Compounds and Methods of Use

Abstract

Provided are compounds of formula (I): (I), and pharma- ceutically acceptable salts thereof, as well as pharmaceutical compositions, processes for preparation, and methods of treatment thereof, wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 wherein n is as defined herein and the compound is selected from the group consisting of the compounds in Table 1. In one aspect, a compound selected from the compounds in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. In one embodiment, a pharmaceutical composition is provided comprising a compound from the compounds in Table 1, or a pharma- ceutically acceptable salt thereof, as defined herein, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. JPEG2025503971000188.jpg37165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 303,497, filed January 26, 2022, which is incorporated herein by reference in its entirety and 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 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 leads to the 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; Markarov et al., 2016). Data from genome-wide genetic variation screens using shRNAs suggest a selective requirement for PRMT5 activity, particularly in MTAP-deficient cancer cell lines (Kruykov et al., 2016, Marjon et al., 2016, and Markarov et al., 2016). The accumulation of MTA caused by MTAP deletion in these cell lines is thought to partially inhibit 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 by binding in an MTA-cooperative binding manner, may exhibit 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 U.S. Food and Drug Administration that exhibit selectivity for MTAP-deficient cancer cell lines. Therefore, there is a need for PRMT5 inhibitors to treat 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 aspect, a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof, is provided.

[0007] In one embodiment, a pharmaceutical composition is provided comprising a compound from Table 1, as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

[0008] In one embodiment, provided is 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 selected from the compounds of Table 1, as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically 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 the 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 with 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 selected from the compounds of Table 1 or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0010] 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 present disclosure, but instead is provided as a description of example embodiments.

[0011] As generally described herein, provided are compounds (e.g., compounds of Table 1, or pharmaceutically acceptable salts thereof) that are MTA-uncompetitive PRMT5 inhibitors useful for treating proliferative disorders associated with MTAP deficiency and / or MTA accumulation (e.g., cancer).

[0012] In some embodiments, provided are compounds (e.g., compounds of Table 1, or pharmaceutically acceptable salts thereof) that are MTA-uncompetitive, non-competitive, 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).

[0013] 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.

[0014] 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. "Wild-type" MTAP refers to the gene encoded by NM_002451 or having the same amino acid sequence (NP_002442). (Schmid et al. Oncogene 2000, 19, pp. 5747-5744). 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-upregulated," and the like, with respect to a cell(s), indicate that either the cell(s), etc., 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 deficiency can be detected using any reagent or technique known in the art, for example, 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 consecutive nucleotides (nt) of the MTAP sequence (the primer is about 30 nt or less).

[0015] 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 condition (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 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, and cancers or sarcomas of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon (see Figure 1). In patients with MTAP-deficiency-associated diseases, some diseased cells (e.g., cancer cells) may be MTAP-deficient, while other cells may not. Similarly, some diseased cells may have MTA accumulation, while 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 exhibit reduced post-translational modification, production, expression, level, stability, and / or activity of the CDKN2A gene or its product. The MTAP and CDKN2A genes are located 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.

[0016] 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, etc. MTA selectively inhibits PRMT5 methyltransferase activity. MTA is the only known catabolic substrate of MTAP. Terms such as "MTA accumulation," "MTA overproduction," and "MTA upregulation" refer to cells (including, but not limited to, cancer cells, cell lines, tissues, tissue types, tumors, etc.) that have significantly increased production, levels, and / or stability of MTA. MTA-accumulating cells include cells that contain at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher MTA production, level, and / or stability than that of normal or non-cancerous cells. In some embodiments, MTA-accumulating cells include cells that contain at least 20% higher MTA production, level, and / or stability than that of normal or non-cancerous cells. In some embodiments, MTA-accumulating cells include cells that contain at least 50% higher MTA production, level, and / or stability than that of normal or non-cancerous cells. Determining MTA accumulation in a test sample (e.g., cells such as cancer cells to be tested for MTA accumulation) and a reference sample, as well as other cells, tissues, samples, etc., can 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 the accumulation of MTA (Williams-Ashman et al. Biochem. Pharm. 1982, 31, pp. 277-288 and Limm et al. Eur. J. Cancer. 2013, 49, Issue 6).

[0017] An "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-storing diseases include, but are not limited to, cancers including 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, and cancers or sarcomas of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon (see Figure 1). In patients with MTAP-deficiency-associated diseases, some diseased cells (e.g., cancer cells) may be MTAP-deficient, while other cells may not. In patients who have or have been diagnosed with an MTA storage disease, some cells may have MTA accumulation, while other cells do not.

[0018] 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 increased binding of an inhibitor to a protein (e.g., PRMT5) in the presence of a cofactor (e.g., MTA) compared to 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 with significantly greater potency in the presence of high concentrations of MTA, thus resulting in selective inhibition of PRMT5 in MTA-accumulating cells compared to normal cells.

[0019] 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 by similar terms if they are susceptible to treatment with a PRMT5 inhibitor, for example, because of their MTAP deficiency and / or MTA accumulation characteristics.

[0020] PRMT5 "PRMT5," as used herein, refers to the gene or protein for protein arginine methyltransferase 5, also known as HRMT1L5, IBP72, JBP1, SKB1, or SKB1Hs. ExteNal IDOMIM: 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 function as a binding site for DNMT3A. Loss of PRMT5 results in decreased DNMT3A binding and gene activity. The tumor suppressor gene ST7 and the chemokines RNATES, IP10, and CXCL11 are targeted and silenced by PRMT5. WO2011 / 079236.

[0021] Additional substrates include E2F1, p53, EGFR, and CRAF. PRMT5 is part of a multiprotein complex that contains the coregulator WDR77 (also known as the CDK4 substrate MEP50) during the G1 / S transition. Phosphorylation increases PRMT5 / WDR77 activity. WDR77 is a non-catalytic component of the complex and mediates interaction with binding partners and substrates. PRMT5 also interacts with pICIn or RioK1 adaptor proteins in a mutually exclusive manner, which may regulate complex composition and substrate specificity.

[0022] PRMT5, when interacting with several complexes, exerts either positive or negative effects on its substrates through 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.

[0023] The term "PRMT5 inhibitor" refers to any compound that can inhibit the production, level, activity, expression, or presence of PRMT5. These include, but are not limited to, 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 the active site, allosteric modulation of protein structure, disruption of protein-protein interactions, or by inhibiting the transcription, translation, post-translational modification, or stability of PRMT5 protein.

[0024] 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 but 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.

[0025] chemical definition Definitions of specific 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 Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 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.

[0026] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present specification further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0027] "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%.

[0028] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0029] "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%.

[0030] Thus, a composition containing 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 may 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, e.g., 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 the element occupying a particular site on the compound.

[0031] 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" refers to C1, C2, C3, C4, C5, C6, 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 and are useful in understanding the description and intended scope of the present invention. When 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 that each definition is intended to include such substituted moieties within its 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" can 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.

[0032] The term "unsaturated bond" refers to a double or triple bond.

[0033] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0034] The term "saturated" refers to a moiety that does not contain double or triple bonds, i.e., contains only single bonds. The affixation with the suffix "-ene" indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0035] The term "azido" refers to the radical -N3. "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. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0036] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, 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 optionally substituted alkyl group substituted by an optionally substituted aryl group. "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20 In some embodiments, the 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, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In 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, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2In some embodiments, the alkyl group has 1 carbon atom (C alkyl). 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 (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. 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 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 It is an alkyl. Common abbreviations for alkyl are Me(-CH3), Et(-CH2CH3), i Pr(-CH(CH3)2), n Pr(-CH2CH2CH3), n Bu(-CH2CH2CH2CH3), or i Bu(-CH2CH(CH3)2).

[0037] "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, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), 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 divalent carbon chain. An alkylene group can be unsubstituted or substituted with one or more substituents described herein.

[0038] "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"). In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms ("C"). 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an 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, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless 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 to 5 substituents, 1 to 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.

[0039] "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) ("C2-20 "Alkynyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). C 2-4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0040] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) 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 to 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 1-9 In 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 ("heteroCi_6 alkyl"). 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 ("heteroC1-2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "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 -CHOH, -CHOCH, -CHNH, -CHNH(CH), -CHN(CH), -CHCHOH, -CHCHOCH, -CHCHNH, -CHCHNH(CH), -CHCHN(CH).

[0041] "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 ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the 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.

[0042] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0043] Representative examples of substituted aryl include the following: [ka] R 56 and R 57 One of R may be hydrogen; 56 and R 57 At least one of the groups is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO 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. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl. "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.

[0044] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement), having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 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 to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, unless otherwise specified, the number of ring members continues to designate 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 to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, where 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 without a heteroatom (e.g., 5-indolyl).

[0045] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl. In some embodiments, a 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 independently selected from nitrogen, oxygen, and sulfur ("8- to 12-membered bicyclic heteroaryl"). In some embodiments, the heteroaryl group is an 8- to 10-membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (an "8- to 10-membered bicyclic heteroaryl").In some embodiments, a heteroaryl group is a 9- to 10-membered bicyclic aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("9- to 10-membered bicyclic heteroaryl"). Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0046] 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, pyridinyl. 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, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, 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.

[0047] Representative examples of heteroaryl include: [ka] where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0048] 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 more than one ring means that the substituent can be attached at any position on each of the rings. A "heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl portion. The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 "Carbocyclyl" refers to the radical of a non-aromatic monocyclic, bicyclic, or tricyclic or polycyclic hydrocarbon ring system having zero heteroatoms. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyl) and partially saturated ring systems. In some embodiments, carbocyclyl groups have 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 5-6In 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), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3-8 The carbocyclyl group may be any of the above-mentioned C 3-6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group may be any of the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) etc.

[0049] 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 systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")), 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.

[0050] As used herein, the term "cycloalkyl" refers to a group having the indicated number of rings and carbon atoms (e.g., C3-C 14 Monocyclic, C4-C 14 Bicyclic, C5-C 14 Tricyclic, or C6-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 3-6In 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). Monocyclic C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8).

[0051] 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, the 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, the bicyclic cycloalkyl group has 8 to 10 ring carbon atoms ("C 8-10 In some embodiments, the bicyclic cycloalkyl group has 7 to 9 ring carbon atoms ("C7-9 Bicyclic cycloalkyls). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[1.1.1]pentane (C5), spiro[2.2]pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (C6), bicyclo[3.1.0]hexane (C6), spiro[2.3]hexane (C6), bicyclo[2.2.1]heptane (norbornane) (C7), bicyclo[3.2.0]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[4.1.0]heptane (C7), spiro[2 .4]heptane (C7), spiro[3.3]heptane (C7), bicyclo[2.2.2]octane (C8), bicyclo[4.1.1]octane (C8), octahydropentalene (C8), bicyclo[3.2.1]octane (C8), bicyclo[4.2.0]octane (C8), spiro[2.5]octane (C8), spiro[3.4]octane (C8), bicyclo[3.3.1]nonane (C9), octahydro-1H-indene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), 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 8-12In some embodiments, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms ("C 10-12 Tricyclic cycloalkyls are examples of tricyclic cycloalkyls, such as adamantine (C 12 ) are mentioned.

[0052] Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "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. "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("3- to 10-membered heterocyclyl"), each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. For heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. 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, where the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of 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- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0053] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 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, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("5- to 8-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("5- to 6-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 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, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0054] 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. Exemplary 5-membered heterocyclyl groups fused to a C6 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-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0055] "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, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0056] "Acyl" means the radical -C(=O)R 20 refers to 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, and R 20 is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(=O)-C1-C8 alkyl, and -C(=O)-(CH2). t (C6-C 10 aryl), -C(=O)-(CH2) t (5-10 membered heteroaryl), -C(=O)-(CH2) t (C3-C 10 cycloalkyl), and -C(=O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0057] The term aminoalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced by an -NH2 group.

[0058] The term hydroxyalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with an —OH group.

[0059] The terms "alkylamino" and "dialkylamino" refer to the -NH(alkyl) and -N(alkyl) radicals, respectively. In some embodiments, an alkylamino is α-NH(C1-C4 alkyl). In some embodiments, an alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, iso-butylamino, sec-butylamino, or tert-butylamino. In some embodiments, a dialkylamino is -N(C1-C6 alkyl). In some embodiments, a dialkylamino is dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, or methyltertbutylamino.

[0060] The term "aryloxy" refers to an -O-aryl radical. In some embodiments, the aryloxy group is phenoxy.

[0061] The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkoxy" includes a haloalkoxy group where the halo is fluorine. In some embodiments, a haloalkoxy group is , difluoromethoxy and trifluoromethoxy.

[0062] "Alkoxy" refers to the group -OR 29 refers to R 29 is 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. Still more particular alkoxy groups have 1 to 4 carbon atoms. In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 It is a group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 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. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group may be present, which itself may be substituted by unsubstituted C-C alkyl, halo, unsubstituted C-C alkoxy, unsubstituted C-C haloalkyl, unsubstituted C-C hydroxyalkyl, or unsubstituted C-C haloalkoxy or hydroxy. Certain exemplary "substituted alkoxy" groups are -OCF, -OCHCF, -OCHPh, -OCH-cyclopropyl, -OCHCHOH, and -OCHCHN(CH).

[0063] "Amino" refers to the radical -NH2.

[0064] An "oxo group" refers to -C(=O)-.

[0065] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 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, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 Cycloalkyl, or C1-C8 alkyl substituted with halo or hydroxy, C3-C8 alkenyl substituted with halo or hydroxy, C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl), and t is a 0-8 membered integer, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy, or which R 38 The groups may also be linked to form an alkylene group.

[0066] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl), and -NR 39 -(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl, and 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 substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 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 encompasses both mono- and di-substituted amino groups.

[0067] 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, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -C1- 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- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with 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, T.W. Greene and P.G.M. Buts, 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, -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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 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, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR 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, -C1-10 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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is the counterion, 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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(Rff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R 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 SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R 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 アルキル、-C1-6 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, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is 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 counterion, 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 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkynyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is 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 3-10Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkynyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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 - , -NH2(C 1-6 alkyl) + X - , -NH3 + 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), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -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), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -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)NH2, -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)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 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)NH2, -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 3-10Carbocyclyl, 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 counterion.

[0068] 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.

[0069] 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 ethyl carbamate (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-isopropylallyl 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-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl 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 methylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate 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,Examples include, but are not limited to, 6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0070] Sulfonamide groups (e.g., -S(=O)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-pyrroline)-3 -yl)amine, quaternary ammonium salts, 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,Examples of suitable amines include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium 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 phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0071] 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 , -CO2R 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 , -SO2R 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, 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, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0072] 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, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- Examples of suitable alkyl esters 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).

[0073] 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 , -CO2R 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 , -SO2R 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, 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. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0074] 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 haloformates. In certain embodiments, the leaving group is halogen, alkanesulfonyloxy, arenesulfonyloxy, diazonium, alkyldiazene, aryldiazene, alkyltriazene, nitro, alkyl nitrate, aryl nitrate, alkyl phosphate, aryl phosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxyammonia, alkylamine, arylamine, hydroxyl group, alkyloxy group, or aryloxy. In some embodiments, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OT), methanesulfonate (mesylate, -OM), p-bromobenzenesulfonyloxy (brosylate, -OB), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, 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.

[0075] "Carboxy" refers to the radical -C(=O)OH.

[0076] "Cyano" refers to the radical -CN.

[0077] "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.

[0078] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF), difluoromethyl (-CHF), fluoromethyl (-CHF), chloromethyl (-CHCl), dichloromethyl (-CHCl), tribromomethyl (-CHBr), and the like.

[0079] "Hydroxy" refers to the radical --OH.

[0080] "Nitro" refers to the radical -NO2.

[0081] "Thioketo" refers to the group ═S.

