In some embodiments, R 10 is -S(=O)R a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 10 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0383] In some embodiments, R 10 is -S(=O)2 R a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 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 10 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 10 is -S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0384] In some embodiments, R 10 -SR a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i In certain embodiments, R 10 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 10 is -Saryl (e.g., -Sphenyl).

[0385] In some embodiments, R 10 is -S(=O)(=NR a10 )R a10 where R a10is as defined in any of the embodiments described herein. In certain embodiments, R 10 is -S(=O)(=NH)R a10 (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 10 is -S(=O)(=NCH 3 )R a10 (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).

[0386] In some embodiments, R 10 -NR a10 S(=O) 2 R a10 where R a10 is as defined in any of the embodiments described herein. In certain embodiments, R 10 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 10 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 10 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 10 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).

[0387] In some embodiments, R 10 is -S(=O) 2 N(R a10 ) 2 where R a10 is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a10 , -S(=O) 2 N(CH 3 )R a10 In some embodiments, R 10 is -S(=O) 2 NH 2 In some embodiments, R 10is -S(=O) 2 NHR a10 (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 10 is -S(=O) 2 N(CH 3 )R a10 (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).

[0388] As generally described herein, each R 11 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 a11 , -N(R a11 ) 2 , -C(=O)R a11 , -C(=O)OR a11 , -NR a11 C(=O)Ra11 , -NR a11 C(=O)OR a11 , -C(=O)N(R a11 ) 2 , -OC(=O)N(R a11 ) 2 , -S(=O)R a11 , -S(=O) 2 R a11 , -SR a11 , -S(=O)(=NR a11 )R a11 , -NR a11 S(=O) 2 R a11 , and -S(=O) 2 N(R a11 ) 2 wherein each R a11 is as defined in any of the embodiments described herein.

[0389] In certain embodiments, R 11 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 a11 , -N(R a11 )2, -C(=O)R a11 , -C(=O)OR a11 , -NR a11 C(=O)R a11 , -NR a11 C(=O)OR a11 , -C(=O)N(R a11 )2, and -OC(=O)N(R a11 ) 2 wherein each R a11 is as defined in any of the embodiments described herein.

[0390] In some embodiments, R 11 H, halo, -CN, -C 1-C 6 Alkyl, -C 1 -C 6 Haloalkyl, and -N(R a11 ) 2 wherein each R a11 is as defined in any of the embodiments described herein. In some embodiments, each R a11 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). 11 -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 ).

[0391] In some embodiments, R 11 is H. In some embodiments, R 11 is -D.

[0392] In certain embodiments, R 11 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 11 is -Cl. In some embodiments, R 11 is -F. In some embodiments, R 11 In some embodiments, R 11 is -I.

[0393] In some embodiments, R 11 is -CN. In certain embodiments, R 11 -C 1 -C 6 In some embodiments, R 11 In some embodiments, R 11 is -Et. In some embodiments, R 11 is -Pr or -iPr.

[0394] In some embodiments, R 11 -C 1 -C 6 In some embodiments, R 11 is methoxymethyl (-CH 2 OCH 3 In some embodiments, R 11 is hydroxymethyl (-CH 2 In some embodiments, R 11 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 It is.

[0395] In some embodiments, R 11 -C 1 -C 6 In some embodiments, R 11 is trifluoromethyl (-CF 3 In another embodiment, R 11 is difluoromethyl (-CHF 2 ). In some embodiments, R 11 -C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R11 is cyclopropyl. In some embodiments, R 11 is cyclobutyl. In some embodiments, R 11 is cyclopentyl. In some embodiments, R 11 is cyclohexyl. In some embodiments, R 11 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 11 is oxetanyl. In some embodiments, R 11 is tetrahydropyranyl. In some embodiments, R 11 is tetrahydrofuranyl. In some embodiments, R 11 is azetidinyl. In some embodiments, R 11 is pyrrolidinyl. In some embodiments, R 11 is piperidinyl. In some embodiments, R 11 is piperazinyl. In some embodiments, R 11 is morpholinyl. In some embodiments, R 11 is azepanil.

[0396] In some embodiments, R 11 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 11 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, R 11 is arylalkyl. In some embodiments, R 11 is benzyl. In some embodiments, R 11 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0397] In some embodiments, R 11 -OR a11 where R a11 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 11 is hydroxy. In some embodiments, R 11 is methoxy. In some embodiments, R 11 is ethoxy. In some embodiments, R 11 is propoxy. In some embodiments, R 11 is isopropoxy. In some embodiments, R 11 is difluoromethoxy (-OCHF 2 In some embodiments, R 11 is trifluoromethoxy (-OCF 3 ).

[0398] In some embodiments, R 11 is -N(R a11 ) 2 where R a11 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a11 , -N(CH 3 )R a11 In some embodiments, R 11 is -NH 2 In some embodiments, R 11 -NHR a11 (For example, -NHCH 3, -NHEt, -NHPr, -NH i In some embodiments, R 11 is -N(CH 3 )R a11 (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).

[0399] In some embodiments, R 11 is -C(=O)R a11 OR -C(=O)OR a11 where R a11 is as defined in any of the embodiments described herein. In some embodiments, R 11 is -C(=O)R a11 where R a11 is as defined in any of the embodiments described herein. In some embodiments, R 11 is —C(═O)alkyl. In some embodiments, R 11 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 11 is acetyl (-C(=O)Me). In some embodiments, R 11 is -C(=O)OR a11 In some embodiments, R 11 is -COOH. In some embodiments, R 11 COOCH 3 It is.

[0400] In some embodiments, R11 -NR a11 C(=O)R a11 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -NHC(=O)R a11 (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 11 is -N(CH 3 )C(=O)R a11 (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.

[0401] In some embodiments, R 11 -NR a11 C(=O)OR a11 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -NHC(=O)OR a11 (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 11 is -N(CH3 )C(=O)OR a11 (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).

[0402] In some embodiments, R 11 is -C(=O)N(R a11 ) 2 where R a11 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a11 , -C(=O)N(CH 3 )R a11 In some embodiments, R 11 is -C(=O)NH 2 In certain embodiments, R 11 is -C(=O)NHR a11 (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 11 is -C(=O)N(CH 3 )R a11 (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).

[0403] In some embodiments, R 11 is -OC(=O)N(R a11 ) 2 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -OC(=O)NHR a11 (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 11 is -OC(=O)N(CH 3 )R a11 (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).

[0404] In some embodiments, R 11 is -S(=O)R a11 where R a11is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i In certain embodiments, R 11 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0405] In some embodiments, R 11 is -S(=O) 2 R a11 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 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 11 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 11 is -S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl).

[0406] In some embodiments, R 11 -SR a11 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S iIn certain embodiments, R 11 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 11 is -Saryl (e.g., -Sphenyl).

[0407] In some embodiments, R 11 is -S(=O)(=NR a11 )R a11 where R a11 is as defined in any of the embodiments described herein. In certain embodiments, R 11 is -S(=O)(=NH)R a11 (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 11 is -S(=O)(=NCH 3 )R a11 (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).

[0408] In some embodiments, R 11 -NR a11 S(=O) 2 R a11 where R a11is as defined in any of the embodiments described herein. In certain embodiments, R 11 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 11 is -NHS(=O) 2 Cycloalkyl (e.g., -NHS(=O) 2 Cyclopropyl, -NHS(=O) 2 Cyclobutyl, -NHS(=O) 2 Cyclopentyl, -NHS(=O) 2 cyclohexyl).

[0409] In certain embodiments, R 11 is -N(CH 3 )S(=O) 2 alkyl, where R a11 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 11 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).

[0410] In some embodiments, R 11 is -S(=O) 2 N(R a11 ) 2 where R a11 is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a11 , -S(=O) 2 N(CH 3 )R a11 In some embodiments, R 11 is -S(=O) 2 NH 2 In some embodiments, R 11 is -S(=O) 2 NHR a11 (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 11 is -S(=O) 2 N(CH 3 )R a11 (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).

[0411] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0412] 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.

[0413] In some embodiments, each aryl and heteroaryl in ring B is selected from 0, 1, 2, or 3 R 3 at any available position, and each R 3 is as defined in any of the embodiments described herein.

[0414] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0415] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0416] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0417] In some embodiments, ring B is selected from the group consisting of thiophenyl, phenyl, and benzo[d]thiazolyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0418] 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, 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0419] In some embodiments, Ring B is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, phenyl, benzo[d]thiazol-5-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 is replaced by R 3is as defined in any of the embodiments described herein).

[0420] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0421] In some embodiments, Ring B is independently selected from the group consisting of phenyl and 8-10 membered bicyclic 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0422] In some embodiments, ring B is selected from the group consisting of phenyl, and benzo[d]thiazolyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 is replaced by R 3 is as defined in any of the embodiments described herein. In some embodiments, Ring B is selected from the group consisting of phenyl, and benzo[d]thiazol-5-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 is replaced by R3 is as defined in any of the embodiments described herein).