[0082] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups 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 specified, 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 in order 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.

[0083] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(ORcc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R 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 SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R 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)2R aa, -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein 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)2R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 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 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 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, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bbThe groups are joined to form a 3- to 14-membered heterocyclyl or 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 dd is substituted with a group, R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 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 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 dd is substituted with a group, Each R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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 , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R 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 SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R 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)2R 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, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may combine to form =O or =S; R ee Each instance of is independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C2-6 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- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl or 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, -NO2, -N3, -SO2H, -SO3H, -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 - , -NH2(C 1-6 alkyl) + X - , -NH3 + 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 1-6alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -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), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -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)NH2, -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)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 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)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC1-6 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 counterion.

[0084] 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 - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of suitable 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 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, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(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- to 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 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 dd substituted with 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 list of substituents.

[0085] Other definitions As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts.

[0086] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that 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 formed by using other methods used in the art, such as ion exchange. Other pharmaceutically 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, lanthanide ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N-methylpropional salts. + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically 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.

[0087] "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.

[0088] Disease, disorder, and condition are used interchangeably herein.

[0089] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an effect that occurs while a subject is afflicted with a specified disease, disorder, or condition and reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate an effect that occurs before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment"). In one embodiment, the compounds provided herein are contemplated for use in therapeutic treatment methods, where the effect occurs while a subject is afflicted with a particular disease, disorder, or condition, resulting in a reduction in the severity of the disease, disorder, or condition, or a delay or slowing of the progression of the disease, disorder, or condition. In an alternative embodiment, the compounds provided herein are contemplated for use in prophylactic treatment methods, where the effect occurs before a subject begins to suffer from a particular disease, disorder, or condition, resulting in the prevention of the 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.

[0090] In general, an "effective amount" of a compound refers to an amount sufficient to elicit 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 encompasses therapeutic and prophylactic treatment (i.e., encompasses a "therapeutically effective amount" and a "prophylactically effective amount").

[0091] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in 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 means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or pathogenesis of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0092] 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 means 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 encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0093] compound In one embodiment, a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof, is provided.

[0094] In one aspect of the invention, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof: During the ceremony, [ka] Each R 1 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 )2, -C(=O)Ra1 , -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)2R a1 , -SR a1 , -S(=O)(=NR a1 )R a1 , -NR a1 S(=O)2R a1 , and -S(=O)2N(R a1 )2 is selected, Each R 2 are independently halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 )2, -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 )2, -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 )2, -S(=O)R a2 , -S(=O)2R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O)2R a2 , and -S(=O)2N(R a2 )2 is selected, Each R 3are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 )2, -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 )2, -OC(=O)N(R a3 )2, -S(=O)R a3 , -S(=O)2R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O)2R a3 , and -S(=O)2N(R a3 )2 is selected, Each R 4 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 )2, -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 )2, -OC(=O)N(R a4 )2, -S(=O)R a4 , -S(=O)2R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , -NR a4 S(=O)2R a4, and -S(=O)2N(R a4 )2 is selected, Each R 6 is independently absent or H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C6 10 Carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, -OC(=O)N(R a6 )2, -S(=O)R a6 , -S(=O)2R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O)2R a6 , and -S(=O)2N(R a6 )2, wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R 7 are independently absent or H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 hydroxyalkyl, -C1-C6 haloalkyl, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a7 , -N(R a7 )2, -C(=O)R a7 , -C(=O)OR a7 , -NRa7 C(=O)R a7 , -NR a7 C(=O)OR a7 , -C(=O)N(R a7 )2, -OC(=O)N(R a7 )2, -S(=O)R a7 , -S(=O)2R a7 , -SR a7 , -S(=O)(=NR a7 )R a7 , -NR a7 S(=O)2R a7 , and -S(=O)2N(R a7 )2 is selected, Each R 8 are independently H, -D, ═O, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C9 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 , -CH2C(=O)N(R a8 )2-C(=O)N(R a8 )2, -OC(=O)N(R a8 )2, -CH2C(=O)N(R a8 )2, -S(=O)R a8 , -S(=O)2R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O)2R a8 , and -S(=O)2N(R a8 )2, and two R 8can 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, together with the piperidine ring of structure I, can form a bridged, fused, or spiro bicyclic heterocyclic ring); Each R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently selected from H, C1-C6 alkyl, —C1-C6 heteroalkyl, C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl, and each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position (e.g., 0, 1, 2, or 3 R 9 Each R is replaced by 9 are independently selected from ═O, halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C3-C9 cycloalkyl, 3- to 10-membered heterocyclyl, C6-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)2R b , -SR b , -S(=O)(=NR b )R b , -NR bS(=O)2R b , and -S(=O)2N(R b )2, and each R b are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -sec-Bu, -iso-Bu), and C3-C9 cycloalkyl (e.g., selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); n is 0, 1, 2, or 3, and the compound is selected from the compounds in Table 1.

[0095] The compounds described herein (eg, the compounds of Table 1, or a pharmaceutically acceptable salt thereof) are useful as inhibitors of PRMT5 (eg, MTA-uncompetitive PRMT5 inhibitors).

[0096] Table 1 shows the IC of exemplary compounds in the SDMA in-cell Western assay (described in Example 97) in the MTAP isogenic cell line pair. 50 and IC 90 Values ​​are shown (columns 4-6). HAP1 MTAP-intact is a cell line expressing endogenous levels of MTAP, and HAP1 MTAP-deleted is an MTAP-null cell line. For Table 1, "a" and "aa" indicate IC<5 nM in the HAP1 MTAP-intact (column 4) and HAP1 MTAP-deleted (column 5) assays, respectively. 50 "b" and "bb" indicate IC values ​​of 5 nM or more and less than 50 nM. 50 "c" and "cc" indicate IC values ​​of 50 nM or higher. 50 Similarly, in the HAP1 MTAP deletion (column 6) assay, "aaa" indicates an IC of <75 nM. 90 "bbb" indicates an IC of 75 nM or greater but less than 125 nM 90 "ccc" indicates IC of 125 nM or higher 90 Shows.

[0097] In column 7, "A" indicates IC in HAP1 MTAP-intact and HAP1 MTAP-deficient cell lines.50 IC over 30 times higher 50 "B" indicates the ratio of IC200 in HAP1 MTAP-intact cell lines and HAP1 MTAP-deficient cell lines. 50 IC between 15-fold or more but less than 30-fold 50 The ratio is shown, and "C" is the IC in HAP1 MTAP-intact and HAP1 MTAP-deficient cell lines. 50 IC less than 15-fold between 50 Ratios are shown. Compounds with a ratio of 3-fold or greater in the SDMA in-cell Western assay are considered MTAP selective.

[0098] Table 1 further shows the IC20 of MTAP-deficient cell lines (described in Example 98) in a viability assay. 50 The values ​​(column 8) show the effect of compound treatment on cell survival. In column 8, A * IC values ​​below 100 nM 50 indicates B * IC values ​​are greater than 100 nM but less than 1 μM 50 indicates C * IC values ​​of 1 μM or greater 50 Shows.

[0099] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. Compounds marked with (or) or (rel) are single enantiomers to which the absolute stereochemistry has been arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section). Compounds marked with (and) or (rac) are mixtures of enantiomers in which the relative stereochemistry is as shown. Compounds with stereocenters in which the configuration is not shown in the depicted structure and is not marked in the "Stereochemistry" column are mixtures of enantiomers. Compounds marked with (abs) are single enantiomers in which the absolute stereochemistry is as shown. In some cases, different indices selected from (abs), (or), and (and) apply to different portions of the molecule. One of skill in the art can separate racemic compounds into their respective enantiomers using methods known to those skilled in the art, such as chiral chromatography, chiral recrystallization, etc. Reference to a compound that is a racemic mixture is meant to include the individual enantiomers contained in the mixture. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

[0100] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may 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, e.g., 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 the element occupying a particular site on the compound.

[0101] Pharmaceutical Composition In another embodiment, a pharmaceutical composition is provided that includes a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Table 1), or a pharmaceutically acceptable salt thereof.

[0102] The term "pharmaceutically acceptable carrier or adjuvant," as used herein, refers to a carrier or adjuvant that may be administered to a patient together with a provided compound, that does not destroy the pharmacological activity of the compound, and that is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0103] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween®, serum proteins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trimethyllithium magnesium, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polypropylene block polymers, polyethylene glycol, and fats. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2 and 3 hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0104] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of pharmaceutical compositions. Such compositions may be prepared in a manner well known in the pharmaceutical arts and may contain at least one active compound.

[0105] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral or a topical carrier.

[0106] Also provided are compounds described herein (e.g., compounds of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical compositions thereof) for use as pharmaceuticals or medicaments (e.g., medicaments for treating MTAP-deficient and / or MTA-accumulating diseases in a subject in need thereof). In one embodiment, the disease is a proliferative disease. In a further embodiment, the disease is an MTAP-deficient and / or MTA-accumulating cancer. In one embodiment, the cancer is 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0107] Also provided are compounds described herein (e.g., compounds of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical compositions thereof) for use in treating an MTAP-deficient and / or MTA-accumulating disease in a subject in need thereof. In one embodiment, the disease is a proliferative disease. In a further embodiment, the disease is an MTAP-deficient and / or MTA-accumulating cancer. In one embodiment, the cancer is 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0108] Also provided are compounds described herein (e.g., compounds of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical compositions thereof) for use in the manufacture of a medicament (e.g., a medicament for the treatment of an MTAP-deficient and / or MTA-accumulating disease in a subject in need thereof). In one embodiment, the disease is a proliferative disease. In a further embodiment, the disease is an MTAP-deficient and / or MTA-accumulating cancer. In one embodiment, the cancer is 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0109] Generally, the compounds provided herein are administered in an effective amount (e.g., a therapeutically effective amount). The amount of compound actually administered will typically be determined by a physician in view of the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0110] The pharmaceutical compositions provided herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably orally or by injection. The pharmaceutical compositions provided herein may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. The term parenteral, as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0111] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders.However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing.The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients.Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. for solid compositions.In such compositions, the compound is usually present in minute amounts. These are minor ingredients (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that aid in forming the desired dosage form.

[0112] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow agents such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0113] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As noted above, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable carrier and the like. Pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween® 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic saline. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, such as carboxymethylcellulose or emulsions and / or suspensions. Other commonly used surfactants, such as Tween® or Span®, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0114] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s) in an amount generally ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient will usually be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream containing, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance the stability of the active ingredient or formulation for skin penetration. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0115] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0116] The pharmaceutical compositions provided herein may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds provided herein with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0117] The pharmaceutical compositions provided herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0118] The above ingredients for orally administrable, injectable or topically administrable, rectally administrable, and nasally administrable compositions are merely representative. Other materials as well as processing techniques and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0119] The compounds described herein can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0120] When the compositions provided herein together include a combination of a compound of the formulae described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels that are about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds provided herein together as part of a multiple-dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds provided herein together in a single composition.

[0121] Also provided are pharmaceutically acceptable acid addition salts of the compounds described herein (eg, the compounds of Table 1).

[0122] Acids that may be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0123] The compounds described herein can be administered, for example, by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously, or in oral, buccal, nasal, transmucosal, topical, or ophthalmic preparations, or by inhalation, at dosages ranging from about 0.5 to about 100 mg / kg body weight, or at dosages of 1 mg to 1000 mg per dose, every 4 to 120 hours, or depending on the requirements of the particular drug. The methods herein contemplate administration of an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions provided herein will be administered about once to about six times per day, or alternatively as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular method of administration. A typical preparation will contain about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0124] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the patient's predisposition to the disease, condition or symptom, and the judgment of the attending physician.

[0125] When patient's condition improves, if necessary, the maintenance dose of the compound, composition or combination provided herein together can be administered.Subsequently, depending on symptoms, dosage or administration frequency, or both, can be reduced to a level that maintains the improved condition when symptoms are reduced to desired level.However, patient may need to be intermittently treated for a long period of time when any disease symptoms recur.

[0126] Treatment and Use Treatment of MTAP-deficient and / or MTA-accumulating proliferative disorders 5-Methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. MTAP deletion is a common genetic event in human cancer. The frequency of MTAP deletion in a subset of human cancers is described in Cerami et al., Cancer Discov. (2012); 2(5):401-4, Gao et al., Sci Signal. (2013); 6(269):pl1, and Lee et al., Nat. Gen. (2014) 46(11):1227-32. For example, more than 50% of malignant peripheral nerve sheath tumors (MPNSTs) have deletions in MTAP (Lee et al., Nat. Gen. (2014)). Other cancers in which MTAP deletion is common include glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous cell lung cancer, melanoma, diffuse large B-cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, gastric cancer, glioma, adrenal cancer, thymoma, breast cancer, liver cancer, ovarian cancer, papillary renal carcinoma, uterine cancer, prostate cancer, and clear cell renal carcinoma. MTAP deletion in cells leads to MTAP deficiency, increased intracellular MTA accumulation, and increased dependency on protein arginine methyltransferase 5 (PRMT5) in cancer cells. Other mechanisms leading to MTAP loss include MTAP translocations and MTAP epigenetic silencing, among others, which can also lead to MTAP-null and / or MTAP-deficient tumors. PRMT5 mediates the formation of symmetric dimethylarginine (SDMA), and therefore PRMT5 activity can be assessed by measuring SDMA levels using antibodies against SDMA or SDMA-modified polypeptides.

[0127] In one embodiment, a method of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Table 1), or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, provided are compounds of the present disclosure (e.g., compounds of Table 1) or pharmaceutical compositions comprising compounds of the present disclosure for use in methods of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0129] In some embodiments, provided are compounds of the present disclosure (e.g., compounds of Table 1), or pharmaceutical compositions comprising compounds of the present disclosure, for use in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0130] In some embodiments, there is provided a use of a compound of the present disclosure (e.g., a compound of Table 1), or a pharmaceutical composition comprising a compound of the present disclosure, in a method of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, a therapeutically effective amount of the compound or composition is used.

[0131] In some embodiments, there is provided a use of a compound of the present disclosure (e.g., a compound of Table 1), or a pharmaceutical composition comprising a compound of the present disclosure, in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, a therapeutically effective amount of the compound or composition is used.

[0132] In one embodiment, a method of treating an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) in a subject in need thereof is provided, comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., a compound of Table 1), or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, a method of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure (e.g., a composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier). In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0134] In one embodiment, a method of treating an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure (e.g., a composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier). In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0135] In some embodiments, the subject is a human.

[0136] In certain embodiments, the disease is an MTAP-deficient and / or MTA-accumulating cancer.

[0137] In one embodiment, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0138] In one embodiment, the cancer is MTAP-deficient and / or MTA-accumulating 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0139] The PRMT5 inhibitors described herein (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) can be used in a method for inhibiting the growth of MTAP-deficient cells in a subject in need of such inhibition, the method comprising administering to the subject a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) in an amount effective to inhibit the growth of MTAP-deficient cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0140] The PRMT5 inhibitors described herein (e.g., an MTA-uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) can be used in a method for inhibiting the proliferation of MTA-accumulating cells in a subject in need of such inhibition, the method comprising administering to the subject a PRMT5 inhibitor (e.g., an MTA-uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) in an amount effective to inhibit the proliferation of MTA-accumulating cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0141] The PRMT5 inhibitors described herein (e.g., MTA-uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitors or MTA cooperative binders, e.g., compounds in Table 1, or pharmaceutically acceptable salts thereof) can be used in a method for inhibiting the proliferation of MTAP-deficient and / or MTA-accumulating cells in a subject in need of such inhibition, the method comprising administering to the subject a PRMT5 inhibitor (e.g., MTA-uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitor or MTA cooperative binder, e.g., compounds in Table 1, or pharmaceutically acceptable salts thereof) in an amount effective to inhibit the proliferation of MTAP-deficient and / or MTA-accumulating cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0142] Combination therapy In some embodiments, methods are provided for treating MTAP-deficient and / or MTA-accumulating proliferative disorders (e.g., cancer) using a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) in combination with one or more therapeutic agents.

[0143] In some embodiments, provided are methods for treating MTAP-deficient and / or MTA-accumulated proliferative disorders (e.g., cancer) using a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) in combination with a second therapeutic agent. In some embodiments, provided are methods for treating MTAP-deficient and / or MTA-accumulated proliferative disorders (e.g., cancer) using a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, provided are methods for treating MTAP-deficient and / or MTA-accumulated proliferative disorders (e.g., cancer) using a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0144] The term "combination" refers to either a fixed combination in a single dosage unit form, or a combined administration in which a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a combination partner (e.g., another drug as described below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently or separately within a time interval, particularly if this time interval allows the combination partners to exhibit a coordinated, e.g., synergistic, effect. Single components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. Terms such as "co-administration" or "co-administration," as used herein, are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combination of two or more therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, e.g., a PRMT5 inhibitor described herein (e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof), and a combination partner are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that both therapeutic agents, e.g., a PRMT5 inhibitor described herein (e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof), and a combination partner are administered to a patient as separate entities, either simultaneously, concurrently, or sequentially, without any specific time limit, such that such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0145] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses co-administration of the therapeutic agents substantially simultaneously, for example, in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple containers for each active ingredient, or in separate containers (e.g., tablets, capsules, powders, and liquids). The powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also encompasses the sequential use of each type of therapeutic agent, either at approximately the same time or at different times.

[0146] In certain embodiments, the PRMT5 inhibitors described herein are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergy agents, anti-nausea agents (or antiemetic agents), analgesics, cytoprotective agents, and combinations thereof.

[0147] In some embodiments, a method of treating a disease or disorder (e.g., cancer) comprises administering to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), as well as anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentanone (Pentan-20), or other anti-cancer drugs. Dicarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adruciline), l (registered trademark), Efudex (registered trademark), flutamide (Eulexin (registered trademark), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea (registered trademark), idarubicin (Idamycin (registered trademark), ifosfamide (IFEX (registered trademark), irinotecan (Camptosar (registered trademark), L-asparaginase (ELSPAR (registered trademark), leucovorin calcium, melphalan (Alkeran (registered trademark), 6-mercaptopurine (Purinethol (registered trademark),Methods are provided that include administering or co-administering, in any order, common chemotherapy agents selected from methotrexate (Folex®), mitoxantrone (Novantrone®), Milotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinnorelbine (Navelbine®).

[0148] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an EGFR inhibitor (e.g., cetuximab, panitumimab, erlotinib, gefitinib, and EGFRi NOS) to a patient in need thereof. In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a MAPK pathway inhibitor (e.g., BRAFi, pan-RAFi, MEKi, ERKi) to a patient in need thereof. In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a PI3K-mTOR pathway inhibitor (e.g., an alpha-specific PI3Ki, a pan-Class I PI3Ki, and an mTOR / PI3Ki, particularly everolimus and its analogs).

[0149] MTAP deletion can occur in conjunction with a mutation in the KRAS gene (e.g., KRASG12C). In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a KRAS inhibitor (e.g., a pan-KRAS or specific G12C, G12D, G13C inhibitor, e.g., adagrasib, sotorasib, LY3537982, RMC-6236, RMC-6291, RMC-9805, RMC-8839).

[0150] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a spliceosome inhibitor (e.g., an SF3b1 inhibitor, e.g., E7107).

[0151] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an HDAC inhibitor or a DNA methyltransferase inhibitor to a patient in need thereof. In some embodiments, the HDAC inhibitor is trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

[0152] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a MAT2A inhibitor to a patient in need thereof.

[0153] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an inhibitor of a protein that interacts with or is necessary for the function of PRMT5, including but not limited to pICIN, WDR77, or RIOK1.

[0154] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), and an HDM2 inhibitor and / or 5-FU or other purine analog (e.g., 6-thioguanine, 6-mercaptopurine).

[0155] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and LEE011 or a CDK4 / 6 inhibitor (e.g., a CDK4 inhibitor, including but not limited to, palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®).

[0156] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering to a patient in need thereof, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a targeted therapy depending on the dependency of the individual target tumor on relevant pathways as determined by suitable predictive markers, including, but not limited to, inhibitors of HDM2i, PI3K / mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, MEti, IGF-I, JAKi, and WNTi).

[0157] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and immunotherapy to a patient in need thereof.

[0158] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), and an immunotherapeutic agent.

[0159] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (eg, ipilimumab, tremelimumab).

[0160] In some embodiments, the immunotherapeutic agent is an anti-PD-1 or anti-PD-L1 agent (e.g., an antibody). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538), CT-011, AMP-224, pembrolizumab (MK-3475), pidilizumab, cemiplimab, dostallimab, prorugolimab, spartalizumab, camrelizumab, sasanlimab, sintilimab, tislelizumab, toripalimab, retifanlimab, MEDI0680, budigalimab, geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody, e.g., BMS936559 (i.e., MDX-1105), durvalumab (MEDI4736), avelumab (MSB0010718C), embafolimab, cosibelimab, sugemalimab, AUNP-12, atezolizumab (MPDL-3280A), or an anti-PD-L1 small molecule (e.g., CA-170)).

[0161] In some embodiments, the immunotherapeutic agent is a checkpoint blockade antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT, including IMP321 and MGA271).

[0162] In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0163] In some embodiments, the immunotherapeutic agent is a costimulatory antibody (eg, anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0164] In some embodiments, the immunotherapeutic agent is a cancer vaccine, such as a neoantigen. These vaccines can be developed using peptides or RNA (e.g., mRNA).

[0165] In some embodiments, the immunotherapeutic agent is an oncolytic virus.

[0166] In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0167] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a disease-specific huMAB (e.g., an anti-HER3 huMAB).

[0168] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and ADC / ADCC in response to expression of relevant surface targets on a target tumor of the subject.

[0169] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and one or more DNA damage pathway inhibitors to a patient in need thereof. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chk1 inhibitor (e.g., AZD7762). In some embodiments, the DNA damage pathway inhibitor is a DNA alkylating agent.

[0170] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a PARP inhibitor to a patient in need thereof. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, iniparib, and 3-aminobenzamide.

[0171] Some patients may experience allergic reactions to the PRMT5 inhibitors described herein and / or other anti-cancer agent(s) during or after administration. Therefore, anti-allergic agents are often administered to minimize the risk of allergic reactions. In some embodiments, a method of treating a disease or disorder (e.g., cancer) includes administering to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an anti-allergy agent (e.g., dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, sold under the trade names Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), prednisolone (sold under the trade names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (Deltasone®, Liquid and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®), antihistamines such as diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine, and corticosteroids including, but not limited to, beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (bronchodilators such as Brethine®), in any order.

[0172] Some patients may experience nausea during and after administration of a PRMT5 inhibitor described herein and / or other anti-cancer agent(s). Therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting. In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an antiemetic (e.g., aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof).

[0173] Medications to alleviate pain experienced during treatment are often prescribed to make patients more comfortable. In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an analgesic (e.g., an over-the-counter analgesic (e.g., Tylenol®), an opioid analgesic (e.g., hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), fentanyl (e.g., Duragesic®)).

[0174] To protect normal cells from treatment toxicity and limit organ toxicity, cytoprotective agents (neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy. In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, to a patient in need thereof a PRMT5 inhibitor described herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a cytoprotective agent (e.g., amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folic acid)).

[0175] The structures of the active compounds identified by code numbers, generic names or trade names can be obtained from the actual edition of the standard catalogue "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0176] The compounds that can be used in combination with the PRMT5 inhibitors described herein can be prepared and administered as described in the art, including but not limited to the above-cited documents.

[0177] In one embodiment, a pharmaceutical composition is provided comprising at least one compound of the present disclosure (e.g., a PRMT5 inhibitor, e.g., a compound in Table 1), or a pharmaceutically acceptable salt thereof, either alone or in combination with other anti-cancer agents, together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0178] In one embodiment, provided is a method of treating a human or animal subject having or diagnosed with an MTAP deficiency and / or MTA accumulation proliferative disorder (e.g., cancer), comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Table 1) or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutic agents described herein.

[0179] In one embodiment, a method of treating an MTAP-deficient and / or MTA-accumulating proliferative disorder (e.g., cancer) in a subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., a compound of Table 1) or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutic agents described herein.

[0180] In particular, the compositions will either be formulated together as a combination therapy or will be administered separately.

[0181] In combination therapy, the PRMT5 inhibitors described herein and other anti-cancer agents(s) may be administered either simultaneously, concurrently, or sequentially without any specific time restriction, and such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0182] In a preferred embodiment, the compound of the present disclosure (e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) and the other anticancer agent(s) are administered sequentially in any order, generally by injection or orally. The dosing regimen may vary depending on the stage of the disease, the patient's physical condition, the safety profile of the individual drugs, and the tolerance of the individual drugs, as well as other criteria known to the attending physician and the physician(s) administering the combination. The PRMT5 inhibitors and other anticancer agent(s) described herein can be administered within minutes, hours, days, or weeks of each other, depending on the particular cycle used in the treatment. In addition, the cycle may include administering one drug more frequently than the other during the treatment cycle, with different doses for each administration of the drug.

[0183] In another embodiment, a kit is provided that includes one or more PRMT5 inhibitor(s) described herein (e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a second therapeutic agent disclosed herein. Exemplary kits include (a) a PRMT5 inhibitor described herein or a pharmaceutically acceptable salt thereof (e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof), and (b) at least one other therapeutic agent, e.g., as set forth above, whereby such kits may include a package insert or other labeling including instructions for administration.

[0184] The PRMT5 inhibitors described herein (e.g., compounds in Table 1, or pharmaceutically acceptable salts thereof) can also be used in combination with known therapeutic processes, such as administration of hormones or, in particular, radiation. The compounds of the present disclosure can be used, in particular, as radiosensitizers, particularly for the treatment of tumors that exhibit low sensitivity to radiation therapy. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer), comprising administering or co-administering, in any order, a PRMT5 inhibitor described herein (e.g., compounds in Table 1, or pharmaceutically acceptable salts thereof) and radiation to a patient in need thereof.

[0185] Patient Selection and Monitoring In one embodiment, a method is provided for determining whether a subject (e.g., a cancer patient) having or diagnosed with cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), comprising: a) contacting a test sample obtained from the subject with a reagent capable of detecting human cancer cells having MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject); The presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0186] In one embodiment, a method is provided for determining whether a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), comprising: a) contacting a test sample obtained from a subject having or diagnosed with the cancer with a reagent capable of detecting human cancer cells having MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject); The presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon. In some embodiments, the method further comprises determining the level of PRMT5 in the cancer cells. The expression level of PRMT5 may be taken into consideration when determining a therapeutically effective dose of a PRMT5 inhibitor.

[0187] In one embodiment, a method for determining the sensitivity of a cancer cell to PRMT5 inhibition (e.g., inhibition by an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) is provided, comprising: a) assaying the production, level, activity, expression or presence of MTAP in said cancer cells; b) comparing the production, level, activity, expression or presence of MTAP in the cancer cells with the production, level, activity, expression or presence of MTAP in non-cancerous or normal control cells, respectively; The method includes a step in which a decrease in level, activity, or expression in the cancer cells indicates MTAP deficiency, and MTAP deficiency indicates that the cancer cells are sensitive to a PRMT5 inhibitor. In some embodiments, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0188] In one embodiment, a method for determining the sensitivity of a cancer cell to a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof) is provided, comprising: a) assaying for the level, activity or expression of the MTAP gene or its gene product in both cancer cells and normal control cells, wherein a decrease in the level, activity or expression in the cancer cells indicates an MTAP deficiency; b) assaying for PRMT5 expression in the cancer cells; and c) comparing PRMT5 expression with PRMT5 expression in the cancer cells and normal control cells, wherein a similarity in PRMT5 expression and the presence of the MTAP deficiency in the cancer cells indicates that the cells are sensitive to a PRMT5 inhibitor.

[0189] In some embodiments, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0190] In one embodiment, a therapeutic method is provided for treating a subject having or diagnosed with cancer (e.g., a cancer associated with MTAP deficiency and / or MTA accumulation), comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells in the test sample obtained from the 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 with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) to the subject identified in step b).

[0191] In one embodiment, a method is provided for treating cancer (e.g., cancer associated with MTAP deficiency and / or MTA accumulation) in a subject in need thereof, comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), 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 with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder); and c) administering a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) to the subject identified in step b).

[0192] In some embodiments, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0193] In some embodiments, the method further comprises determining the level of PRMT5 in the cancer cells.

[0194] In one embodiment, a therapeutic method is provided for treating a subject having or diagnosed with a cancer associated with MTAP deficiency and / or MTA accumulation, comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), 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 with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder); and c) administering a composition comprising a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) to the subject identified in step b).

[0195] In one embodiment, a method is provided for treating a cancer associated with MTAP deficiency and / or MTA accumulation in a subject in need thereof, comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), 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 with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder); and c) administering a composition comprising a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) to the subject identified in step b).

[0196] In some embodiments, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0197] In some embodiments, the method further comprises determining the level of PRMT5 in the cancer cells.

[0198] In one embodiment, a method is provided for determining whether a subject having or diagnosed with a cancer associated with MTAP deficiency and / or MTA accumulation will respond to treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), 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 with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder).

[0199] In one embodiment, a method is provided for determining whether a cancer associated with MTAP deficiency and / or MTA accumulation will respond to treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from a subject having or diagnosed with the cancer (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), 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 with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder).

[0200] In some embodiments, the cancer is a 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

[0201] In some embodiments, the method further comprises determining the level of PRMT5 in the cancer cells.

[0202] Sample preparation Assays for detecting MTAP deficiency and / or MTA accumulation are further provided. The assays can include, for example, detecting mutations associated with MTAP deficiency and / or MTA accumulation in body fluids, such as blood (e.g., serum or plasma), bone marrow, cerebrospinal fluid, peritoneal / pleural fluid, lymph, ascites, serous fluid, sputum, tears, feces, and urine, or in tissues, such as tumor tissue. The tumor tissue can be fresh or archived (e.g., formalin-fixed, e.g., paraffin-embedded).

[0203] Body fluid samples can be obtained from subjects using any method known in the art. Methods for extracting cellular DNA from body fluid samples are well known in the art. Usually, cells are dissolved with detergent. After cell lysis, proteins are removed from DNA using various proteases. Then, DNA is extracted with phenol, precipitated in alcohol, and dissolved in aqueous solution. Methods for extracting cell-free DNA from body fluid samples are also known in the art. Usually, the cellular DNA in body fluid samples is separated from cells, precipitated in alcohol, and dissolved in aqueous solution.

[0204] Detection of PRMT5 selectivity Once prepared, the sample can be tested for MTAP deficiency and / or MTA accumulation, either or both of which indicate that the sample is sensitive to treatment with a PRMT5 inhibitor. Cells can be determined to have MTA accumulation by techniques known in the art, including, but not limited to, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS / MS), as described in Stevens et al. 2010. J. Chromatogr. A. 1217:3282-3288 and Kirovski et al. 2011 Am. J. Pathol. 178:1145-1152, and references cited therein. Detecting MTAP deficiency can be performed by many methods, including DNA sequencing, PCR-based methods including RT-PCR, microarray analysis, Southern blotting, Northern blotting, next-generation sequencing, and dipstick analysis. In some embodiments, MTAP deficiency is assessed by any technique known in the art, such as immunohistochemistry using anti-MTAP antibodies or derivatives thereof, and / or genomic sequencing, or nucleic acid hybridization or amplification using at least one probe or primer comprising at least 12 consecutive nucleotides (nt) of the MTAP sequence (the primer is about 30 nt or less).