[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 and 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0424] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein).

[0425] In some embodiments, ring B is selected from the group consisting of thiophenyl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 is replaced by R 3 is as defined in any of the embodiments described herein. In some embodiments, Ring B is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, and phenyl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3is replaced by R 3 is as defined in any of the embodiments described herein).

[0426] In some embodiments, ring B is unsubstituted. In some embodiments, ring B is unsubstituted. 3 In some embodiments, ring B is substituted with two R 3 In some embodiments, ring B is substituted with 3 R 3 is replaced by.

[0427] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0428] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0429] 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 3 is replaced by R 3 is as defined in any of the embodiments described herein.

[0430] In some embodiments, Ring B is an optionally substituted phenyl. In some embodiments, Ring B is 0, 1, 2, or 3 R 3 and each R 3 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 3 In some embodiments, the phenyl is substituted with one R 3In some embodiments, the phenyl is substituted with one R meta to the point of attachment to the piperidine. 3 In some embodiments, the phenyl is substituted with two R 3 In some embodiments, the phenyl is substituted with three R 3 is replaced by.

[0431] In some embodiments, ring B is [ka] wherein each R 3 is as defined herein.

[0432] In some embodiments, ring B is [ka] where each R 3 is as defined herein.

[0433] In some embodiments, ring B is [ka] where each R 3 is as defined herein.

[0434] In some embodiments, ring B is [ka] where each R 3 is as defined herein.

[0435] In some embodiments, ring B is [ka] where each R 3 is as defined herein.

[0436] In some embodiments, ring B is [ka] where each R 3 is as defined herein.

[0437] In some embodiments, ring B is [ka] It is.

[0438] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] wherein X, ring A, R 1 , R 2 and n is as defined herein, and phenyl is selected from 0, 1, 2, or 3 R 3 In some embodiments, the compound of formula (I) is substituted with a compound of formula (IVa): [ka] and In the formula, X, ring A, R 1 , R 2 and n is as defined herein, and phenyl is selected from 0, 1, 2, or 3 R 3 In some embodiments, the phenyl is unsubstituted. In some embodiments, the phenyl is substituted with one R 3 In some embodiments, the phenyl is substituted with one R 3 In some embodiments, the phenyl is substituted with one R meta to the point of attachment to the piperidine. 3 In some embodiments, the phenyl is substituted with two R 3 In some embodiments, the phenyl is substituted with three R3 is replaced by.

[0439] In further embodiments, the compound of formula (I) is a compound of formula (IV_1): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0440] In further embodiments, the compound of formula (I) is a compound of formula (IV_1a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0441] In another embodiment, the compound of formula (I) is a compound of formula (IV_2): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0442] In another embodiment, the compound of formula (I) is a compound of formula (IV_2a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0443] In certain embodiments, the compound of formula (I) is a compound of formula (IV_3): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0444] In certain embodiments, the compound of formula (I) is a compound of formula (IV_3a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0445] In certain embodiments, the compound of formula (I) is a compound of formula (IV_4): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0446] In certain embodiments, the compound of formula (I) is a compound of formula (IV_4a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0447] In certain embodiments, the compound of formula (I) is a compound of formula (IV_5): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0448] In certain embodiments, the compound of formula (I) is a compound of formula (IV_5a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0449] 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

[0450] 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).

[0451] 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 3 Each R 3 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 3 In some embodiments, the bicyclic aryl is substituted with one R 3 is replaced by R 3 is selected from the group consisting of halo (e.g., -F, -Cl, -Br), -Me, ═O.

[0452] 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).

[0453] 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 3 Each R 3 is as defined in any of the embodiments described herein. In some embodiments, the 5-6 membered monocyclic heteroaryl is selected from one R 3 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with two R 3 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with two R 3 In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with three R 3 is replaced by.

[0454] 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). 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 is selected from the group consisting of one R 3 In some embodiments, the 5-membered monocyclic heteroaryl is substituted with two R 3 In some embodiments, the 5-membered monocyclic heteroaryl is substituted with 3 R 3 is replaced by.

[0455] 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 3 In some embodiments, the 6-membered monocyclic heteroaryl is substituted with one R 3 In some embodiments, the 6-membered monocyclic heteroaryl is substituted with two R 3 In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 3 R 3 In some embodiments, Ring B is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, Ring B is pyridin-2-yl. In some embodiments, Ring B is pyridin-3-yl. In some embodiments, Ring B is pyridin-4-yl. In some embodiments, Ring B is pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).

[0456] In some embodiments, the compound of formula (I) is a compound of formula (V_1): [ka] wherein X, ring A, R 1 , R 2 and n is as defined herein, and thiophenyl is selected from 0, 1, 2, or 3 R 3 In some embodiments, the compound of formula (I) is substituted with a compound of formula (V_1a): [ka] and In the formula, X, ring A, R 1 , R 2 and n is as defined herein, and thiophenyl is selected from 0, 1, 2, or 3 R 3In some embodiments, the thiophenyl is unsubstituted. In some embodiments, the thiophenyl is substituted with one R 3 In some embodiments, the thiophenyl is substituted with two R 3 In some embodiments, the thiophenyl is substituted with three R 3 is replaced by.

[0457] In some embodiments, the compound of formula (I) is a compound of formula (V_2): [ka] wherein X, ring A, R 1 , R 2 and n is as defined herein, and thiophenyl is selected from 0, 1, 2, or 3 R 3 In some embodiments, the compound of formula (I) is substituted with a compound of formula (V_2a): [ka] and In the formula, X, ring A, R 1 , R 2 and n is as defined herein, and thiophenyl is selected from 0, 1, 2, or 3 R 3 In some embodiments, the thiophenyl is unsubstituted. In some embodiments, the thiophenyl is substituted with one R 3 In some embodiments, the thiophenyl is substituted with two R 3 In some embodiments, the thiophenyl is substituted with three R 3 is replaced by.

[0458] 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 3 is replaced by R 3are as defined 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 3 In the case of R 3 is as defined 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).

[0459] 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).

[0460] 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).

[0461] 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.

[0462] 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 3 (Replaced by ).

[0463] 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 3 In some embodiments, Ring B is an optionally substituted 2H-indazolyl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted quinolinyl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted isoquinolinyl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted benzo[d]thiazolyl (e.g., 0, 1, 2, or 3 R 3 (replaced by ).

[0464] 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-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]oxazol-4-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]isothiazol-5-yl, benzo[d]oxazol-4-yl, benzo[d]isothiazol-5-yl, benzo[d]isothiaz ... 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, and thiazolo[5,4-b]pyridin-6-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 (Replaced by ).

[0465] In some embodiments, Ring B is independently selected from the group consisting of 2H-indazol-6-yl, 2H-indazol-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, and benzo[d]thiazol-5-yl, each of which is optionally substituted (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted 2H-indazol-6-yl (e.g., 0, 1, 2, or 3 R 3In some embodiments, Ring B is an optionally substituted 2H-indazol-5-yl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted quinolin-6-yl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted quinolin-7-yl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted isoquinolin-6-yl (e.g., 0, 1, 2, or 3 R 3 In some embodiments, Ring B is an optionally substituted benzo[d]thiazol-5-yl (e.g., 0, 1, 2, or 3 R 3 (replaced by ).

[0466] In some embodiments, ring B is [ka] and each is optionally substituted (e.g., 0, 1, 2, or 3 R 3 (Replaced by ).

[0467] In certain embodiments, ring B is [ka] and each is optionally substituted (e.g., 0, 1, 2, or 3 R 3 (Replaced by ).

[0468] In some embodiments, the 8-10 membered bicyclic heteroaryl is unsubstituted. In some embodiments, the 8-10 membered bicyclic heteroaryl is unsubstituted. 3 In some embodiments, the 8-10 membered bicyclic heteroaryl is substituted with two R 3 In some embodiments, the 8-10 membered bicyclic heteroaryl is substituted with three R 3is replaced by.

[0469] In certain embodiments, ring B is [ka] wherein R 3 is as defined herein.

[0470] In certain embodiments, ring B is [ka] wherein R 3 is as defined herein.

[0471] In some embodiments, ring B is [ka] wherein R 3 is as defined herein.

[0472] In some embodiments, ring B is [ka] wherein R 3 is as defined herein.

[0473] In certain embodiments, ring B is [ka] wherein R 3 is as defined herein.

[0474] In some embodiments, ring B is [ka] wherein R3 is as defined herein.

[0475] In certain embodiments, ring B is [ka] It is.

[0476] In certain embodiments, ring B is [ka] It is.

[0477] In certain embodiments, ring B is [ka] where R 3 is as defined herein.

[0478] In certain embodiments, ring B is [ka] where R 3 is as defined herein. In some embodiments, Ring B is [ka] where R 3 is as defined herein. In other embodiments, Ring B is [ka] It is.

[0479] In certain embodiments, ring B is [ka] where R 3 is as defined herein.