[0205] Polymerase chain reaction (PCR) can be used to amplify MTAP from either genomic DNA or RNA extracted from tumor tissue and identify MTAP deletions. PCR is well known in the art and is described in detail in Saiki et al., Science 1988, 239:487.

[0206] A method for detecting MTAP deletion by hybridization is provided. The method involves identifying MTAP deletion in a sample by the sample's inability to hybridize to MTAP nucleic acid. The nucleic acid probe is detectably labeled with a label, such as a radioisotope, a fluorescent agent, or a chromogenic agent. Radioisotopes include, but are not limited to, 3 H, 32 P, 33 P and 35 Examples of fluorescent agents include, but are not limited to, FITC, Texas Red, rhodamine, and the like.

[0207] The probes used for detection that can hybridize to MTAP nucleic acids can be about 8 to about 100 nucleotides, about 10 to about 75 nucleotides, about 15 to about 50 nucleotides, or about 20 to about 30 nucleotides. The kits can also provide instructions for analyzing patient cancer samples, where the presence or absence of an MTAP deficiency indicates whether the subject is sensitive or insensitive to treatment with a PRMT5 inhibitor.

[0208] Single-strand conformation polymorphism (SSCP) can also be used to detect MTAP deficiency. This technique is fully described in Orita et al., PNAS 1989, 86:2766-2770.

[0209] Measurement of gene expression Assessment of MTAP deficiency and measurement of MTAP gene expression, as well as measurement of PRMT5 gene expression, can be performed using any method or reagent known in the art.

[0210] The detection of gene expression can be carried out by any suitable method, including, for example, detecting the amount of mRNA transcribed from gene, or the amount of cDNA generated from reverse transcription of mRNA transcribed from gene, or the amount of polypeptide or protein coded by gene.These methods can be carried out on a sample-by-sample basis, or can be modified for high-throughput analysis.For example, Affymetrix (TM) U133 microarray chip is used.

[0211] In one embodiment, gene expression is detected and quantified for that biomarker by hybridization to a probe that specifically hybridizes to an appropriate probe. The probe can also be attached to a solid support for use in high-throughput screening assays, using methods known in the art.

[0212] In one embodiment, the expression level of the gene is determined by exposing the nucleic acid sample to a probe-modified chip. The extracted nucleic acid is labeled, for example with a fluorescent tag, preferably during the amplification step.

[0213] Hybridization of the labeled sample is carried out at an appropriate stringency level, and the degree of probe-nucleic acid hybridization is quantitatively measured using a detection device.

[0214] Alternatively, gene copy number, transcription, or translation can all be determined using known techniques. For example, amplification methods such as PCR can be useful. A general procedure for PCR is taught in MacPherson et al., PCR: A Practical Approach, (IRL Press at Oxford University Press (1991)). However, PCR conditions for each application reaction are determined empirically. Several parameters affect the success of the reaction, including annealing temperature and time, extension time, Mg2+ and / or ATP concentration, pH, and the relative concentrations of primers, template, and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis followed by visualization with ethidium bromide staining and ultraviolet illumination. In one embodiment, hybridized nucleic acids are detected by detecting one or more labels attached to the sample nucleic acids. Labels can be incorporated by any of a number of means well known to those skilled in the art. However, in one embodiment, labels are simultaneously incorporated during the amplification step in the preparation of the sample nucleic acids. Thus, for example, polymerase chain reaction (PCR) using labeled primers or labeled nucleotides will provide labeled amplification products. In another embodiment, transcription amplification as described above using labeled nucleotides (e.g., fluorescein-labeled UTP and / or CTP) incorporates a label into the transcribed nucleic acid.

[0215] Alternatively, a label may be added directly to the original nucleic acid sample (e.g., mRNA, polyA, mRNA, cDNA, etc.) or to the amplification product after amplification is completed. Means for attaching labels to nucleic acids are well known to those of skill in the art and include, for example, nick translation, or end-labeling (e.g., with labeled RNA), in which the sample nucleic acid is attached to a label (e.g., a fluorophore) by kinase treatment of the nucleic acid followed by attachment (ligation) of a nucleic acid linker.

[0216] In one example, gene expression can be measured by in situ hybridization protocols (eg, by RNAscope®) that can detect RNA molecules on tissue sections or slides containing cells.

[0217] Detectable labels suitable for use in the methods disclosed herein include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Useful labels include labeled streptavidin conjugates, magnetic beads (e.g., Dynabeads™), fluorescent dyes (e.g., fluorescein, Texas Red, rhodamine, green fluorescent protein, etc.), radioactive labels (e.g., 3 H, 125 I, 35 S, 14 C, or 32 P) Enzymes (e.g., horseradish peroxidase, alkaline phosphatase, and others commonly used in ELISA), and biotin for staining with colorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads.

[0218] Detection of labels is well known to those skilled in the art. Thus, for example, radioactive labels may be detected using photographic film or a scintillation counter, and fluorescent markers may be detected using a photodetector to detect emitted light. Enzyme labels are typically detected by providing a substrate to the enzyme and detecting the reaction product produced by the action of the enzyme on the substrate, while calorimetric labels are detected by simply visualizing the colored label. Detectable labels may be added to the target (sample) nucleic acid(s) before or after hybridization, as described in WO97 / 10365, for example. These detectable labels are directly attached to or incorporated into the target (sample) nucleic acid before hybridization. In contrast, "indirect labels" are attached to the hybrid duplex after hybridization. Generally, indirect labels are attached to a binding moiety that is attached to the target nucleic acid before hybridization. For example, the target nucleic acid may be biotinylated before hybridization. After hybridization, an avidin-conjugated fluorophore binds to the hybrid duplex bearing biotin, providing an easily detectable label. For a detailed review of methods for labeling nucleic acids and detecting labeled hybridized nucleic acids, see Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24: Hybridization with Nucleic Acid Probes, P. Tijssen, ed. Elsevier, NY (1993).

[0219] Polypeptide detection The protein level of MTAP is determined by examining protein expression or protein product, which involves measuring the amount of any immunospecific binding that occurs between antibodies that selectively recognize and bind to the biomarker polypeptide in a sample obtained from a subject, and comparing this to the amount of immunospecific binding of at least one biomarker in a control sample.

[0220] A variety of techniques are available in the art for protein analysis, including, but not limited to, radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassays, immunoradiometric assays, in situ immunoassays (using, for example, colloidal gold, enzyme, or radioisotope labels), Western blot analysis, immunoprecipitation assays, immunofluorescence assays, flow cytometry, immunohistochemistry, HPLC, mass spectrometry, confocal microscopy, enzyme assays, surface plasmon resonance, and PAGE-SDS.

[0221] Adjacent biomarkers Several other biomarkers are located near or adjacent to MTAP on chromosome 9. CDKN2A is often, but not commonly, deleted along with MTAP. Additional genes or pseudogenes in this region include C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0222] In some embodiments of the method, the cells that are MTAP-deficient are also deficient in CDKN2A, hi some embodiments, the cells that are MTAP-deficient are also deficient in one or more of CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0223] Thus, in various methods that include assessing cells for MTAP deficiency or determining whether a cell is MTAP deficient, this step may include determining whether the cell is deficient in one or more of these markers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0224] Thus, in some embodiments, the present disclosure encompasses: a method of determining whether a subject having or diagnosed with cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder), comprising: a) assessing a test sample obtained from the subject for MTAP deficiency and assessing a reference sample from a non-cancerous or normal control subject for MTAP deficiency, wherein MTAP deficiency in the test sample compared to the reference sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), and wherein MTAP deficiency is assessed by assessing deficiency in one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, the method comprising the steps of: b) determining the level of MTAP in the subject, wherein steps a) and b) may be performed in any order; c) administering to the subject a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof); and d) After step c), the method may further include determining the level of PRMT5 activity in the subject, wherein a decrease in the level of PRMT5 activity correlates with inhibition of cancer growth, and steps c) and d) are performed after steps a) and b).

[0225] In some embodiments, the present disclosure encompasses a method of determining whether a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder), comprising: a) assessing a test sample obtained from a subject having or diagnosed with the cancer for MTAP deficiency and assessing a reference sample from a non-cancerous or normal control subject for MTAP deficiency, wherein MTAP deficiency in the test sample compared to the reference sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), and wherein MTAP deficiency is assessed by assessing deficiency in one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, the method comprising the steps of: b) determining the level of MTAP in the subject, wherein steps a) and b) may be performed in any order; c) administering to the subject a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof); and d) After step c), the method may further include determining the level of PRMT5 activity in the subject, wherein a decrease in the level of PRMT5 activity correlates with inhibition of cancer growth, and steps c) and d) are performed after steps a) and b).

[0226] Biomarker assays and PRMT5 inhibitor treatment Several patient stratification strategies can be used to identify patients who may be sensitive to PRMT5 inhibition with an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder (e.g., a PRMT5 inhibitor of the present disclosure, e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof), including, but not limited to, testing for MTAP deficiency and / or MTA accumulation.

[0227] Once a patient has been assayed for MTAP deficiency and / or MTA accumulation and is predicted to be sensitive to treatment with a PRMT5 inhibitor, any PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA cooperative binder, e.g., a compound in Table 1, or a pharmaceutically acceptable salt thereof) can be administered to the patient in a single dose continuously or intermittently throughout the course of treatment. Methods for determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the composition used in therapy, the purpose of the therapy, the target cells being treated, and the subject being treated. Single or multiple administrations can be administered, with the dose level and pattern selected by the attending physician. Suitable dosage formulations and methods of administering the agents can be empirically adjusted.

[0228] kit In some embodiments, kits are provided relating to the methods of use described herein.

[0229] In one embodiment, a kit for predicting the sensitivity of a subject having or diagnosed with an MTAP-deficiency-associated cancer to treatment with a PRMT5 inhibitor is provided, comprising: i) a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells; and ii) instructions on how to use the kit. [Example]

[0230] In order that the invention(s) described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed in any way as limiting the scope thereof. In the synthetic examples below, a description of experimental procedures within a series of reactions is listed in numerical order. Abbreviation overview ADDP 1,1'-(azodicarbonyl)dipiperidine anhy. aq. water-based satd. saturation min(s) Minute(s) hr(s) Time(s) mL milliliter mmol millimoles(s) mol mole(s) MS mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography HPLC High-Performance Liquid Chromatography Me methyl i-Pr Isopropyl t-Bu tert-butyl t BuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Ph Phenyl Et Ethyl Bz Benzoyl RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl Spectrum Hz Hertz δ chemical shift J coupling constant s Single line d double line t triple line q quartet m multiplet br wide line qd doublet quartet dquin double line dd double line double line dt Triple line double line Solvents and Reagents DAST Diethylaminosulfur trifluoride CHCl3Chloroform DCM dichloromethane DMF Dimethylformamide Et2O diethyl ether EtOH Ethyl alcohol EtOAc ethyl acetate MeOH methyl alcohol MeCN acetonitrile PE Petroleum Ether THF tetrahydrofuran DMSO dimethyl sulfoxide t-BuOK Potassium tert-butoxide 9-BBN 9-Borabicyclo[3.3.1]nonane AcOH acetic acid HCl Hydrochloric acid H2SO4 Sulfuric Acid NH4Cl Ammonium chloride KOH Potassium hydroxide NaOH Sodium hydroxide K2CO3 Potassium Carbonate Na2CO3 Sodium Carbonate TFA trifluoroacetic acid Na2SO4 Sodium Sulfate NaBH4 Sodium borohydride NaHCO3 Sodium Bicarbonate LiHMDS Lithium hexamethyldisilylamide NaBH4 Sodium borohydride Et3N Triethylamine Py pyridine PCC Pyridinium chlorochromate DMAP 4-(dimethylamino)pyridine DIPEA N,N-Diisopropylethylamine BINAP 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl dppf 1,1'-bis(diphenylphosphino)ferrocene PEP Phospho(enol)pyruvate LDH lactate dehydrogenase DTT DL-Dithiothreitol BSA Bovine serum albumin NADH β-nicotinamide adenine dinucleotide (reduced form) Pd(t-Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0) AcCl Acetyl chloride i-PrMgCl Isopropyl magnesium chloride TBSCl tert-butyl(chloro)dimethylsilane (i-PrO)4Ti Titanium tetraisopropoxide BHT 2,6-di-t-butyl-4-methylphenoxide BzCl Benzoyl chloride CsF Cesium Fluoride DCC dicyclohexylcarbodiimide DMP Dess-Martin Periodinane EtMgBr Ethyl magnesium bromide EtOAc ethyl acetate TEA Triethylamine AlaOH alanine TBAF Tetra-n-butylammonium fluoride TBS t-butyldimethylsilyl TMS trimethylsilyl TMSCF3 (trifluoromethyl)trimethylsilane Ts p-Toluenesulfonyl Bu butyl Ti(O i Pr)4Tetraisopropoxytitanium LAH Lithium aluminum hydride LDA Lithium diisopropylamide LiOH.H2O Lithium hydroxide hydrate MAD Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide) NBS N-Bromosuccinimide Na2SO4 Sodium Sulfate Na2S2O3 Sodium thiosulfate PE Petroleum Ether MeCN acetonitrile Boc t-butoxycarbonyl MTBE Methyl tert-butyl ether DIAD Diisopropyl azodicarboxylate

[0231] General Lab Notes: In the following examples, chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) and used without further purification.

[0232] In some examples, purification of intermediates and final compounds was carried out using HPLC (Agilent 1260 Infinity system equipped with HO-MeOH, DAD, and mass detector). Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 100 mm, equipped with a SunFire C18 Prep Guard Cartridge (100 Å, 10 μm, 19 mm × 10 mm). The material was dissolved in 0.7 mL of DMSO. Flow rate: 30 mL / min. The purity of the obtained fractions was confirmed by analytical LCMS. Spectra were recorded for each fraction, as each fraction was obtained in solution form immediately after chromatography. The solvent was evaporated by heating to 80 °C under a stream of N2. Fractions were combined based on the chromatographic LCMS analysis. The solid fraction was dissolved in 0.5 mL of MeOH and transferred into a pre-weighed and marked vial. The resulting solution was evaporated again by heating to 80 °C under a stream of N2. After drying, the product was subjected to lyophilization using an acetonitrile-water mixture and finally analyzed by LCMS and 1 Characterized by 1 H NMR.

[0233] Nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AVANCE DRX 500, a Bruker 400 spectrometer, or a Varian UNITYplus 400. Proton chemical shifts are reported as parts per million on the δ scale using the solvent residual peak (CHCl3: 7.27 ppm), (methanol-d4: 3.31 ppm), (DMSO-d6: 2.50 ppm) or tetramethylsilane (0.00 ppm) as internal standard. 13Chemical shifts for C NMR spectra are reported in ppm from the central peak of CDCl3 (77.00 ppm) (methanol-d4: 49.15 ppm) (DMSO-d6: 39.51 ppm) on the δ scale. Data are expressed as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet, br = broad line), coupling constant (J, Hz), and integration.

[0234] In certain examples, mass spectra were recorded on an Agilent 1100 Series LC / MSD system equipped with a DAD\ELSD and an Agilent LC\MSD VL (G1956A), SL (G1956B) mass spectrometer or an Agilent 1200 Series LC / MSD system equipped with a DAD\ELSD and an Agilent LC / MSD SL (G6130A), SL (G6140A) mass spectrometer. All LC / MS data was acquired using positive / negative mode switching. Column: Zorbax SB-C18 1.8 μm 4.6 x 15 mm Rapid Resolution Cartridge (PN821975-932) Mobile phase A - acetonitrile, 0.1% formic acid B - Water (0.1% formic acid) Flow rate 3ml / min Gradient 0 min - 100% B 0.01 min-100%B 1.5 minutes-0%B 1.8 minutes-0%B 1.81 min-100%B Injection volume 1μl Ionization mode: atmospheric pressure chemical ionization (APCI) Scan range m / z 80–1000.

[0235] Other exemplary analytical LC / MS instruments and conditions are described below: Instrument: Agilent LC1100-MS6100 Series G1956B; Column: Xbridge Shield RP-18, 50*2.1mm*5μm; Mobile phase A: H2O containing 0.05% NH3-H2O (v%); Mobile phase B: MeCN; Flow rate: 1.0mL / min; Wavelength: UV 220nm, 254nm; Column temperature: 30℃; MS ionization: ESI. 0-30CD: Gradient: 0% to 30% B in 2 min, hold at 30% for 0.48 min; 0-60CD: Gradient: 0% to 60% B in 2 min, hold at 60% for 0.48 min; 10-80CD: Gradient: 10% to 80% B in 2 min, hold at 80% for 0.48 min; 30-90CD: Gradient: 30% to 90% B in 2 min, hold at 90% for 0.48 min; 50-100CD: Gradient: 50% to 100% B in 2 min, hold at 100% for 0.48 min.

[0236] Instrument: Agilent LC1100-MS6100 Series G1956B; Column: Xtimate C18, 30*2.1mm*3μm; Mobile phase A: H2O containing 0.0375% TFA (v%); Mobile phase B: MeCN containing 0.01875% TFA (v%); Flow rate: 0.8mL / min; Wavelength: UV 220nm, 254nm; Column temperature: 50℃; MS ionization: ESI. 0-30AB: Gradient: 0% to 30% B in 3 min, hold at 30% for 0.5 min; 0-60AB: Gradient: 0% to 60% B in 3 min, hold at 30% for 0.5 min; 10-80AB: Gradient: 10% to 80% B in 3 min, hold at 30% for 0.5 min; 30-90AB: Gradient: 0% to 30% B in 3 min, hold at 30% for 0.5 min; 50-100AB: Gradient: 50% to 100% B in 3 min, hold at 100% for 0.5 min.

[0237] Instrument: Shimadzu LC20-MS2010; Column: Agilent Pursit 5 C18 20*2.0mm; Mobile phase A: 0.0375% TFA in H2O (v%); Mobile phase B: 0.01875% TFA in MeCN (v%); Gradient: 5-95% B in 0.7 min, hold at 95% for 0.4 min; Flow rate: 1.5 mL / min; Wavelength: UV 220 nm, 254 nm, 215 nm; Column temperature: 50 °C; MS ionization: ESI.

[0238] Instrument: Shimadzu LC20-MS2020; Column: Agilent Pursit 5 C18 20*2.0mm; Mobile phase A: 0.0375% TFA in H2O (v%); Mobile phase B: 0.01875% TFA in MeCN (v%); Gradient: 5-95% B in 0.7 min, hold at 95% for 0.4 min; Flow rate: 1.5 mL / min; Wavelength: UV 220 nm, 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0239] Exemplary HPLC Instrumentation and Conditions Instrument: Shimadzu LC20; Column: YMC-Pack ODS-A 150*4.6mm; Mobile phase A: 0.06875% TFA in H2O (v%); Mobile phase B: 0.0625% TFA in MeCN (v%); Flow rate: 1.5mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 0-30: Gradient: 0-30% B in 10 min, hold at 30% for 5 min; 0-60: Gradient: 0-60% B in 10 min, hold at 60% for 5 min; 0-95: Gradient: 0-95% B in 10 min, hold at 95% for 5 min; 10-80: Gradient: 10-80% B in 10 min, hold at 80% for 5 min; 30-90: Gradient: 30-90% B in 10 min, hold at 90% for 5 min; 50-100: Gradient: 50-100% B in 10 minutes, hold at 100% for 5 minutes.

[0240] Equipment: Shimadzu LC20; Column: Xbridge Shield RP-18 50*2.1mm, 5μm; Mobile phase A: H2O with 0.01% NH3-H2O; Mobile phase B: MeCN; Flow rate: 1.2mL / min; Wavelength: UV220nm, 215nm, 254nm; Column temperature: 40℃. 0-30CD: Gradient: 0-30% B in 6 min, hold at 30% for 2 min; 0-60CD: Gradient: 0-60% B in 6 min, hold at 60% for 2 min; 10-80CD: Gradient: 10-80% B in 6 min, hold at 80% for 2 min; 30-90CD: Gradient: 30-90% B in 6 min, hold at 90% for 2 min; 50-100CD: Gradient: 10-80% B in 6 min, hold at 100% for 2 min.

[0241] Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile phase A: 0.06875% TFA in H2O (v%); Mobile phase B: 0.0625% TFA in MeCN (v%); Flow rate: 1.2mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 0-30AB: Gradient: 0-30% B in 2.5 min, hold at 30% for 0.75 min; 0-60AB: Gradient: 0-60% B in 2.5 min, hold at 60% for 0.75 min; 5-95AB: Gradient: 5 to 95% B in 2.5 minutes, hold at 95% for 0.75 minutes.

[0242] Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile phase A: 0.06875% TFA in H2O (v%); Mobile phase B: 0.0625% TFA in MeCN (v%); Flow rate: 1.2mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 10-80AB: Gradient: 10-80% B in 4 min, hold at 80% for 2 min.

[0243] Exemplary TLC, concentration and normal phase chromatography. Analytical thin-layer chromatography (TLC) was performed using silica gel 60 F254 aluminum plates. Visualization was achieved by immersion in iodine or ethanolic phosphomolybdic acid (PMA) or potassium permanganate (KMnO4) under a UV lamp (254 nm), followed by heating using a heat gun. Organic solutions were concentrated by rotary evaporation at 20-40°C. Purification of reaction products was typically achieved by flash column chromatography using 230-400 mesh silica gel or Agela flash silica columns.

[0244] Exemplary Chiral SFC Analysis Methods Column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; Mobile phase: A: supercritical CO2; Mobile phase B: EtOH (0.05% DEA), Gradient: 5% to 40% B in 5 min, hold 40% for 2.5 min, then hold 5% B for 2.5 min; Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0245] Column: Chiralpak AD-3 100 × 4.6 mm ID, 3 μm; Mobile phase: A: supercritical CO2; Mobile phase B: EtOH (0.1% ethanolamine); Gradient: 5% to 40% B in 4.5 min, hold 40% for 2.5 min, then hold 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40 °C.

[0246] Exemplary Preparative HPLC Separation Methods Basic conditions (NH3-H2O): Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase A: H2O containing 0.05% NH3-H2O (v%); Mobile phase B: MeCN; Gradient: 22% to 52% B in 9.5 min, hold 100% B in 1 min; Flow rate: 25 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm.

[0247] Acidic conditions (HCOOH): Equipment: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Agela Durashell C18 150*25mm 5μm; Mobile phase A: HO (0.0225% HCOOH); Mobile phase B: MeCN; Gradient: 7% to 37% B in 9 min, hold 100% B at 0 min; Flow rate: 25mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm.

[0248] Acidic conditions (HCl): Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Xtimate C18 150*25mm*5μm; Mobile phase A: HO containing 0.05% HCl (v%); Mobile phase B: MeCN; Gradient: 0% to 30% B in 6.5 min, hold 100% B in 2.5 min; Flow rate: 25mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm).

[0249] Neutral conditions (NH4HCO3): (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase A: H2O containing 10 mmol NH4HCO3; Mobile phase B: MeCN; Gradient: 39% to 69% B in 10 min, hold 100% B in 2.5 min; Flow rate: 25 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm).

[0250] Exemplary Large-Scale Separation Basic conditions: Equipment: Shimadzu LC-8A Pumps, Shimadzu SCL-10A VP System Controller, Shimadzu SPD-20AV UV / VIS Detector; Column: Phenomenex Gemini C18 250*50mm*10μm; Mobile phase A: Water (0.04% NH3-H2O + 10mM NH4HCO3); Mobile phase B: MeCN; Gradient: 65% to 95% B in 26 minutes, hold 100% B in 3 minutes; Flow rate: 110mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm.

[0251] Acidic conditions (TFA): Instrument: Shimadzu LC-20AP Pumps, Shimadzu CBM-20A System Controller, Shimadzu SPD-20AV UV / VIS Detector; Column: Phenomenex luna C18 250 x 50 mm x 10 μm; Mobile phase A: HO containing 0.1% TFA (v%); Mobile phase B: MeCN; Gradient: 0% to 25% B in 15 min, hold 100% B in 4 min; Flow rate: 120 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm.

[0252] Exemplary preparative chiral SFC methods: Exemplary chiral columns available for use in the enantiomer / diastereomer separation / purification provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0253] In one particular example, chiral separation was performed under the following conditions: Instrument: Thar 80; Column: Daicel Chiralpak AD. 250 x 30 mm ID 10 μm; Mobile phase: Supercritical CO2 / MeOH (0.1% NH3-H2O, v%) = 60 / 40; Flow rate: 70 mL / min; Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0254] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0255] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to protect certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, "Protecting Groups in Organic Synthesis," Second Edition, Wiley, New York, 1991, and references cited therein.

[0256] The compounds provided herein can be isolated and purified by known standard procedures, including, but not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details regarding the preparation of representative pyrazoles listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents.