[0480] In certain embodiments, ring B is [ka] It is.

[0481] In certain embodiments, ring B is [ka] where R 3 is as defined herein.

[0482] In certain embodiments, ring B is [ka] where R 3 is as defined herein.

[0483] In certain embodiments, ring B is [ka] It is.

[0484] In certain embodiments, ring B is [ka] where R 3 is as defined herein.

[0485] In some embodiments, the compound of formula (I) is a compound of formula (VI): [ka] wherein X, ring A, R 1 , R 2 and n are as defined herein, and the benzothiazole comprises 0, 1, 2, or 3 R 3In some embodiments, the benzothiazole is unsubstituted. In some embodiments, the benzothiazole is substituted with one R 3 In some embodiments, the benzothiazole is substituted with two R 3 In some embodiments, the benzothiazole is substituted with three R 3 is replaced by.

[0486] In some embodiments, the compound of formula (I) is a compound of formula (VIa): [ka] wherein X, ring A, R 1 , R 2 and n are as defined herein, and the benzothiazole comprises 0, 1, 2, or 3 R 3 is replaced by.

[0487] In further embodiments, the compound of formula (I) is a compound of formula (VI_1) [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0488] In some embodiments, the compound of formula (I) is a compound of formula (VI_1a): [ka] wherein X, ring A, R 1 , R 2 , R 3 , and n are as defined herein.

[0489] As generally defined herein, each R 1 is independently absent or H, -D, halo, -CN, -C 1 -C6 Alkyl, -C 1 -C 6 Hydroxyalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 )R a1 , -NR a1 S(=O) 2 R a1 , and -S(=O) 2 N(R a1 ) 2 wherein R a1 is as defined herein.

[0490] In some embodiments, each R 1 are independently H, halo (e.g., -F, -Cl), -CN, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu), 5-membered heteroaryl (e.g., pyrazolyl), -C 1 -C 6 Haloalkyl (e.g., -CF 3 , -CHF 2 , -CH 2 CF 3), -C 1 -C 6 Hydroxyalkyl (e.g., -CH 2 OH), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), -OR a1 (e.g., -OH, -OCH 3 , -OCHF 2 ), -N(R a1 ) 2 , and -C(=O)N(R a1 ) 2 (For example, -C(=O)NH 2 , -C(=O)NHCH 3 ) wherein R a1 is as defined herein. In some embodiments, each R a1 are independently H and -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t -Bu, -sec-Bu, -iso-Bu).

[0491] In certain embodiments, each R 1 is independently selected from the group consisting of H and methyl.

[0492] In some embodiments, R 1 is H. In some embodiments, R 1 is -D.

[0493] In certain embodiments, R 1 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 1 is -Cl. In some embodiments, R 1 is -F. In some embodiments, R 1 In some embodiments, R 1 is -I.

[0494] In some embodiments, R 1 is -CN.

[0495] In certain embodiments, R 1 -C 1 -C 6 In some embodiments, R 1 In some embodiments, R 1 is -Et. In some embodiments, R 1 is -Pr or -iPr.

[0496] In some embodiments, R 1 -C 1 -C 6 In some embodiments, R 1 is hydroxymethyl (-CH 2 OH).

[0497] In some embodiments, R 1 -C 1 -C 6 In some embodiments, R 1 is trifluoromethyl (-CF 3 In another embodiment, R 1 is difluoromethyl (-CHF 2 ).

[0498] In some embodiments, R 1 is C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). 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.

[0499] In some embodiments, R 1 is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 1 is oxetanyl. 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, R 1 is piperidinyl. In some embodiments, R 1 is piperazinyl. In some embodiments, R 1 is morpholinyl. In some embodiments, R 1 is azepanil.

[0500] In some embodiments, R 1 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0501] In some embodiments, R 1 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0502] In some embodiments, R 1 is arylalkyl. In some embodiments, R 1 is benzyl.

[0503] In some embodiments, R 1is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0504] In some embodiments, R 1 -OR a1 where R a1 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 1 is hydroxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is ethoxy. In some embodiments, R 1 is propoxy. In some embodiments, R 1 is isopropoxy. In some embodiments, R 1 is difluoromethoxy (-OCHF 2 In some embodiments, R 1 is trifluoromethoxy (-OCF 3 ).

[0505] In some embodiments, R 1 is -N(R a1 ) 2 where R a1 is as defined in any of the embodiments described herein (e.g., -NH 2 , -NHR a1 , -N(CH 3 )R a1 In some embodiments, R 1 is -NH 2 In some embodiments, R 1 -NHR a1 (For example, -NHCH 3 , -NHCH 2 CH 3, -NHPr, -NH i In some embodiments, R 1 is -N(CH 3 )R a1 (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). In some embodiments, R 1 is -C(=O)R a1 OR -C(=O)OR a1 where R a1 is as defined in any of the embodiments described herein. In some embodiments, R 1 is -C(=O)R a1 where R a1 is as defined in any of the embodiments described herein. In some embodiments, R 1 is —C(═O)alkyl. In some embodiments, R 1 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 1 is acetyl (-C(=O)CH 3 In some embodiments, R 1 is -C(=O)OR a1 where R a1is as defined in any of the embodiments described herein. In some embodiments, R 1 is -COOH. In some embodiments, R 1 COOCH 3 It is.

[0506] In some embodiments, R 1 -NR a1 C(=O)R a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -NHC(=O)R a1 (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 1 is -N(CH 3 )C(=O)R a1 (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).

[0507] In some embodiments, R1 -NR a1 C(=O)OR a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -NHC(=O)OR a1 (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 1 is -N(CH 3 )C(=O)OR a1 (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).

[0508] In some embodiments, R 1 is -C(=O)N(R a1 ) 2 where R a1 is as defined in any of the embodiments described herein (e.g., -C(=O)NH 2 , -C(=O)NHR a1, -C(=O)N(CH 3 )R a1 In some embodiments, R 1 is -C(=O)NH 2 In certain embodiments, R 1 is -C(=O)NHR a1 (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 1 is -C(=O)N(CH 3 )R a1 (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).

[0509] In some embodiments, R 1 is -OC(=O)N(R a1 ) 2 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -OC(=O)NHR a1 (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 1 is -OC(=O)N(CH 3 )R a1 (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).

[0510] In some embodiments, R 1 is -S(=O)R a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 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) i In certain embodiments, R 1 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0511] In some embodiments, R 1 is -S(=O) 2 R a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 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 1 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 1 is -S(=O) 2 Aryl (e.g., -S(=O) 2 phenyl). In some embodiments, R 1 -SR a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -S alkyl (e.g., -SCH 3 , -SCH 2 CH 3 , -SPr, -S i In certain embodiments, R 1 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 1 is -Saryl (e.g., -Sphenyl). In some embodiments, R 1 is -S(=O)(=NR a1 )Ra1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -S(=O)(=NH)R a1 (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 1 is -S(=O)(=NCH 3 )R a1 (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).

[0512] In some embodiments, R 1 -NR a1 S(=O) 2 R a1 where R a1 is as defined in any of the embodiments described herein. In certain embodiments, R 1 is -NHS(=O) 2Alkyl (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 1 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 1 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 1 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).

[0513] In some embodiments, R 1 is -S(=O) 2 N(R a1 )2 where R a1 is as defined in any of the embodiments described herein (e.g., -S(=O) 2 NH 2 , -S(=O) 2 NHR a1 , -S(=O) 2 N(CH 3 )R a1 In some embodiments, R 1 is -S(=O) 2 NH 2 In some embodiments, R 1 is -S(=O) 2 NHR a1 (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 1 is -S(=O) 2 N(CH 3 )R a1 (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) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0514] As generally defined herein, each R 2 are independently -D, =O, 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 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 , -OC(=O)N(R a2 ) 2 , -CH 2 C(=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 and two R 2 can be taken together with the atom(s) to which they are attached to form a 3- to 10-membered cycloalkyl or heterocyclyl ring (e.g., a ring which can be taken together with the morpholine or piperazine ring of structure I to form a bridged, fused, or spiro bicyclic heterocyclic ring), where R a2 is as defined herein.

[0515] In some embodiments of Formula (I), two R 2 The groups, together with the atoms to which they are attached, form a 3- to 10-membered spirocycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), or spiroheterocyclyl ring (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydrothiopyranyl, thiomorpholinyl).

[0516] In some embodiments of Formula (I), two R 2 The groups, together with the adjacent atoms to which they are attached, form a 3- to 10-membered fused cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), or a fused heterocyclyl ring (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydrothiopyranyl, thiomorpholinyl).

[0517] In some embodiments, two R 2 The groups, together with the atoms to which they are attached, form a bridged piperazine- or morpholine-containing heterocyclyl ring.

[0518] In other embodiments, R 2 The groups, taken together, do not form a cycloalkyl or heterocyclyl ring (i.e., each R 2 are independently -D, =O, 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 a2 , -N(Ra2 ) 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 , -OC(=O)N(R a2 ) 2 , -CH 2 C(=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 wherein R a2 is as defined herein.