[0257] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min

[0258] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5% to 95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm, 45 °C. Other piperidine intermediate synthesis 3EEE. 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-(pyrrolidin-1-yl)propan-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of ethyl 2-methyl-3-(pyrrolidin-1-yl)propanoate Pyrrolidine (7 g, 98.42 mmol, 8.18 mL) and ethyl 2-methylprop-2-enoate (10.21 g, 89.48 mmol, 11.14 mL) were mixed together and acetic acid (537.32 mg, 8.95 mmol, 512.22 μL) was added. The resulting reaction mixture was stirred at 70 °C for 17 h. Upon completion, the reaction mixture was diluted with hexane (30 mL) and washed with NaHCO. The solution was filtered through a silica pad and washed with hexane (3 * 10 mL). The combined organic solution was evaporated under reduced pressure to give ethyl 2-methyl-3-pyrrolidin-1-yl-propanoate (13 g, 70.17 mmol, 78.42% yield). 1 H NMR (400 MHz, CDCl3) δ (ppm) (d, 3H), 1.19 (t, 3H), 1.67 (m, 4H), 2.43 (m, 5H), 2.58 (m, 1H), 2.69 (m, 1H), 4.09 (m, 2H). Step 2: Synthesis of 5-bromo-2-(1-(pyrrolidin-1-yl)propan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 1A. Yield: 5 g (28.48%). LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 0.760 min. Step 3: Synthesis of 2-(1-(pyrrolidin-1-yl)propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 2. Yield: 7.7 g crude. LCMS(ESI):[M] + m / z: calculated 372.2; found 373.2; Rt = 1.154 min. Step 4: Synthesis of (3S)-tert-butyl 3-methyl-6-(2-(1-(pyrrolidin-1-yl)propan-2-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 9 g crude. LCMS(ESI):[M] + m / z: calculated 441.2; found 442.2; Rt = 1.273 min. Step 5: Synthesis of 5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-(pyrrolidin-1-yl)propan-2-yl)benzo[d]thiazole tert-Butyl (3S)-3-methyl-6-[2-[1-methyl-2-pyrrolidin-1-yl-ethyl]-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine-1-carboxylate (4.98 g, 11.27 mmol) was dissolved in dioxane / HCl (30 mL) and the resulting reaction mixture was stirred for 16 hours at 25° C. After completion, the solvent was evaporated under reduced pressure to provide crude 2-[1-methyl-2-pyrrolidin-1-yl-ethyl]-5-[(3S)-3-methyl-1,2,3,4-tetrahydropyridin-6-yl]-1,3-benzothiazole, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 341.2; found 342.2; Rt = 0.678 min. Step 6: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-(pyrrolidin-1-yl)propan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 step 5. Yield: 3 g crude. LCMS(ESI):[M] + m / z: calculated 343.2; found 344.2; Rt = 0.586 min. 3FFF. 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazole [ka] Step 1: Synthesis of 5-bromo-2-(5,5-dimethylpyrrolidin-3-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 1A. Yield: 9.5 g (98.88%). LCMS(ESI):[M] + m / z: calculated 311.2; found 312.2; Rt = 0.949 min. Step 2: Synthesis of 5-bromo-2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazole A 37% w / w aqueous formaldehyde solution (3.47 g, 42.73 mmol, 3.20 mL, 37% purity) stabilized with 7-8% MeOH and acetic acid (3.67 g, 61.05 mmol, 3.49 mL) were added to a stirred solution of 5-bromo-2-(5,5-dimethylpyrrolidin-3-yl)-1,3-benzothiazole (9.5 g, 30.52 mmol) in MeOH (250 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h, then sodium cyanoborohydride (1.92 g, 30.52 mmol) was added in one portion at 25 °C (foam!). The reaction mixture was stirred at 25 °C for 18 h and then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-bromo-2-(1,5,5-trimethylpyrrolidin-3-yl)-1,3-benzothiazole (9.5 g, 29.21 mmol, 95.69% yield) as a light yellow solid, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 2.518 min. Step 3: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 2. Yield: 5.7 g crude. LCMS(ESI):[M] + m / z: calculated 372.2; found 373.2; Rt = 1.171 min. Step 4: Synthesis of (3S)-tert-butyl 3-methyl-6-(2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 16.5 g crude. LCMS(ESI):[M] + m / z: calculated 441.2; found 442.2; Rt = 1.289 min. Step 5: Synthesis of 5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 4.7 g crude. LCMS(ESI):[M] + m / z: calculated 341.2; found 342.2; Rt = 0.635 min. Step 6: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1,5,5-trimethylpyrrolidin-3-yl)benzo[d]thiazole Sodium borohydride (780.94 mg, 20.64 mmol, 727.13 μL) was added in one portion to a stirred solution of 5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-2-(1,5,5-trimethylpyrrolidin-3-yl)-1,3-benzothiazole (4.7 g, 13.76 mmol) in MeOH (60 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then concentrated in vacuo. The residue was diluted with water (25 ml) and extracted with DCM (2*50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-[(2R,5S)-5-methyl-2-piperidyl]-2-(1,5,5-trimethylpyrrolidin-3-yl)-1,3-benzothiazole (4 g, 11.64 mmol, 84.61% yield) as a light brown gum, which was used directly in the next step. Further purification of 1 g of the crude amine by reverse-phase HPLC (Column: XBridge C18 100 × 19 mm, 5 μm; Mobile phase: 35-60% 0-5 min HO / MeCN / 0.1% NH4OH, Flow rate: 30 ml / min (Loading pump 4 ml / min MeCN)) afforded pure 5-[(2R,5S)-5-methyl-2-piperidyl]-2-(1,5,5-trimethylpyrrolidin-3-yl)-1,3-benzothiazole (530 mg, 1.54 mmol, 11.21% yield) as a red gum. LCMS(ESI):[M] + m / z: calculated 343.2; found 344.2; Rt = 0.789 min. 3GGG.(S)-N,N-Dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine [ka] Step 1: Synthesis of (2R,5S)-allyl 2-(2-((S)-2-((tert-butoxycarbonyl)amino)propyl)benzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylate Allyl (2R,5S)-2-(3-amino-4-sulfanyl-phenyl)-5-methyl-piperidine-1-carboxylate (2.3 g, 7.51 mmol) and tert-butyl N-[(1S)-1-methyl-3-oxo-propyl]carbamate (1.6 g, 8.55 mmol) were mixed together in DMSO (20 mL) under an argon atmosphere, and the resulting solution was heated at 90 °C for 16 h. Upon completion, the reaction mixture was quenched with ethyl acetate (30 mL). The organic phase was extracted with brine (3 * 30 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The desired product, allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (3.5 g, 7.39 mmol, 98.45% yield), was isolated. LCMS(ESI):[M] + m / z: calculated 473.2; found 474.2; Rt = 1.540 min. Step 2: Synthesis of (2R,5S)-allyl 2-(2-((S)-2-aminopropyl)benzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylate Allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (3.50 g, 7.39 mmol) was stirred in MeOH (30 mL) and dioxane / HCl (15 mL) at 25 °C for 16 h. Upon completion, the reaction mixture was evaporated and the crude product was quenched with water (20 mL) and neutralized to pH = 8 with NaHCO. The aqueous phase was extracted with CHCl (2 * 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The desired product, allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-aminopropyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (2.5 g, 6.69 mmol, 90.57% yield), was isolated. LCMS(ESI):[M] + m / z: calculated 373.2; found 374.2; Rt = 1.146 min. Step 3: Synthesis of (2R,5S)-allyl 2-(2-((S)-2-(dimethylamino)propyl)benzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylate Allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-aminopropyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (2.5 g, 6.69 mmol) and 37% w / w aqueous formaldehyde solution (5.42 g, 180.32 mmol, 5 mL) stabilized with 7-8% MeOH were mixed together in MeOH (50 mL), and the resulting solution was cooled to 5 °C in an ice bath. Sodium cyanoborohydride (2.10 g, 33.47 mmol) was added to the previous solution, and the resulting mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was evaporated, and the crude product was quenched with water (30 mL). The aqueous phase was extracted with CHCl (2 * 30 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The desired product, allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-(dimethylamino)propyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (2.5 g, 6.23 mmol, 93.01% yield), was isolated. LCMS(ESI):[M] + m / z: calculated 401.2; found 402.2; Rt = 0.991 min. Step 4: Synthesis of (S)-N,N-dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine To a stirred solution of allyl (2R,5S)-5-methyl-2-[2-[(2S)-2-(dimethylamino)propyl]-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (2.5 g, 6.23 mmol) and morpholine (1.10 g, 12.58 mmol, 1.1 mL) in DCM (25 mL) was added palladium(0) tetrakis(triphenylphosphine) (0.3 g, 259.61 μmol). The resulting suspension was degassed with argon at 25 °C for 0.5 h. The reaction mixture was stirred at 25 °C for 6 h. Upon completion, the reaction mixture was extracted with water (2 * 25 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The desired product (2S)-N,N-dimethyl-1-[5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazol-2-yl]propan-2-amine (1.9 g, 5.98 mmol, 96.13% yield) was isolated. LCMS(ESI):[M] + m / z: calculated 317.2; found 318.2; Rt = 0.501 min. 3HHH.N,N,2-trimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine [ka] Step 1: Synthesis of tert-butyl (1-(5-bromobenzo[d]thiazol-2-yl)-2-methylpropan-2-yl)carbamate Prepared by general procedure Scheme 4.1 Step 1B. Yield: 6.14 g (76.66%). LCMS(ESI):[M-Boc] + m / z: calculated 285.2; found 286.2; Rt = 0.668 min. Step 2: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-2-methylpropan-2-amine tert-Butyl N-[2-(5-bromo-1,3-benzothiazol-2-yl)-1,1-dimethyl-ethyl]carbamate (6.14 g, 15.93 mmol) was dissolved in DCM (20 mL) and TFA (20 mL) was added. The mixture was stirred at 25 °C for 1 hour. It was then evaporated, dissolved in water, and Na2CO3 was added. The mixture was extracted twice with DCM, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give 1-(5-bromo-1,3-benzothiazol-2-yl)-2-methyl-propan-2-amine (4.5 g, 15.78 mmol, 99.02% yield). LCMS(ESI):[M] + m / z: calculated 285.2; found 286.2; Rt = 1.010 min. Step 3: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-N,N,2-trimethylpropan-2-amine 1-(5-Bromo-1,3-benzothiazol-2-yl)-2-methyl-propan-2-amine (4.5 g, 15.78 mmol) was dissolved in MeOH (40.46 mL) and ACS stabilized with 10-15% MeOH, 37% formaldehyde in 36.5-38.0% water (5.69 g, 189.34 mmol, 5.25 mL), sodium cyanoborohydride (2.97 g, 47.33 mmol), and acetic acid (3.79 g, 63.11 mmol, 3.61 mL) were added. The reaction was stirred at 25 °C for 12 h. The reaction mixture was evaporated. Then H2O was added, it was extracted twice with DCM, the combined organic phases were dried over Na2SO4 and evaporated to give 1-(5-bromo-1,3-benzothiazol-2-yl)-N,N,2-trimethyl-propan-2-amine (4.2 g, 13.41 mmol, 84.98% yield). LCMS(ESI):[M] + m / z: calculated 313.2; found 314.2; Rt = 1.034 min. Step 4: Synthesis of N,N,2-trimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-amine Prepared by general procedure Scheme 4.1 Step 2. Yield: 4.37 g crude. LCMS(ESI):[M] + m / z: calculated 360.2; found 361.2; Rt = 1.001 min. Step 5: Synthesis of (S)-tert-butyl 6-(2-(2-(dimethylamino)-2-methylpropyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 7 g crude. LCMS(ESI):[M] + m / z: calculated 429.2; found 430.2; Rt = 1.040 min. Step 6: Synthesis of (S)-N,N,2-trimethyl-1-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine tert-Butyl (3S)-6-[2-[2-(dimethylamino)-2-methyl-propyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate (7 g, 16.29 mmol) was dissolved in DCM (20 mL) and TFA (20 mL) was added. The mixture was stirred at 25 °C for 1 hour. It was then evaporated, dissolved in water, and filtered. Na2CO3 was added to the filtrate. The mixture was extracted twice with DCM, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give N,N,2-trimethyl-1-[5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazol-2-yl]propan-2-amine (2.05 g, crude). LCMS(ESI):[M] + m / z: calculated 329.2; found 330.2; Rt = 0.481 min. Step 7: Synthesis of N,N,2-trimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine Prepared by general procedure Scheme 4.1 Step 5. Yield: 1.14 g crude. LCMS(ESI):[M] + m / z: calculated 331.2; found 332.2; Rt = 0.737 min. 3III. 2-((1,3-dimethylpiperidin-4-yl)methyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of (E)-ethyl 2-(1,3-dimethylpiperidin-4-ylidene)acetate To a stirred solution of sodium hydride (in oil dispersion) 60% dispersion in mineral oil (1.90 g, 82.56 mmol) in THF (300 mL), ethyl 2-(diethoxyphosphoryl)acetate (19.39 g, 86.49 mmol, 17.24 mL) was added dropwise, followed by a THF solution of 1,3-dimethylpiperidin-4-one (10 g, 78.63 mmol) after 1 hour. The resulting reaction mixture was stirred at 25 °C for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. It was then extracted with MTBE / water (150 mL / 30 mL), and the organic layer was dried over Na SO and evaporated. The desired product, ethyl (2E)-2-(1,3-dimethyl-4-piperidylidene)acetate (13.5 g, 68.43 mmol, 87.04% yield), was isolated as a yellow liquid. 1 H NMR (500 MHz, CDCl3) δ (ppm) 1.07 (d, 3H), 1.25 (t, 3H), 1.90 (m, 1H), 2.01 (m, 1H), 2.21 (s, 3H), 2.48 (m, 2H), 2.73 (m, 2H), 3.54 (m, 1H), 4.14 (m, 2H), 5.60 (s, 1H). Step 2: Synthesis of ethyl 2-(1,3-dimethylpiperidin-4-yl)acetate To a stirred solution of ethyl (2E)-2-(1,3-dimethyl-4-piperidylidene)acetate (6 g, 30.41 mmol) in MeOH (50 mL) was added 10% palladium on carbon (0.5 g, 4.70 mmol) at 25° C. The resulting reaction mixture was evacuated and stirred under hydrogen (61.31 mg, 30.41 mmol) at 25° C. for 16 hours. The reaction mixture was filtered and concentrated in vacuo to give ethyl 2-(1,3-dimethyl-4-piperidyl)acetate (5.48 g, crude). GCMS: [M]: Calculated 199.2; Found 199.2; Rt = 6.739 min. Step 3: Synthesis of potassium 2-(1,3-dimethylpiperidin-4-yl)acetate To a stirred solution of ethyl 2-(1,3-dimethyl-4-piperidyl)acetate (5.48 g, 27.50 mmol) in MeOH (40.04 mL) was added potassium hydroxide (2.31 g, 41.25 mmol, 1.13 mL) at 25° C. The resulting reaction mixture was stirred at 25° C. for 12 h and then concentrated in vacuo to give potassium 2-(1,3-dimethyl-4-piperidyl)acetate (8 g, crude). GCMS: [M]: Calculated 209.2; Found 209.2; Rt = 2.211 min. Step 4: Synthesis of 5-bromo-2-((1,3-dimethylpiperidin-4-yl)methyl)benzo[d]thiazole To stirred H3PO4 (27.75 g, 240.70 mmol, 15 mL, 85% purity) was added PO5 (4.5 g, 31.70 mmol) at 60 °C and then heated to 120 °C. The resulting reaction mixture was stirred at 120 °C for 30 min, then potassium 2-(1,3-dimethyl-4-piperidyl)acetate (7.5 g, 21.50 mmol), and 2-amino-4-bromobenzenethiol (4.39 g, 21.50 mmol) were added and stirred overnight. Upon completion, the reaction mixture was cooled to room temperature. A solution of ice-cold NaOH was then added to quench the reaction until pH = 14. The desired product was extracted with EtOAc. The organic layer was washed twice with water, dried over Na2SO4 and evaporated to give 5-bromo-2-[(1,3-dimethyl-4-piperidyl)methyl]-1,3-benzothiazole (5.5 g, crude). LCMS(ESI):[M] + m / z: calculated 339.2; found 340.2; Rt = 0.933 min. Step 5: Synthesis of 2-((1,3-dimethylpiperidin-4-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 3.8 g crude. LCMS(ESI):[M] + m / z: calculated 386.2; found 387.2; Rt = 1.010 min. Step 6: Synthesis of (3S)-tert-butyl 6-(2-((1,3-dimethylpiperidin-4-yl)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 3.8 g crude. LCMS(ESI):[M] + m / z: calculated 455.2; found 456.2; Rt = 1.171 min. Step 7: Synthesis of 2-((1,3-dimethylpiperidin-4-yl)methyl)-5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole To a solution of tert-butyl (3S)-6-[2-[(1,3-dimethyl-4-piperidyl)methyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate (3.8 g, 4.17 mmol) in DCM (10 mL) was added TFA (15 g, 131.55 mmol, 10.14 mL), followed by stirring at 20 °C for 6 h. The reaction mixture was concentrated in vacuo and treated with water and DCM. The aqueous layer was washed twice with DCM. An aqueous solution of NaHCO was added to the basic pH of the solution, and the desired product was extracted with DCM (2 * 50 ml). The organic layer was dried over Na2SO4 and then concentrated in vacuo to give 2-[(1,3-dimethyl-4-piperidyl)methyl]-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole (0.8 g, crude). LCMS(ESI):[M] + m / z: calculated 355.2; found 356.2; Rt = 0.542 min. Step 8: Synthesis of 2-((1,3-dimethylpiperidin-4-yl)methyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 5. Yield: 0.51 g crude. LCMS(ESI):[M] + m / z: calculated 357.2; found 358.2; Rt = 0.484 min. Step 9: Synthesis of 2-((2R,5S)-2-(2-((1,3-dimethylpiperidin-4-yl)methyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxo-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)acetamide Prepared by general procedure Scheme 4.1, Step 6B. Yield: 84.9 mg (26.42%). HPLC conditions: Column: SunFire C18 100*19mm, 5 micrometers; 2-10 min 30-65% MeOH; (loading pump 4ml / min MeOH). LCMS(ESI):[M] + m / z: calculated 675.2; found 676.2; Rt = 3.129 min. 3JJJ. 2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of tert-butyl 4-(5-chlorobenzo[d]thiazol-2-yl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate Sodium carbonate (19.48 g, 183.75 mmol, 7.69 mL) was added to a solution of 2,5-dichloro-1,3-benzothiazole (15 g, 73.50 mmol) and tert-butyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (23.76 g, 73.50 mmol) in dioxane (200 mL) and water (65 mL). The reaction flask was evacuated and refilled with argon three times. Pd(dppf)Cl*DCM (3.00 g, 3.68 mmol) was then added under a stream of argon. The resulting mixture was stirred at 95 °C for 15 hours under an inert atmosphere. The reaction solution was decanted and concentrated under reduced pressure to give the crude product, which was diluted with MTBE (300 mL). The resulting cloudy solution was decanted from the oily residue. MTBE was evaporated in vacuo to give tert-butyl 4-(5-chloro-1,3-benzothiazol-2-yl)-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (18 g, 49.33 mmol, 67.11% yield). LCMS(ESI):[M] + m / z: calculated 364.2; found 365.2; Rt = 1.802 min. Step 2: Synthesis of 5-chloro-2-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole To a stirred solution of tert-butyl 4-(5-chloro-1,3-benzothiazol-2-yl)-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (18 g, 49.33 mmol) in DCM (150 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (80.00 g, 2.19 mol, 100 mL). The resulting mixture was stirred at 25 °C for 14 hours. The solvent was evaporated in vacuo. The residue was diluted with MTBE (200 ml). The solid was filtered, washed with MTBE, and then dried in vacuo to give 5-chloro-2-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-benzothiazole (8.5 g, 28.22 mmol, 57.20% yield, HCl). 