[0519] In some embodiments, each R 2 are independently halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), 3- to 6-membered heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a4 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 )2 , -OC(=O)N(R a2 ) 2 wherein each R a2 is as defined herein. In some embodiments, each R 2 are independently halo, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), 3- to 6-membered heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2、 -C(=O)R a2 , -C(=O)N(OR a2 )(R a2 ), and -C(=O)N(R a2 ) 2 wherein R a2 is as defined herein. In some embodiments, each R a2 are independently H and -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t -Bu, -sec-Bu, -iso-Bu).

[0520] In some embodiments, each R 2 are independently halo (e.g., -Cl), -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), -C 1 -C 6 Haloalkyl (e.g., -CF 3 , -CHF 2 ), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl), -C1 -C 6 Haloalkoxy (e.g., -OCF 3 , -OCHF 2 ), --OCH 3 , -C(=O)H, -C(=O)NHOH, and -C(=O)NH 2 is selected from the group consisting of:

[0521] In some embodiments, each R 2 are independently halo (e.g., -Cl), -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and --OCH 3 is selected from the group consisting of:

[0522] In some embodiments, R 2 is -D.

[0523] In certain embodiments, R 2 is =O.

[0524] 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.

[0525] In some embodiments, R 2 is -CN.

[0526] In certain embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 In some embodiments, R2 is -Et. In some embodiments, R 2 is -Pr or -iPr.

[0527] 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.

[0528] In some embodiments, R 2 -C 1 -C 6 In some embodiments, R 2 is trifluoromethyl (-CF 3 ).

[0529] 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.

[0530] In some embodiments, R 2is 3-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). 2 is 3-6 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl). 2 is oxetanyl. 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.

[0531] In some embodiments, R 2 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 2 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). 2 is arylalkyl (e.g., benzyl). In some embodiments, R 2 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0532] In some embodiments, R 2 -OR a2 where each R a2 is as defined herein (e.g., -OH, methoxy, isopropoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 2 is -OH. 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 difluoromethoxy (-OCHF 2 In some embodiments, R 2 is trifluoromethoxy (-OCF 3 ).

[0533] In some embodiments, R 2 is -N(R a2 ) 2 where each R a2 is as defined 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 iIn 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).

[0534] 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)R a2 where R a2 is C 1 -C 6 Alkyl, C 3 -C 9 Cycloalkyl, or 3-10 membered heterocyclyl (e.g., -C(=O)CH 3 , -C(=O)CH 2 CH 3 , -C(=O) t Bu, -C(=O) i Pr, -C(=O)CH 2 CH 2 CH 3 , -C(=O) i In some embodiments, R is selected from the group consisting of -Bu, -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O)oxetanyl, and -C(=O)tetrahydropyranyl. 2 is -C(=O)CH 3 , -C(=O)CH 2 CH 3 , -C(=O) t Bu, -C(=O) iPr, or -C(=O)CH 2 CH 2 CH 3 In some embodiments, R 2 is -C(=O) i Pr.

[0535] In some embodiments, R 2 is -C(=O)OR a2 where R a2 is as defined in any of the embodiments described herein. In some embodiments, R 2 is -C(=O)OR a2 where R a2 is C 1 -C 6 Alkyl (e.g., -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)O t Bu, -C(=O)O i Pr, -C(=O)OCH 2 CH 2 CH 3 ).

[0536] 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 certain embodiments, R 2 is NHC(=O)CH 3In 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).

[0537] In some embodiments, R 2 -NR a2 C(=O)OR a2 and R a2 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 CH3 , -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).

[0538] In some embodiments, R 2 is -C(=O)N(R a2 ) 2 where 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 2 is -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 2CH 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).

[0539] In some embodiments, R 2 is -OC(=O)N(R a2 ) 2 where R a2 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).

[0540] In some embodiments, R 2 is -S(=O)R a2 where 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) i In certain embodiments, R 2 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0541] In some embodiments, R 2 is -S(=O) 2 R a2 where 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) 2Aryl (e.g., -S(=O) 2 phenyl).

[0542] In some embodiments, R 2 -SR a2 where 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 2 is -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 where 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 2CH 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).

[0543] In some embodiments, R 2 -NR a2 S(=O) 2 R a2 where 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 CH2 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) 2 Cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

[0544] In some embodiments, R 2 is -S(=O) 2 N(R a2 ) 2 where 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) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0545] As generally defined herein, each R 3 are 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 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)R a3 , -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 wherein R 3 Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof), wherein R a3 is as defined herein.

[0546] In some embodiments, R 3 Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl in R is unsubstituted. 3 Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently represents one -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , or -NHC(=O)CH 3 In some embodiments, R 3Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently represents two -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof. In some embodiments, R 3 Each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently represents three -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or a combination thereof.

[0547] In some embodiments, each R 3 are independently -D, ═O, halo (e.g., -F, -Cl, -Br), -CN, -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH 2 (CH 3 )( i Pr)), -C 1 -C 6 Heteroalkyl (e.g., -CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 N(CH 3 ) 2 , -CH 2CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )N(CH 3 ) 2 , -CH 2 CH(CH 3 )N(CH 3 ) 2 , -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 ), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperidin-2-onyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), piperazinyl, piperazin-2-onyl, azetidinyl, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[ 2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl), cycloalkylalkyl (e.g., -CH 2-cyclopropyl), heterocyclylalkyl (e.g., -CH 2 -morpholinyl, -CH 2 -pyrrolidinyl, -CH(CH 3 )CH 2 -pyrrolidinyl, -(CH 2 ) 2 -pyrrolidinyl, -(CH 2 ) 3 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl), -OR a3 (e.g., -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -O-Tetrahydrofuranyl, -O-Tetrahydropyran-4-yl, -OCF 3 , -OCHF 2 , -OCH 2 CH(CH 3 )N(CH 3 ) 2 , -Opiperidinyl, -O-(CH 2 ) 2 -pyrrolidinyl, -O-CH 2 -piperidinyl, -O-CH 2 -Oxetanyl, -O-CH 2 -Tetrahydrofuranyl, -O-CH 2 -tetrahydropyranyl), -N(R a3 ) 2 (For example, -NH 2 , -NHR a3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CF 3 , -NH-oxetan-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), and -C(=O)N(R a3 ) 2 (For example, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)CH2 CH 2 N(CH 3 ) 2 ), each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof), wherein each R a3 is as defined herein.

[0548] In some embodiments, each R 3 are independently -D, ═O, 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 ), -C 3 -C 9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl), 5- to 10-membered heteroaryl (e.g., pyrazolyl, thiazolyl, thiophenyl, pyridinyl), cycloalkylalkyl (e.g., -CH 2 -cyclopropyl), heterocyclylalkyl (e.g., -CH2 -morpholinyl), heteroarylalkyl (e.g., -CH 2 -Triazolyl, -CH 2 -Imidazolyl, -CH 2 -pyrazolyl), -OR a3 (e.g., -OH, -OCH 3 , -O-Tetrahydrofuranyl, -O-Tetrahydropyran-4-yl, -OCF 3 , -OCHF 2 ), -N(R a3 ) 2 (For example, -NH 2 , -NHR a3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CF 3 , -NH-oxetan-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), -NR a3 C(=O)R a3 (e.g., -NHC(=O)Me), -C(=O)N(R a3 ) 2 (For example, -C(=O)NH 2 , -C(=O)NHCH 3 ), -OC(=O)R a3 (e.g., -OC(=O)Me), -S(=O)R a3 (For example, -SO 2 Me), -NR a3 S(=O) 2 R a3 (For example, -NHSO 2 Me), and -S(=O) 2 N(R a3 ) 2 (For example, -SO 2 NH 2 , -SO 2 NHCH 3 ), each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted (e.g., 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof), wherein R a3 is as defined herein.

[0549] In some embodiments, each R 3 are independently -CN, halo (e.g., -F, -Cl, -Br), -C 1 -C 6 Alkyl (e.g., -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH 2 (CH 3 )( i Pr)), -C 1 -C 6 Heteroalkyl (e.g., -CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )N(CH 3 ) 2 , -CH 2 CH(CH 3 )N(CH 3 ) 2 ), -C 1 -C 6 Haloalkyl (e.g., -CF 3 ), -C 3 -C 9Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), piperidin-2-onyl, piperazinyl, piperazin-2-onyl, azetidinyl, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[ 2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl), cycloalkylalkyl (e.g., -CH 2 -cyclopropyl), heterocyclylalkyl (e.g., -CH 2 -morpholinyl, -CH 2 -piperidinyl, -CH 2 -pyrrolidinyl, -CH(CH 3 )CH 2 -pyrrolidinyl, -(CH 2 ) 2 -pyrrolidinyl, -(CH 2 ) 3 -pyrrolidinyl), -OR a3 (e.g., -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 CH(CH 3 )N(CH 3 ) 2 , -OCF3 , -OCHF 2 , -O-piperidinyl, -OCH 2 -pyrrolidinyl), -NR a3 C(=O)R a3 (For example, -NHC(=O)CH 3 ), -NHC(=O)CH 2 CH 2 N(CH 3 ) 2 ), each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl is optionally substituted (e.g., 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), wherein R a3 is as defined herein.

[0550] In some embodiments, R 3 are independently -Me, -CN, -F, -Cl, -Br, -CF 3 , -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CH 2 (CH 3 )( i Pr), -CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )N(CH 3 ) 2 , -CH 2 CH(CH 3 )N(CH 3) 2 , -CH(CH 3 )N(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridine), piperidin-2-one, piperazinyl, piperazin-2-onyl, azetidinyl, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]o 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl, -CH 2 -Cyclopropyl, -CH 2 -morpholinyl, -CH 2 -piperidinyl, -CH 2 -pyrrolidinyl, -CH(CH 3 )CH 2 -pyrrolidinyl, -(CH 2 ) 2 -pyrrolidinyl, -(CH 2 ) 3 -pyrrolidinyl), -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCF3 , -OCH 2 CH(CH 3 )N(CH 3 ) 2 , -OCH 2 (pyrrolidinyl), -Opiperidinyl, -OCHF 2 , -C(=O)CH 3 ), and -C(=O)CH 2 CH 2 N(CH 3 ) 2 ), each of which is optionally substituted (e.g., 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).

[0551] In some embodiments, each R 3 are independently: -D, =O, -F, -Cl, -Br, -CN, -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CHF 2 , -CH 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, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrazolyl, thiazolyl, thiophenyl, -CH 2 -Cyclopropyl, -CH 2 -morpholinyl, -CH 2 -1,2,4-Triazolyl, -CH 2 -Imidazolyl, -CH 2 -Pyrazolyl, -OH, -OCH 3 , -OCF 3 , -OCHF 2, -O-Tetrahydrofuranyl, -O-Tetrahydropyranyl, -O-(N-Me-2-oxo-pyrrolidinyl), -OCF 3 , -OCHF 2、 -NH 2 , -NHCH 3 , -NHCH 2 CF 3 , -NH-oxetanyl, -NH-(N-Me-2-oxo-pyrrolidinyl), -N(CH 3 ) 2 , -NHC(=O)Me, -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)Me, -SO 2 Me, -NHSO 2 Me, -SO 2 NH 2 , and -SO 2 NHCH 3 Each of the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrazolyl, thiazolyl, thiophenyl, -CH 2 -Cyclopropyl, -CH 2 -morpholin-4-yl, -CH 2 -1,2,4-Triazol-1-yl-CH 2 -imidazol-1-yl and -CH 2 -Cyclopropyl, -CH 2 -morpholinyl, -CH 2 -1,2,4-Triazolyl, -CH 2 -imidazolyl, and -CH 2 -pyrazolyl is independently selected from 0, 1, 2, or 3 -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or combinations thereof.

[0552] In some embodiments, each R 3 are independently: -D, =O, -F, -Cl, -Br, -CN, -Me, -Et, -Pr, - i Pr, -sec-Bu, - t Bu, -CHF 2 , -CH 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, 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-Me-2-oxo-pyrrolidin-3-yl), -OCF 3 , -OCHF 2 , -NH 2 , -NHCH 3 , -NHCH 2 CF 3 , -NH-oxetan-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), -N(CH 3 ) 2 , -NHC(=O)Me, -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)Me, -SO 2 Me, -NHSO 2 Me, -SO 2 NH 2 , and -SO 2 NHCH 3 each of which is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 , or combinations thereof.

[0553] In some embodiments, each R 3 are independently -D, =O, -F, -Cl, -Me, - i Pr, -CHF 2 , -CF 3 , cyclopropyl, piperidin-4-yl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, -OH, -OCH 3 , -OCF 3 , -OCHF 2wherein each cyclopropyl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl is independently 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 combinations thereof.

[0554] In some embodiments, each R 3 are independently -F, -Cl, -Me, -CF 3 , N-methylpiperazin-4-yl, N-methylpiperidin-4-yl, and -OCH 2 CH 2 N(CH 3 ) 2 is selected from the group consisting of:

[0555] In some embodiments, R 3 is H. In some embodiments, R 3 is -D.

[0556] 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 -Pr or - i In some embodiments, R 3 teeth,- t Bu or -sec-Bu.

[0557] In certain embodiments, R 3 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 3 is -F or -Cl. In some embodiments, R 3 is -Cl. In some embodiments, R3 is -F. In some embodiments, R 3 In some embodiments, R 3 is -I.

[0558] In some embodiments, R 3 is -CN.

[0559] 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 -CH(OH)CH 3 , -C(OH)(CH3) 2 In some embodiments, R 3 is aminomethyl (e.g., -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 -CH 2 N(CH 3 ) 2 , -CH(CH 3 )(N(CH 3 ) 2 ), -CH(CH 3 )CH 2 (N(CH 3 ) 2 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2N(Me)(oxetan-3-yl), -CH(CH 3 )N(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 N(CH 3 ) 2 , -CH 2 CH(CH 3 )(N(CH 3 ) 2 In some embodiments, heteroalkyl is ═O (e.g., —CH 2 NHC(=O)CH 3 In some embodiments, R 3 -C 1 -C 6 In some embodiments, R 3 is trifluoromethyl (-CF 3 In another embodiment, R 3 is difluoromethyl (-CHF 2 In some embodiments, R 3 is trifluoroethyl (-CH 2 CF 3 ).

[0560] In some embodiments, R 3 is C 3 -C 9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 3 is cyclopropyl. In some embodiments, cyclopropyl is selected from one -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , or -NHC(=O)CH 3 In some embodiments, R 3 is one -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , or -NHC(=O)CH 3In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl.

[0561] In some embodiments, R 3 is a 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), piperazinyl, morpholinyl, azepanyl, piperidin-2-onyl, piperazin-2-onyl, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-aza bicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl), each of which 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.

[0562] In some embodiments, R 3is a 3- to 8-membered monocyclic heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), piperazinyl, morpholinyl, azepanyl, piperidin-2-onyl, piperazin-2-onyl), or a 5- to 10-membered bicyclic heterocyclyl (decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2 ]octanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl), each of which 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.

[0563] In some embodiments, R 3 are 3-8 membered monocyclic heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6 tetrahydropyridinyl), piperazinyl, morpholinyl, azepanyl, piperidin-2-onyl, piperazin-2-onyl), each of which may contain 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof. In some embodiments, R3 is selected from the group consisting of oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl (e.g., 1,2,3,6 tetrahydropyridinyl), piperazinyl, morpholinyl, azepanyl, piperidin-2-onyl, and piperazin-2-onyl, each of which contains 0, 1, 2, or 3 of -Me, -OH, -C(=O)CH 3 , -C(=O)NHCH 3 , -NH 2 , -NHC(=O)CH 3 or combinations thereof. In some embodiments, R 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 tetrahydropyridinyl (e.g., 1,2,3,6 tetrahydropyridinyl). In some embodiments, R 3 is piperazinyl. In some embodiments, R 3 is morpholinyl. In some embodiments, R 3 is azepanyl. In some embodiments, R 3 is piperidin-2-onyl. In some embodiments, R 3 is piperazin-2-onyl.

[0564] In some embodiments, R 3is selected from the group consisting of azetidin-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-2-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, 1,2,3,6 tetrahydropyridin-4-yl, piperidin-3-yl, piperidin-2-one-4-yl, piperazin-4-yl, and piperazin-2-one-5-yl. 3 is selected from the group consisting of azetidin-3-yl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, 1,2,3,6 tetrahydropyridin-4-yl, piperidin-2-one-4-yl, and piperazin-4-yl.

[0565] In some embodiments, R 3 is tetrahydrofuran-3-yl. In some embodiments, R 3 is tetrahydropyran-4-yl. In some embodiments, R 3 is oxetan-3-yl. In some embodiments, R 3 is morpholin-2-yl. In some embodiments, R 3 is pyrrolidin-1-yl. In some embodiments, R 3 is pyrrolidin-3-yl. In some embodiments, R 3 is piperidin-4-yl. In some embodiments, R 3 is piperidin-3-yl. In some embodiments, R 3 is 1,2,3,6 tetrahydropyridin-4-yl. In some embodiments, R 3 is piperidin-2-one-4-yl. In some embodiments, R 3 is piperazin-4-yl (e.g., 1-methyl-piperazin-4-yl). In some embodiments, R 3 is piperazin-2-one-5-yl. In some embodiments, R 3 is azetidin-3-yl.

[0566] In some embodiments, R 3 is a 5- to 10-membered bicyclic heterocyclyl (e.g., decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.0]heptanyl, bicyclo[1.1.1]pentanyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, decahydro-2,7-naphthyridinyl), each of which 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.

[0567] In some embodiments, the heterocyclyl is selected from the group consisting of 0, 1, 2, or 3 -D, ═O, -Me, -CD 3 , -Et, -C(=O)CH 3 Cyclopropyl, oxetan-3-yl, -OH, -N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , or -C(=O)NHCH 3 In some embodiments, the heterocyclyl is substituted with 0 or 1 -Me.

[0568] In some embodiments, R 3is a monocyclic heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, -CH(CH 3 )CH 2 -pyrrolidinyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, R 3 -CH 2 -Oxetan-3-yl, -CH 2 -piperidin-4-yl, -CH 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -CH(CH 3 )CH 2 -pyrrolidin-1-yl. In some embodiments, R 3 -CH 2 -piperidin-4-yl, -CH 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -CH(CH 3 )CH 2 -pyrrolidin-1-yl. In some embodiments, R 3 -CH 2 -piperidin-4-yl, -CH 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -CH(CH 3 )CH 2 -pyrrolidin-1-yl.

[0569] In some embodiments, the monocyclic heterocyclylalkyl is unsubstituted. In some embodiments, the monocyclic heterocyclylalkyl is optionally substituted (e.g., substituted with 0, 1, 2, or 3 -Me, -OH, -C(=O)Me, -NHC(=O)Me, or combinations thereof). In some embodiments, the monocyclic heterocyclylalkyl is substituted with 0, 1, or 2 -Me. In some embodiments, R 3 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 3 is cyclopropylmethyl.

[0570] In some embodiments, R 3 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). In some embodiments, R 3 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 3 is a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). 3 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.

[0571] In some embodiments, R 3 is a 6-10 membered monocyclic or bicyclic aryl. In some embodiments, R 3 is phenyl. In some embodiments, the phenyl is substituted with 0, 1, 2, or 3 -Me, -OH, -C(=O)Me, -NHC(=O)Me, or combinations thereof.

[0572] In some embodiments, R 3 is arylalkyl. In some embodiments, R 3 is benzyl.

[0573] In some embodiments, R 3 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0574] In some embodiments, R 3 -OR a3 where R a3 is as defined herein (e.g., hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, -O(CH 2 ) 2 N(CH 3 ) 2 , -O-tetrahydrofuran-3-yl, -O-tetrahydropyran-4-yl, -O(N-methylpiperidin-4-yl), -O-(N-Me-2-oxo-pyrrolidin-3-yl), -OCH 2 CH(CH 3 )N(CH 3 ) 2 , -OCH 2 (N-methylpyrrolidin-2-yl), -O(N-methylpiperidin-4-yl), -O-(CH 2 ) 2 -pyrrolidin-2-yl, -O-CH 2-piperidin-4-yl, -O-CH 2 -oxetan-3-yl). In some embodiments, R 3 is hydroxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is difluoromethoxy (-OCHF 2 In some embodiments, R 3 is trifluoromethoxy (-OCF 3 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 cyclopropyloxy. In some embodiments, R 3 is cyclobutyloxy. In some embodiments, R 3 is -O(CH 2 ) 2 N(CH 3 ) 2 It is.

[0575] 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 In some embodiments, R 3 is -O(CH 2 ) 2 N(CH 3 ) 2 It is.

[0576] In some embodiments, R 3 is -N(R a3 ) 2 where R a3 is as 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 , -NHCH 2 CH 3 , -NHPr, -NHCH 2 CF 3 , -NH i In some embodiments, R 3 ,NHCH 2 CF 3 In some embodiments, R 3 is -N(CH 3 )R a3 (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).

[0577] In some embodiments, R 3 is -C(=O)R a3 OR -C(=O)OR a3 where R a3 is as defined herein. In some embodiments, R 3 is -C(=O)R a3 where Ra3 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)CH 2 CH 2 CH 3 , -C(=O)OCH 3 , or -C(=O)CH 2 CH 2 N(CH 3 ) 2 In some embodiments, R 3 is acetyl (-C(=O)CH 3 In some embodiments, R 3 is -C(=O)CH 2 CH 2 N(CH 3 ) 2 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.

[0578] In some embodiments, R 3 -NR a3 C(=O)R a3 where R a3 is as defined herein. In certain embodiments, R 3 is --NHC(=O)R a3 (For example, -NHC(=O)CH 3 , -NHC(=O)CH 2 CH 3 , -NHC(=O)CH 2 CH 2 CH 3 , -NHC(=O) iPr, -NHC(=O)Bu, -NHC(=O) t Bu, -NHC(=O)cyclopropyl, -NHC(=O)cyclobutyl, -C(=O)CH 2 CH 2 N(CH 3 ) 2 In some embodiments, R 3 is -NHC(=O)CH 3 In some embodiments, R 3 is -C(=O)CH 2 CH 2 N(CH 3 ) 2 In some embodiments, R 3 is -N(CH 3 )C(=O)R a3 (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).

[0579] In some embodiments, R 3 -NR a3 C(=O)OR a3 where R a3 is as defined herein. In certain embodiments, R 3 is -NHC(=O)OR a3 (For example, -NHC(=O)OCH 3 , -NHC(=O)OCH 2 CH 3 , -NHC(=O)OCH 2 CH2 CH 3 , -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)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).

[0580] In some embodiments, R 3 is -C(=O)N(R a3 ) 2 where R a3 is as defined 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)NHCH 2 CH 3 , -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NHt In some embodiments, R 3 is -C(=O)NHCH 3 In 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 )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).

[0581] In some embodiments, R 3 is -OC(=O)N(R a3 ) 2 where R a3 is as defined herein. In certain embodiments, R 3 is -OC(=O)NHR a3 (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 3 is -OC(=O)N(CH 3 )R a3 (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).

[0582] In some embodiments, R 3 is -OC(=O)R a3 where R a3 is as defined herein (e.g., -OC(=O)CH 3 , -OC(=O)CH 2 CH 3 , -OC(=O)CH 2 CH 2 CH 3 , -OC(=O)CH 2 CH 2 CH 3 , -OC(=O)Bu, -OC(=O)Bu, -OC(=O)cyclopropyl, -OC(=O)cyclobutyl). In some embodiments, R 3 is -OC(=O)CH 3 It is.

[0583] In some embodiments, R 3 is -S(=O)R a3 where R a3 is as defined herein. In certain embodiments, R 3 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)i In some embodiments, R 3 is -S(=O)CH 3 In certain embodiments, R 3 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0584] In some embodiments, R 3 is -S(=O) 2 R a3 where R a3 is as defined herein. In certain embodiments, R 3 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 some embodiments, R 3 is -S(=O) 2 CH 3 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).

[0585] In some embodiments, R 3 -SR a3 where R a3 is as defined herein. In certain embodiments, R 3 is -S alkyl (e.g., -SCH3 , -SCH 2 CH 3 , -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).

[0586] In some embodiments, R 3 is -S(=O)(=NR a3 )R a3 where R a3 is as defined herein. In certain embodiments, R 3 is -S(=O)(=NH)R a3 (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 3 is -S(=O)(=NCH 3 )R a3 (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 ) tBu, -S(=O)(=NCH 3 ) cyclopropyl, -S(=O)(=NCH 3 )cyclobutyl).

[0587] In some embodiments, R 3 -NR a3 S(=O) 2 R a3 where R a3 is as defined herein. In certain embodiments, R 3 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 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 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 3 is -N(CH 3 )S(=O) 2 Cycloalkyl (e.g., -N(CH3 )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).

[0588] In some embodiments, R 3 is -S(=O) 2 N(R a3 ) 2 and R a3 is as defined 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 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 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 )CH 2 CH 3, -S(=O) 2 N(CH 3 )CH 2 CH 2 CH 3 , -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 ) Cyclopropyl, -S(=O) 2 N(CH 3 )cyclobutyl).

[0589] As generally defined herein, each R 7 are independently H, -D, and -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, -C(=O)R a7 , -C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , and -S(=O) 2 N(R a7 ) 2 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; a7 is as defined in any of the embodiments described herein.

[0590] In some embodiments, each R 7 are independently H, -D, and -C1...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, During the ceremony, 【Chemistry 1】 X is —O— and —NR ７ - selected from the group consisting of Ring A is selected from the group consisting of optionally substituted fused bicyclic 8-10 membered heteroaryl ring systems containing at least one nitrogen atom, wherein the 8-10 members refer to the total number of atoms in the fused system and the optionally substituted pyridin-3-yl; Ring B is C ６ -C １０ aryl, and 5- to 10-membered heteroaryl, each of which is optionally substituted at any available position; Each R １ is independently absent or H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Hydroxyalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ１ , -N(R ａ１ ) ２ , -C(=O)R ａ１ , -C(=O)OR ａ１ , -NR ａ１ C(=O)R ａ１ , -NR ａ１ C(=O)OR ａ１ , -C(=O)N(R ａ１ ) ２ , -OC(=O)N(R ａ１ ) ２ , -S(=O)R ａ１ , -S(=O) ２ R ａ１ , -SR ａ１ , -S(=O)(=NR ａ１ ) R ａ１ , -NR ａ１ S (= O) ２ R ａ１ , and -S(=O) ２ N (R ａ１ ) ２ is selected from the group consisting of Each R ２ are independently -D, ═O, 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 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 , -OC(=O)N(R ａ２ ) ２ , -CH ２ C(=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 and two R ２ can be taken together with the atom(s) to which they are attached to form a 3- to 10-membered cycloalkyl or heterocyclyl ring (e.g., a ring which can be taken together with the morpholine or piperazine ring of structure I to form a bridged, fused, or spiro bicyclic heterocyclic ring); Each R ７ However, independently, H, -D, -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, —C(═O)R ａ７ , -C(=O)OR ａ７ , -C(=O)N(R ａ７ ) ２ , -S(=O)R ａ７ , -S(=O) ２ R ａ７ , and -S(=O) ２ N (R ａ７ ) ２ wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R ａ１ , R ａ２ , and R ａ７ are independently H, -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, cycloalkylalkyl, heterocyclylalkyl, C ６ -C １０ 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 ５ and each R ５ 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); The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

2. R １ is not absent or H, and rings B and R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R １ is not absent or H, and rings B and R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 4】 【Chemistry 2】 The part expressed as 【Transformation 3】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. The compound is a compound of formula (Ia) or (Ib): 【Chemistry 4】 5. The compound of claim 4, wherein:

6. 5. The compound of claim 4, wherein the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof.

7. 5. The compound of claim 4, wherein the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

9. The compound is a compound of formula (II): 【Transformation 5】 9. The compound of claim 8, wherein:

10. X is -NR ７ 2. The compound of claim 1, wherein: -, or a pharmaceutically acceptable salt thereof.

11. The compound is a compound of formula (III): 【Transformation 6】 11. The compound of claim 10, wherein:

12. The compound is a compound of formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId): 【Transformation 7】 12. The compound of claim 11, wherein:

13. 13. The compound of claim 12, wherein the compound is a compound of formula (IIIa) or formula (IIIb), or a pharmaceutically acceptable salt thereof.

14. Ring A is selected from the group consisting of optionally substituted fused bicyclic 8-10 membered heteroaryl ring systems containing at least one nitrogen atom, wherein the 8-10 members refer to the total number of atoms in the fused system and pyridin-3-yl, each of which may be selected from 0, 1, 2, 3, or 4 R ４ is substituted in any available position with Each R ４ 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 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 , -C(=O)N(OR ａ４ ) (R ａ４ ), -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 ａ４ are independently H, -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, cycloalkylalkyl, heterocyclylalkyl, C ６ -C １０ 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 ５ and each R ５ are independently ═O, 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, 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. The compound of claim 1, wherein the cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or a pharmaceutically acceptable salt thereof.

15. Ring A is 【Transformation 8】 is selected from the group consisting of During the ceremony, Ring A １ , A ２ , and A ４ each is independently a 4- to 6-membered carbocyclyl, a 4- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; Each ring A ３ is independently a 4- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein said heterocyclyl and heteroaryl contain at least one nitrogen atom; Each ring A ５ is independently a 5- to 6-membered heteroaryl, said heteroaryl containing at least one nitrogen atom; Each R ４ 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, 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 , -C(=O)N(OR ａ４ ) (R ａ４ ), -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 ａ４ are independently H, -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, cycloalkylalkyl, heterocyclylalkyl, C ６ -C １０ 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 ５ and each R ５ are independently ═O, 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, 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, cyclohexyl); 2. The compound of claim 1, wherein m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

16. Ring A is 【Chemistry 9】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. Ring A is 【Chemistry 10】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. Ring A is 【Chemistry 11】 16. The compound of claim 15, wherein:

19. Ring A is 【Chemistry 12】 16. The compound of claim 15, wherein:

20. Ring A is 【Chemistry 13】 16. The compound of claim 15, wherein:

21. Ring A is 【Chemistry 14】 wherein: Each R ４ 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 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 , -C(=O)N(OR ａ４ ) (R ａ４ ), -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 ８ 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 ａ８ , -N(R ａ８ ) ２ , -C(=O)R ａ８ , -C(=O)OR ａ８ , -NR ａ８ C(=O)R ａ８ , -NR ａ８ C(=O)OR ａ８ , -C(=O)N(R ａ８ ) ２ , -OC(=O)N(R ａ８ ) ２ , -S(=O)R ａ８ , -S(=O) ２ R ａ８ , -SR ａ８ , -S(=O)(=NR ａ８ ) R ａ８ , -NR ａ８ S (= O) ２ R ａ８ , and -S(=O) ２ N (R ａ８ ) ２ is selected from the group consisting of Each R ９ 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 ａ９ , -N(R ａ９ ) ２ , -C(=O)R ａ９ , -C(=O)OR ａ９ , -NR ａ９ C(=O)R ａ９ , -NR ａ９ C(=O)OR ａ９ , -C(=O)N(R ａ９ ) ２ , -OC(=O)N(R ａ９ ) ２ , -S(=O)R ａ９ , -S(=O) ２ R ａ９ , -SR ａ９ , -S(=O)(=NR ａ９ ) R ａ９ , -NR ａ９ S (= O) ２ R ａ９ , and -S(=O) ２ N (R ａ９ ) ２ is selected from the group consisting of Each R １０ 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 ａ１０ , -N(R ａ１０ ) ２ , -C(=O)R ａ１０ , -C(=O)OR ａ１０ , -NR ａ１０ C(=O)R ａ１０ , -NR ａ１０ C(=O)OR ａ１０ , -C(=O)N(R ａ１０ ) ２ , -OC(=O)N(R ａ１０ ) ２ , -S(=O)R ａ１０ , -S(=O) ２ R ａ１０ , -SR ａ１０ , -S(=O)(=NR ａ１０ ) R ａ１０ , -NR ａ１０ S (= O) ２ R ａ１０ , and -S(=O) ２ N (R ａ１０ ) ２ is selected from the group consisting of Each R １１ 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 ａ１１ , -N(R ａ１１ ) ２ , -C(=O)R ａ１１ , -C(=O)OR ａ１１ , -NR ａ１１ C(=O)R ａ１１ , -NR ａ１１ C(=O)OR ａ１１ , -C(=O)N(R ａ１１ ) ２ , -OC(=O)N(R ａ１１ ) ２ , -S(=O)R ａ１１ , -S(=O) ２ R ａ１１ , -SR ａ１１ , -S(=O)(=NR ａ１１ ) R ａ１１ , -NR ａ１１ S (= O) ２ R ａ１１ , and -S(=O) ２ N (R ａ１１ ) ２ is selected from the group consisting of Each R ａ４ , R ａ８ , R ａ９ , R ａ１０ , and R ａ１１ are independently H, -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, cycloalkylalkyl, heterocyclylalkyl, C ６ -C １０ 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 ５ and each R ５ 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 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl (e.g., selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

22. Ring A is 【Chemistry 15】 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. Ring A is 【Chemistry 16】 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

24. Each R ４ 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 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 , -C(=O)N(OR ａ４ ) (R ａ４ ), and —OC(═O)N(R ａ４ ) ２ 15. The compound of claim 14, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. Each R ４ are independently ═O, -C １ -C ６ Alkyl, and —N(R ａ４ ) ２ 15. The compound of claim 14, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. Each R ａ４ is H, or a pharmaceutically acceptable salt thereof.

27. Each R ４ are independently -NH ２ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:

28. Ring A is 【Chemistry 17】 22. The compound of claim 21, wherein:

29. R １０ H, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ haloalkyl, and —N(R ａ１０ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

30. R ａ１０ is H, and -C １ -C ６ 22. The compound of claim 21, 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).

31. R １０ 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of H and -Me.

32. R １０ 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein: is -H.

33. R １１ H, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ haloalkyl, and —N(R ａ１１ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

34. Each R ａ１１ are independently H and -C １ -C ６ 22. The compound of claim 21, 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).

35. R １１ 22. The compound of claim 21, wherein is H, or a pharmaceutically acceptable salt thereof.

36. Ring A is [Chemistry 18] 22. The compound of claim 21, wherein:

37. R ８ But H, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -OR ａ８ , and −N(R ａ８ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

38. R ８ But, -OR ａ８ , and −N(R ａ８ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

39. Each R ａ８ 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 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

40. R ８ H, -Me, -CHF ２ , -OCH ３ , and —NH ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

41. R ８ But NH ２ , and -OCH ３ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42. R ８ But, -OCH ３ 22. The compound of claim 21, wherein:

43. R ８ But -NH ２ 22. The compound of claim 21, wherein:

44. R ９ But halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ cycloalkyl (e.g., cyclopropyl), 3- to 10-membered heterocyclyl, —OR ａ９ , -N(R ａ９ ) ２ , -C(=O)R ａ９ , -C(=O)OR ａ９ , -NR ａ９ C(=O)R ａ９ , -NR ａ９ C(=O)OR ａ９ , -C(=O)N(R ａ９ ) ２ , -OC(=O)N(R ａ９ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

45. R ９ 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 ａ９ ) ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

46. Each R ａ９ are independently H and -C １ -C ６ 22. The compound of claim 21, 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).

47. R ９ 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 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

48. R ９ -Me, -Et, oxetan-3-yl, cyclopropyl, and -C(=O)NH ２ 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

49. R ９ is -C(=O)NH ２ 22. The compound of claim 21, wherein:

50. R ９ 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of -Me, -Et, oxetan-3-yl, and cyclopropyl.

51. R ８ But, -OCH ３ and R ９ is -C(=O)NH ２ 22. The compound of claim 21, wherein:

52. R ８ But -NH ２ and R ９ 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of -Me, -Et, oxetan-3-yl, cyclopropyl.

53. Ring A is 【Chemistry 19】 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

54. Ring A is 【Chemistry 20】 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

55. Ring A is 【Chemistry 21】 22. The compound of claim 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

56. Each R ７ But independently, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu, neopentyl), -C ３ -C ９ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), —C(═O)R ａ７ , and —C(═O)OR ａ７ wherein said alkyl and cycloalkyl are selected from the group consisting of 0, 1, 2 or 3 -OH, -OCH ３ , —CN, halo (e.g., —Cl, —F), —NH ２ , -C １ -C ６ Alkyl (e.g., -Me, -Et), -C １ -C ６ Haloalkyl (e.g., —CF ３ , -CHF ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted at any available position with:

57. Each R ７ are independently -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu, neopentyl, cyclopropyl, cyclobutyl, -C(=O)R ａ７ , and —C(═O)OR ａ７ and wherein said cyclopropyl and cyclobutyl are substituted with 0, 1, or 2 -Me at any available position, or a pharmaceutically acceptable salt thereof.

58. Each R ７ But -C(=O)R ａ７ 2. The compound of claim 1, wherein:

59. Each R ７ is -C(=O)OR ａ７ 2. The compound of claim 1, wherein:

60. Each R ａ７ are independently H, -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu), C ３ -C ９ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, spiro[2.2]pentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl), cycloalkylalkyl (e.g., —CH ２ -cyclopropyl, -CH ２ -cyclobutyl, -CH ２ -cyclopentyl, -CH ２ -cyclohexyl, -CH ２ -cycloheptyl), wherein each alkyl, cycloalkyl, and cycloalkylalkyl is selected from the group consisting of 0, 1, 2, or 3 R ５ at any available position, and each R ５ are independently ═O, halo (e.g., —F, —Cl), —CN, —C １ -C ６ Alkyl (e.g., -Me, -Et, iPr), -C １ -C ６ Heteroalkyl, —C １ -C ６ Hydroxyalkyl (e.g., —CH ２ OH), -C １ -C ６ Haloalkyl (e.g., —CF ３ , -CH ２ CF ３ , -CF ２ CH ３ , -CHF ２ , -CH ２ F), 3- to 10-membered heterocyclyl (e.g., N-Me-piperazinyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinyl), —N(R ｂ ) ２ (For example, -N(CH ３ ) ２ ), —OH, and —OC １ -C ６ Alkyl (e.g., —OCH ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

61. Each R ａ７ independently 0, 1, 2, or 3 R ５ -C substituted with １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu), and each R ５ are independently halo (e.g., —F, —Cl), —CN, —C １ -C ６ Haloalkyl (e.g., —CF ３ , -CH ２ CF ３ , -CF ２ CH ３ , -CHF ２ , -CH ２ F), 3- to 10-membered heterocyclyl (e.g., N-Me-piperazinyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinyl), —N(R ｂ ) ２ (For example, -N(CH ３ ) ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of —CH 2 —, ...

62. Each R ５ are independently -Me, -CF ３ , -N(CH ３ ) ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-Me-piperazinyl, and 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-2-yl.

63. Each R ａ７ are independently -Me, -Et, - ｉ Pr,- ｔ Bu, -iso-Bu, cyclopropyl, -CH ２ -cyclopropyl, each of which is selected from the group consisting of 0, 1, 2, or 3 R ５ at any available position, and each R ５ are independently Me, -CF ３ , -N(CH ３ ) ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-Me-piperazinyl, and 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-2-yl.

64. Each R ７ But independently, C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ 2. The compound of claim 1, wherein the aryl group is -Bu, -sec-Bu, -iso-Bu, neopentyl), or a pharmaceutically acceptable salt thereof.

65. Each R ７ are independently -Me, -Et, - ｉ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of Pr, -iso-Bu, and neopentyl.

66. Each R ７ But independently, 【Chemistry 22】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

67. Ring B is C ６ -C １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of aryl and 8- to 10-membered bicyclic heteroaryl, wherein said aryl and heteroaryl are optionally substituted at any available position.

68. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of thiophenyl, phenyl, and benzo[d]thiazolyl, each of which is optionally substituted.

69. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl and is optionally substituted at any available position.

70. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- to 6-membered monocyclic heteroaryl, said heteroaryl being optionally substituted at any available position.

71. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is thiophenyl and is optionally substituted.

72. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is an 8- to 10-membered bicyclic heteroaryl, said bicyclic heteroaryl being optionally substituted at any available position.

73. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is benzo[d]thiazolyl and is optionally substituted.

74. Each ring B may contain 0, 1, 2, or 3 R ３ at any available position, wherein Each R ３ are 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- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -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)R ａ３ , -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 and R ３ 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 ａ３ 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 The compound of claim 1, which is a cycloalkyl or a 3- to 10-membered heterocyclyl substituted with 0 or 1 =0, -Me, or a combination thereof.

75. Ring B is 【Chemistry 23】 75. The compound of claim 74, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

76. Each R ３ are independently —F, —Cl, —Me, —CF ３ , N-methylpiperazin-4-yl, N-methylpiperidin-4-yl, and —OCH ２ CH ２ N (CH ３ ) ２ 75. The compound of claim 74, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

77. Each R ３ is independently selected from the group consisting of -F and -Cl, or a pharmaceutically acceptable salt thereof.

78. Each R １ is independently selected from the group consisting of H and methyl.

79. Each R １ The compound of claim 1 , wherein is H.

80. Each R １ The compound of claim 1 , wherein is methyl.

81. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

82. Each R ２ are independently halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl, —C １ -C ６ Haloalkyl, —C ３ -C ９ Cycloalkyl (e.g., cyclopropyl), 3- to 6-membered heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl), —OR ａ２ , -N(R ａ２ ) ２ , -C(=O)R ａ２ , -C(=O)OR ａ２ , -NR ａ４ C(=O)R ａ２ , -NR ａ２ C(=O)OR ａ２ , -C(=O)N(R ａ２ ) ２ , -OC(=O)N(R ａ２ ) ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

83. Each R ａ２ are independently H and -C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -Bu, -sec-Bu, -iso-Bu.

84. Each R ２ are independently halo (e.g., —Cl), —C １ -C ６ Alkyl (e.g., -Me, -Et, -Pr, - ｉ Pr,- ｎ Bu,- ｔ Bu, -sec-Bu, -iso-Bu), and -OCH ３ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

85. R ２ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is -Me.

86. The compound is 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 【Chemistry 24-5】 【Chemistry 24-6】 【Chemistry 24-7】 【Chemistry 24-8】 【Chemistry 24-9】 【Chemistry 24-10】 【Chemistry 24-11】 or a pharmaceutically acceptable salt thereof.

87. 87. A pharmaceutical composition comprising a compound according to any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

88. 88. The pharmaceutical composition of claim 87, further comprising a second therapeutic agent.

89. A composition comprising a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for treating an MTAP deficiency and / or an MTA accumulation disease in a subject in need thereof.

90. The composition or pharmaceutical composition of claim 89, wherein the composition or pharmaceutical composition is configured to be administered in combination with a second therapeutic agent.

91. 89. The pharmaceutical composition of claim 88 for use in treating an MTAP deficiency and / or MTA storage disorder in a subject in need thereof.

92. 90. The composition or pharmaceutical composition of claim 89, wherein the disease is a proliferative disease.

93. 93. The composition or pharmaceutical composition of claim 92, wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

94. 94. The composition or pharmaceutical composition of claim 93, 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.

95. Use of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating an MTAP deficiency and / or an MTA storage disease in a subject in need thereof.

96. 96. The use of claim 95, wherein the medicament is configured to be administered in combination with a second therapeutic agent.

97. 90. Use of the pharmaceutical composition of claim 88 in the manufacture of a medicament for treating an MTAP deficiency and / or an MTA storage disorder in a subject in need thereof.

98. 96. The use of claim 95, wherein the disease is a proliferative disease.

99. 99. The use of claim 98, wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

100. 100. The use of claim 99, 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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