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 2.12 (s, 3H), 2.85 (m, 2H), 3.26 (m, 2H), 3.75 (m, 2H), 7.49 (d, 1H), 8.08 (s, 1H), 8.16 (d, 1H), 9.73 (bds, 2H). Step 3: Synthesis of 5-chloro-2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole To a stirred solution of 5-chloro-2-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-benzothiazole (8.5 g, 28.22 mmol, HCl) in MeOH (300 mL) was added 37% w / w aqueous formaldehyde (3.43 g, 42.33 mmol, 3.17 mL, 37% purity) stabilized with 7-8% MeOH, and anhydrous sodium acetate (5.79 g, 70.54 mmol, 3.79 mL). The resulting mixture was stirred at 25 °C for 2 h. Sodium cyanoborohydride (1.95 g, 31.04 mmol) was then added portionwise. The resulting mixture was stirred at 25 °C for 12 h. MeOH was evaporated. The residue was diluted with 10% aqueous sodium hydroxide (150 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-chloro-2-(1,5-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazole (6.1 g, 21.88 mmol, 77.54% yield). LCMS(ESI):[M] + m / z: calculated 278.2; found 279.2; Rt = 1.006 min. Step 4: Synthesis of 2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 5-Chloro-2-(1,5-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazole (6.2 g, 22.24 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.65 g, 22.24 mmol), and potassium acetate (4.37 g, 44.48 mmol, 2.78 mL) were mixed in dioxane (70 mL). The resulting mixture was evacuated and then backfilled with argon; this procedure was repeated three times. Then, tris(dibenzylideneacetone)dipalladium(0) (1.02 g, 1.11 mmol) and XPhos (1.06 g, 2.22 mmol) were added under argon. The reaction mixture was stirred under argon at 90°C for 15 hours. The reaction mixture was cooled and filtered. The filter cake was washed with dioxane (2 * 10 ml) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with MTBE (100 ml) and extracted with aqueous NaHSO4 (30 ml) (repeated three times). The combined aqueous layers were basified to pH 10 with 10% aqueous sodium hydroxide to give an aqueous solution of 2-(1,5-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (8 g, 21.60 mmol, 97.14% yield), which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 370.2; found 371.2; Rt = 1.178 min. Step 5: Synthesis of (S)-tert-butyl 6-(2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1 step 3. Yield: 6 g crude. LCMS(ESI):[M] + m / z: calculated 439.2; found 440.2; Rt = 1.141 min. Step 6: Synthesis of (S)-2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole tert-Butyl (3S)-6-[2-(1,5-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate (6 g, 13.65 mmol) was diluted with TFA (88.80 g, 778.79 mmol, 60.00 mL). The resulting mixture was stirred at 25 °C for 1.5 h. TFA was evaporated in vacuo. The residue was diluted with water (150 mL). The resulting cloudy solution was decanted from the oily residue and then basified with NaHCO3. The product was extracted with DCM (3 * 50 ml). The combined organic layers were dried over Na2SO4. The DCM was evaporated in vacuo to give 2-(1,5-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole (3.2 g, 9.43 mmol, 69.06% yield). LCMS(ESI):[M] + m / z: calculated 339.2; found 340.2; Rt = 0.583 min. Step 7: Synthesis of 2-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 5. Yield: 2.3 g crude. LCMS(ESI):[M] + m / z: calculated 341.2; found 342.2; Rt = 0.628 min. 3JJJ. 2-(rac-(3S,4R)-3-methoxy-1-methylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of rac-(3S,4R)-tert-butyl 4-(5-bromobenzo[d]thiazol-2-yl)-3-methoxypiperidine-1-carboxylate Oxalyl chloride (1.08 g, 8.48 mmol, 740.16 μL) was added in one portion to a stirred slurry of 1-tert-butoxycarbonyl-3-methoxy-piperidine-4-carboxylic acid (2 g, 7.71 mmol) in CHCl (60 mL). After several minutes, DMF (0.1 mL) (catalytic amount) was added, and the resulting mixture was stirred at 25 °C until a clear solution formed and the evolution of gaseous products ceased (approximately 1 h). 2-Amino-4-bromo-benzenethiol (1.57 g, 7.71 mmol) was then added in one portion under argon. The resulting slurry was vigorously stirred at 25 °C for 18 h, and the resulting heavy slurry was neutralized with 10% aqueous sodium carbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to give 2.2 g of crude product (50% purity by LCMS), which was purified by column chromatography on silica using a hexane / MTBE gradient (0-17% MTBE) to give tert-butyl rac-(3S,4R)-4-(5-bromo-1,3-benzothiazol-2-yl)-3-methoxy-piperidine-1-carboxylate (1 g, 2.34 mmol, 30.34% yield) as a bright yellow solid. LCMS(ESI):[M] + m / z: calculated 427.2; found 428.2; Rt = 1.652 min. Step 2: Synthesis of rac-5-bromo-2-((3S,4R)-3-methoxypiperidin-4-yl)benzo[d]thiazole TFA (7.40 g, 64.90 mmol, 5 mL) was added in one portion to a stirred solution of tert-butyl rac-(3S,4R)-4-(5-bromo-1,3-benzothiazol-2-yl)-3-methoxy-piperidine-1-carboxylate (1 g, 2.34 mmol) in DCM (5 mL). The resulting solution was stirred at 25 °C for 0.5 h and then concentrated in vacuo. The residue was diluted with water (10 ml), basified to pH 10-11 with 10% aqueous sodium carbonate, and then extracted with DCM (2 * 15 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 5-bromo-2-[rac-(3S,4R)-3-methoxy-4-piperidyl]-1,3-benzothiazole (650 mg, 1.99 mmol, 84.89% yield) as a bright yellow gum, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 327.2; found 328.2; Rt = 0.975 min. Step 3: Synthesis of rac-5-bromo-2-((3S,4R)-3-methoxy-1-methylpiperidin-4-yl)benzo[d]thiazole 37% w / w aqueous formaldehyde (241.82 mg, 2.98 mmol, 223.29 μL, 37% purity) stabilized with 7-8% MeOH, and acetic acid (238.56 mg, 3.97 mmol, 227.41 μL) were added to a stirred solution of 5-bromo-2-[rac-(3S,4R)-3-methoxy-4-piperidyl]-1,3-benzothiazole (650 mg, 1.99 mmol) in MeOH (20 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h, then sodium cyanoborohydride (149.78 mg, 2.38 mmol) was added in one portion at 25 °C (foam!). The reaction mixture was stirred at 25 °C for 18 h and then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide (50 ml) and extracted with DCM (2 * 30 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-bromo-2-[rac-(3S,4R)-3-methoxy-1-methyl-4-piperidyl]-1,3-benzothiazole (600 mg, 1.76 mmol, 88.51% yield) as a light brown gum, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 341.2; found 342.2; Rt = 0.750 min. Step 4: Synthesis of rac-2-((3S,4R)-3-methoxy-1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 2. Yield: 680 mg crude. LCMS(ESI):[M] + m / z: calculated 388.2; found 389.2; Rt = 1.018 min. Step 5: Synthesis of (S)-tert-butyl 6-(2-(rac-(3S,4R)-3-methoxy-1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 1.5 g crude. LCMS(ESI):[M]+ m / z: calculated 457.2; found 458.2; Rt = 1.241 min. Step 6: Synthesis of 2-(rac-(3S,4R)-3-methoxy-1-methylpiperidin-4-yl)-5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 0.4 g crude. LCMS(ESI):[M] + m / z: calculated 357.2; found 358.2; Rt = 0.668 min. Step 7: Synthesis of 2-(rac-(3S,4R)-3-methoxy-1-methylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 5. Yield: 340 mg crude. LCMS(ESI):[M] + m / z: calculated 359.2; found 360.2; Rt = 0.721 min. 3JJJ. 2-(1,4-dimethylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of 5-chloro-2-(1,4-dimethylpiperidin-4-yl)benzo[d]thiazolamine Prepared by general procedure Scheme 4.1 Step 1A. Yield: 3 g (41.38%). CC conditions: The crude product was purified on silica gel using MeCN / MeOH (gradient 10-100% MeOH) as the eluent mixture. LCMS(ESI):[M] + m / z: calculated 280.2; found 281.2; Rt = 1.529 min. Step 2: Synthesis of 2-(1,4-dimethylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Tris(dibenzylideneacetone)dipalladium(0) (652.18 mg, 712.21 μmol) and XPhos (1.36 g, 2.85 mmol) were added to a solution of 5-chloro-2-(1,4-dimethyl-4-piperidyl)-1,3-benzothiazole (4 g, 14.24 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.70 g, 18.52 mmol) in dioxane (60.00 mL). The reaction flask was evacuated and refilled with argon three times. Potassium acetate (2.80 g, 28.49 mmol, 1.78 mL) was then added under a stream of argon. The resulting mixture was stirred at 100°C under an inert atmosphere for 15 hours, then cooled, evaporated in vacuo, poured into water (120ml), extracted with DCM (2x50ml), dried over sodium sulfate and evaporated in vacuo to give 2-(1,4-dimethyl-4-piperidyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (0.9g, 2.42mmol, 16.97% yield). LCMS(ESI):[M] + m / z: calculated 372.2; found 373.2; Rt = 3.119 min. Step 3: Synthesis of (S)-tert-butyl 6-(2-(1,4-dimethylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 1.3 g crude. LCMS(ESI):[M] + m / z: calculated 441.2; found 442.2; Rt = 1.289 min. Step 4: Synthesis of (S)-2-(1,4-dimethylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 0.7 g crude. LCMS(ESI):[M]+ m / z: calculated 341.2; found 342.2; Rt = 0.724 min. Step 5: Synthesis of 2-(1,4-dimethylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 step 5. Yield: 0.55 g crude. LCMS(ESI):[M] + m / z: calculated 343.2; found 344.2; Rt = 1.772 min. 3KKK. 2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-bromobenzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 1A. Yield: 3.5 g (92.4%). LCMS(ESI):[M] + m / z: calculated 309.2; found 310.2; Rt = 0.961 min. Step 2: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 4 g crude. LCMS(ESI):[M] + m / z: calculated 356.2; found 357.2; Rt = 1.025 min. Step 3: Synthesis of (S)-tert-butyl 6-(2-(1-azabicyclo[2.2.1]heptan-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 8 g crude. LCMS(ESI):[M] + m / z: calculated 425.2; found 426.2; Rt = 1.254 min. Step 4: Synthesis of (S)-2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 4. Yield: 6 g crude. LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 0.683 min. Step 5: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 step 5. Yield: 2 g crude. LCMS(ESI):[M] + m / z: calculated 327.2; found 328.2; Rt = 0.709 min. 3LLL.N,N-Dimethyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)cyclobutanamine [ka] Step 1: Synthesis of tert-butyl (3-(5-bromobenzo[d]thiazol-2-yl)cyclobutyl)carbamate Prepared by general procedure Scheme 4.1 Step 1B. Yield: 5 g (53.24%). LCMS(ESI):[M] + m / z: calculated 383.2; found 384.2; Rt = 1.402 min. Step 2: Synthesis of 3-(5-bromobenzo[d]thiazol-2-yl)cyclobutanamine tert-Butyl N-[3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutyl]carbamate (5 g, 13.04 mmol) was treated with a 4.0 M solution of hydrogen chloride in dioxane (24.00 g, 658.26 mmol, 30 mL). The resulting mixture was stirred at 25 °C for 14 hours. The precipitate was filtered and further washed with MTBE. It was then dried in vacuo to give 3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutanamine (4 g, 12.51 mmol, 95.93% yield, HCl). LCMS(ESI):[M] + m / z: calculated 284.2; found 285.2; Rt = 0.931 min. Step 3: Synthesis of 3-(5-bromobenzo[d]thiazol-2-yl)-N,N-dimethylcyclobutanamine To a stirred solution of 3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutanamine (4 g, 12.51 mmol, HCl) in MeOH (71.00 mL) was added 37% w / w aqueous formaldehyde (2.54 g, 31.28 mmol, 2.34 mL, 37% purity) stabilized with 7-8% MeOH, and anhydrous sodium acetate (2.57 g, 31.28 mmol, 1.68 mL). The resulting mixture was stirred at 25 °C for 2 h. Sodium cyanoborohydride (1.57 g, 25.03 mmol) was then added portionwise. The resulting mixture was stirred at 25 °C for 12 h. MeOH was evaporated. The residue was diluted with water (100 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were dried over Na2SO4. The DCM was evaporated in vacuo to give 3-(5-bromo-1,3-benzothiazol-2-yl)-N,N-dimethyl-cyclobutanamine (3.9 g, crude). LCMS(ESI):[M] + m / z: calculated 311.2; found 312.2; Rt = 0.829 min. Step 4: Synthesis of N,N-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclobutanamine Prepared by general procedure Scheme 4.1 Step 2. Yield: 4 g crude. LCMS(ESI):[M] + m / z: calculated 358.2; found 359.2; Rt = 1.029 min. Step 5: Synthesis of (S)-tert-butyl 6-(2-(3-(dimethylamino)cyclobutyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 7 g crude. LCMS(ESI):[M] + m / z: calculated 427.2; found 428.2; Rt = 1.057 min. Step 6: Synthesis of (S)-N,N-dimethyl-3-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)cyclobutanamine Prepared by general procedure Scheme 4.1 Step 4. Yield: 3 g crude. LCMS(ESI):[M] + m / z: calculated 327.2; found 328.2; Rt = 0.635 min. Step 7: Synthesis of N,N-dimethyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)cyclobutanamine Prepared by general procedure Scheme 4.1, step 5. Yield: 80 mg (2.65%). HPLC conditions: Column: Chromatorex C18 100*19mm, 5 micrometers; 0-1-6 min 45-45-85% water-MeOH, flow rate: 30 ml / min; (loading pump 4 ml / min MeOH). LCMS(ESI):[M] + m / z: calculated 329.2; found 330.2; Rt = 1.324 min. 3MMM. 2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of tert-butyl 4-(5-bromobenzo[d]thiazol-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate Prepared by general procedure Scheme 4.1 Step 1B. Yield: 2.82 g (79.7%). LCMS(ESI):[M] + m / z: calculated 423.2; found 424.2; Rt = 1.572 min. Step 2: Synthesis of 2-(2-azabicyclo[2.2.2]octan-4-yl)-5-bromobenzo[d]thiazole TFA (7.56 g, 66.29 mmol, 5.11 mL) was added to a solution of tert-butyl 4-(5-bromo-3a,7a-dihydro-1,3-benzothiazol-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (2.82 g, 6.63 mmol) in DCM (20 mL). The resulting mixture was stirred at 20 °C for 4 h. The volatiles were then removed under reduced pressure to leave 2-(2-azabicyclo[2.2.2]octan-4-yl)-5-bromo-1,3-benzothiazole (3 g, crude, TFA). LCMS(ESI):[M] + m / z: calculated 323.2; found 324.2; Rt = 1.025 min. Step 3: Synthesis of 5-bromo-2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)benzo[d]thiazole A 37% w / w aqueous formaldehyde solution (1.12 g, 13.75 mmol, 1.03 mL, 37% purity) stabilized with 7–8% MeOH and sodium acetate (1.69 g, 20.63 mmol, 1.11 mL) were added to a solution of 2-(2-azabicyclo[2.2.2]octan-4-yl)-5-bromo-1,3-benzothiazole (3 g, 6.88 mmol, TFA) in MeOH (50 mL). The resulting mixture was stirred at 20 °C for 1 h, followed by the addition of sodium cyanoborohydride (864.27 mg, 13.75 mmol). Stirring was then continued for 18 h. The solvent was then removed under reduced pressure, and the residue was partitioned between 15% aqueous KCO (30 mL) and DCM (50 mL). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to give 5-bromo-2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)-1,3-benzothiazole (2.37 g, crude). LCMS(ESI):[M] + m / z: calculated 337.2; found 338.2; Rt = 1.026 min. Step 4: Synthesis of 2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 2.95 g crude. LCMS(ESI):[M] + m / z: calculated 384.2; found 385.2; Rt = 1.183 min. Step 5: Synthesis of (S)-tert-butyl 3-methyl-6-(2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 4.14 g crude. LCMS(ESI):[M] + m / z: calculated 453.2; found 454.2; Rt = 1.189 min. Step 6: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 1.98 g crude. LCMS(ESI):[M] + m / z: calculated 353.2; found 354.2; Rt = 0.723 min. Step 7: Synthesis of 2-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 5. Yield: 1.71 g (85.87%). LCMS(ESI):[M] + m / z: calculated 355.2; found 356.2; Rt = 0.781 min. 3NNN, 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of 5-bromo-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 1A. Yield: 2.5 g crude. LCMS(ESI):[M] + m / z: calculated 295.2; found 296.2; Rt = 0.961 min. Step 2: Synthesis of 5-bromo-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole A 37% w / w aqueous solution of formaldehyde (1.03 g, 12.70 mmol, 952.01 μL, 37% purity) stabilized with 7-8% MeOH, and acetic acid (1.02 g, 16.94 mmol, 969.60 μL) were added to a stirred solution of 5-bromo-2-(1,2,3,6-tetrahydropyridin-4-yl)-1,3-benzothiazole (2.5 g, 8.47 mmol) in MeOH (100 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h, then sodium cyanoborohydride (638.62 mg, 10.16 mmol) was added in one portion at 25 °C (foam!). The reaction mixture was stirred at 25 °C for 18 h and then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide (70 ml) and extracted with DCM (2 * 60 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-bromo-2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazole (2.5 g, 8.08 mmol, 95.46% yield) as a light brown gum, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 309.2; found 310.2; Rt = 2.242 min. Step 3: Synthesis of 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 2.88 g crude. LCMS(ESI):[M] + m / z: calculated 356.2; found 357.2; Rt = 1.131 min. Step 4: Synthesis of (S)-tert-butyl 3-methyl-6-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 7 g crude. LCMS(ESI):[M] +m / z: calculated 425.2; found 426.2; Rt = 1.236 min. Step 5: Synthesis of (S)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole TFA (29.60 g, 259.60 mmol, 20 mL) was added in one portion to a stirred solution of tert-butyl (3S)-3-methyl-6-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine-1-carboxylate (7 g, 16.45 mmol) in DCM (20 mL). The resulting solution was stirred at 25 °C for 0.5 h and then concentrated in vacuo. The residue was diluted with water (100 mL). The resulting solution of the TFA salt of the product was decanted from the dark brown oily residue, which was further rinsed with water (2 * 25 mL). The combined aqueous solution was filtered through a cotton pad to remove traces of oily impurities, then basified to pH 11-12 with 10% aqueous sodium hydroxide and extracted with DCM (2 * 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole (2.7 g, 8.30 mmol, 50.44% yield) as a brown solid, which was used directly in the next step. LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 0.673 min. Step 6: Synthesis of 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 step 5. Yield: 1.4 g crude. LCMS(ESI):[M] + m / z: calculated 327.2; found 328.2; Rt = 0.719 min. 3OOO.2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of (3aR,5s,6aS)-tert-butyl 5-(5-bromobenzo[d]thiazol-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Triphenylphosphine (6.17 g, 23.52 mmol) was added in one portion to a solution of (3aR,6aS)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-carboxylic acid (2.50 g, 9.80 mmol), 2-amino-4-bromo-benzenethiol (2 g, 9.80 mmol), carbon tetrachloride (8.74 g, 56.84 mmol), and triethanolamine (TEA) (4.96 g, 49.00 mmol, 6.83 mL). The resulting reaction mixture was briefly warmed to approximately 50–60 °C due to an exothermic reaction. It was then stirred at 20 °C for 18 h. The volatiles were then removed under reduced pressure, and the residue was triturated with MTBE (100 mL). The resulting light precipitate was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by gradient column chromatography (SiO, hexane / MTBE) to give tert-butyl 5-(5-bromo-1,3-benzothiazol-2-yl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (1.55 g, 3.66 mmol, 37.36% yield). LCMS(ESI):[Mt-Bu] + m / z: calculated 367.2; found 368.2; Rt = 1.737 min. Step 2: Synthesis of 5-bromo-2-((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole TFA (4.17 g, 36.61 mmol, 2.82 mL) was added to a solution of tert-butyl 5-(5-bromo-1,3-benzothiazol-2-yl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (1.55 g, 3.66 mmol) in DCM (7.18 mL). The resulting mixture was stirred at 20 °C for 5 h. It was then concentrated under reduced pressure to leave 5-bromo-2-[(3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-1,3-benzothiazole (1.2 g, 2.75 mmol, 75.13% yield, TFA). LCMS(ESI):[M] + m / z: calculated 324.2; found 325.2; Rt = 0.999 min. Step 3: Synthesis of 5-bromo-2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole A 37% w / w aqueous solution of formaldehyde (222.93 mg, 7.42 mmol, 205.85 μL) stabilized with 7-8% MeOH and sodium acetate (609.07 mg, 7.42 mmol, 398.60 μL) were added to a solution of 5-bromo-2-[(3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-1,3-benzothiazole (1.2 g, 3.71 mmol) in MeOH (19.40 mL). The resulting mixture was stirred at 20 °C for 1 h, and then sodium cyanoborohydride (466.58 mg, 7.42 mmol) was added. Stirring was continued for 16 h. The solvent was then removed under reduced pressure, and the residue was partitioned between 15% aqueous K2CO3 (30 mL) and DCM (50 mL). The organic layer was separated, dried over solid K2CO3, and concentrated under reduced pressure to leave 5-bromo-2-[(3aR,6aS)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-1,3-benzothiazole (1.2 g, 3.56 mmol, 95.84% yield). LCMS(ESI):[M] +m / z: calculated 337.2; found 338.2; Rt = 0.918 min. Step 4: Synthesis of (2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazol-5-yl)boronic acid Prepared by general procedure Scheme 4.1 Step 2. Yield: 0.5 g crude. LCMS(ESI):[M] + m / z: calculated 302.2; found 303.2; Rt = 0.618 min. Step 5: Synthesis of (S)-tert-butyl 3-methyl-6-(2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 0.7 g crude. LCMS(ESI):[M] + m / z: calculated 453.2; found 454.2; Rt = 1.152 min. Step 6: Synthesis of 5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 0.5 g crude. LCMS(ESI):[M] + m / z: calculated 353.2; found 354.2; Rt = 0.603 min. Step 7: Synthesis of 2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 step 5. Yield: 0.3 g crude. LCMS(ESI):[M] + m / z: calculated 355.2; found 356.2; Rt = 0.710 min. 3PPP.N,N-dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-1-amine [ka] Step 1: Synthesis of 2-(5-chlorobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-1-amine A stirred solution of 2-amino-4-chloro-benzenethiol (1.5 g, 9.40 mmol) and 2-amino-4-chloro-benzenethiol (1.5 g, 9.40 mmol) in PPA (10 mL) was stirred at 140 °C for 16 h. Upon completion, the reaction mixture was quenched with water (200 mL) and neutralized to pH = 8 with NaOH. The aqueous phase was extracted with EtOAc (2 * 20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The desired product, 2-(5-chloro-1,3-benzothiazol-2-yl)-N,N-dimethyl-propan-1-amine (1.5 g, 5.89 mmol, 62.66% yield), was isolated. LCMS(ESI):[M] + m / z: calculated 254.2; found 255.2; Rt = 0.672 min. Step 2: Synthesis of N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-1-amine To a stirred solution of 2-(5-chloro-1,3-benzothiazol-2-yl)-N,N-dimethyl-propan-1-amine (1.5 g, 5.89 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.50 g, 5.89 mmol) in dioxane (30 mL) was added Pd(dba) (1.08 g, 1.18 mmol) and XPhos (1.12 g, 2.35 mmol). The resulting suspension was degassed with argon at 50 °C for 0.5 h. Potassium acetate (1.2 g, 12.23 mmol, 764.33 μL) was added. The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure, quenched with water (50 mL), and the aqueous phase was extracted with CHCl3 (2 * 50 mL). The organic phase was extracted with 10% HCl (2 * 50 ml). The aqueous phase was neutralized to pH = 8 with NaHCO3 and extracted with CHCl3 (2 * 50 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo. The desired product N,N-dimethyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]propan-1-amine (1.4 g, 4.04 mmol, 68.67% yield) was isolated. LCMS(ESI):[M] + m / z: calculated 346.2; found 347.2; Rt = 1.121 min. Step 3: Synthesis of (3S)-tert-butyl 6-(2-(1-(dimethylamino)propan-2-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 0.7 g crude. LCMS(ESI):[M] + m / z: calculated 415.2; found 416.2; Rt = 1.238 min. Step 4: Synthesis of N,N-dimethyl-2-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)propan-1-amine A stirred solution of tert-butyl (3S)-6-[2-[2-(dimethylamino)-1-methyl-ethyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate (700.00 mg, 1.68 mmol) in MeOH (10 mL) and dioxane / HCl (10 mL) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was evaporated and the crude product was quenched with water (20 mL) and neutralized to pH = 8 with NaHCO. The aqueous phase was extracted with CHCl (2 * 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The desired product N,N-dimethyl-2-[5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazol-2-yl]propan-1-amine (0.5 g, 1.58 mmol, 94.10% yield) was isolated. LCMS(ESI):[M] + m / z: calculated 315.2; found 316.2; Rt = 0.666 min. Step 5: Synthesis of N,N-dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-1-amine Prepared by general procedure Scheme 4.1 step 5. Yield: 0.5 g crude. LCMS(ESI):[M] + m / z: calculated 317.2; found 318.2; Rt = 0.471 min. 3QQQ. Synthesis of 2-(1-azabicyclo[2.2.1]heptan-3-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole (c) [ka] Step 1: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-3-yl)-5-bromobenzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 1A. Yield: 1.4 g crude. LCMS(ESI):[M] +m / z: calculated 308.2; found 309.2; Rt = 0.915 min. Step 2: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 1.8 g crude. LCMS(ESI):[M] + m / z: calculated 356.2; found 357.2; Rt = 1.138 min. Step 3: Synthesis of tert-butyl (3S)-6-(2-(1-azabicyclo[2.2.1]heptan-3-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 1.4 g crude. LCMS(ESI):[M] + m / z: calculated 425.2; found 426.2; Rt = 0.920 min. Step 4: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-3-yl)-5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 4. Yield: 0.6 g crude. LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 0.534 min. Step 5: Synthesis of 2-(1-azabicyclo[2.2.1]heptan-3-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole (c) Prepared by general procedure Scheme 4.1 step 5. Yield: 0.6 g crude. LCMS(ESI):[M] + m / z: calculated 327.2; found 328.2; Rt = 0.700 min. 3RRR.2-(1-methyl-4-piperidyl)-7-[(2R,5S)-5-methyl-2-piperidyl]quinoline [ka] Step 1: 7-Bromo-2-(1-methyl-4-piperidyl)quinoline ( 2-Amino-4-bromo-benzaldehyde (1.3 g, 6.50 mmol), 1-(1-methyl-4-piperidyl)ethanone (917.72 mg, 6.50 mmol), and sodium tert-butoxide (1.25 g, 13.00 mmol) were mixed in ethanol (20 mL) and stirred at 80 °C for 12 h. The RM was concentrated in vacuo, then treated with DCM and washed with water. The organic phase was dried over Na SO and evaporated to give 7-bromo-2-(1-methyl-4-piperidyl)quinoline (1.65 g, crude). LCMS(ESI):[M+1] + m / z: calculated 304.1; found 305; Rt = 0.934 min. Step 2: 2-(1-methyl-4-piperidyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline A mixture of 7-bromo-2-(1-methyl-4-piperidyl)quinoline (1.95 g, 6.39 mmol) (300 mg), bis(pinacolato)diboron (2.11 g, 8.31 mmol), and potassium acetate (1.88 g, 19.17 mmol, 1.20 mL) in dioxane (30.03 mL) was degassed with argon for 10 minutes. Pd(dppf)Cl*DCM (521.75 mg, 638.90 μmol) was then added, and the reaction mixture was heated at 80° C. for 12 hours. The reaction mixture was filtered and then concentrated in vacuo. The residue was treated with a mixture of MTBE-Hex (1:1), filtered, and concentrated under reduced pressure to give 2-(1-methyl-4-piperidyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (3 g, crude). LCMS(ESI):[M+1] + m / z: calculated 352.3; found 353.2; Rt = 1.119 min. Step 3: tert-Butyl (3S)-3-methyl-6-[2-(1-methyl-4-piperidyl)-7-quinolyl]-3,4-dihydro-2H-pyridine-1-carboxylate 2-(1-Methyl-4-piperidyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.8 g, 7.95 mmol), sodium carbonate (2.53 g, 23.84 mmol, 998.15 μL), tert-butyl (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylate (2.74 g, 7.95 mmol), and Pd(dppf)Cl*DCM (0.5 g, 612.75 μmol) were mixed in HO (15 mL) and dioxane (50 mL) under argon and stirred at 75° C. for 12 h. The reaction mixture was diluted with water, and the desired product was extracted with DCM, dried over NaSO, and concentrated in vacuo. tert-Butyl (3S)-3-methyl-6-[2-(1-methyl-4-piperidyl)-7-quinolyl]-3,4-dihydro-2H-pyridine-1-carboxylate (4 g, crude) was obtained. LCMS(ESI):[M+1] + m / z: calculated 421.3; found 422.2; Rt = 1.174 min. Step 4: 2-(1-methyl-4-piperidyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]quinoline tert-Butyl (3S)-3-methyl-6-[2-(1-methyl-4-piperidyl)-7-quinolyl]-3,4-dihydro-2H-pyridine-1-carboxylate (4 g, 9.49 mmol) was dissolved in DCM (40 mL) and CF3COOH (15 g, 9.49 mmol) was added. The RM was stirred for 2 h and then concentrated. The residue was treated twice with MTBE. The black gum was treated with an aqueous solution of NaHCO3 and then extracted with DCM. The organic phase was dried over Na2SO4 and then concentrated in vacuo to give 2-(1-methyl-4-piperidyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]quinoline (1 g, crude). LCMS(ESI):[M+1]+ m / z: calculated 321.2; found 322.2; Rt = 0.682 min. Step 5: 2-(1-methyl-4-piperidyl)-7-[(2R,5S)-5-methyl-2-piperidyl]quinoline To a solution of 2-(1-methyl-4-piperidyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]quinoline (1 g, 2.49 mmol) in methanol (30 mL) was added sodium borohydride (188.30 mg, 4.98 mmol, 175.33 μL) and stirred overnight. The RM was concentrated in vacuo, then treated with DCM, filtered, and evaporated to give 2-(1-methyl-4-piperidyl)-7-[(2R,5S)-5-methyl-2-piperidyl]quinoline (0.75 g, crude). LCMS(ESI):[M+1] + m / z: calculated 323.2; found 324.2; Rt = 0.705 min. 3SSS. 2-((1,4-dimethylpiperidin-4-yl)methyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole [ka] Step 1: Synthesis of tert-butyl 4-methyl-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)-4-methyl-piperidine-1-carboxylate (8.97 g, 35.20 mmol), TEA (4.27 g, 42.25 mmol, 5.89 mL) in DCM (17.21 mL) was added methanesulfonyl chloride (4.44 g, 38.73 mmol, 3.00 mL) portionwise at 0° C. and warmed to room temperature. The resulting solution was washed with 10% aqueous HCl and brine, dried over NaSO, and evaporated to dryness to give tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (9 g, 29.28 mmol, 83.16% yield) as a brownish gum. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.05 (s, 3H), 1.34 (m, 2H), 1.43 (s, 9H), 1.48 (m, 2H), 2.99 (s, 3H), 3.14 (m, 2H), 3.66 (m, 2H), 3.94 (s, 2H). Step 2: Synthesis of tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate To a solution of tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (10 g, 32.53 mmol) in DMSO (75 mL) was added potassium cyanide (8.47 g, 130.12 mmol) and the resulting mixture was heated at 130° C. for 12 h. The resulting mixture was poured into water and extracted with EtOAc (3×100 mL) and the combined organics were washed with water, brine, dried and evaporated to give tert-butyl 4-(cyanomethyl)-4-methyl-piperidine-1-carboxylate (7.3 g, crude) as a yellow gum. 1 H NMR (500 MHz, CDCl3) δ (ppm) 1.14 (s, 3H), 1.44 (s, 9H), 1.46 (m, 4H), 2.29 (s, 2H), 3.22 (m, 2H), 3.57 (m, 2H). Step 3: Synthesis of tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(cyanomethyl)-4-methyl-piperidine-1-carboxylate (6.93 g, 29.08 mmol) in DCM (250 mL) was slowly added DIBAL (10.34 g, 72.69 mmol, 72.69 mL) at -30 °C, and the mixture was stirred at the same temperature for 30 min. 15 mL of methanol was added, followed by 25 mL of saturated citric acid solution, and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with 250 mL of DCM. The organic layer was washed with brine solution and concentrated in vacuo to give tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate (4.2 g, crude) as a light yellow oil. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 1.13 (s, 3H), 1.40 (s, 9H), 1.52 (m, 4H), 2.34 (s, 2H), 3.29 (m, 2H), 3.51 (m, 2H), 9.84 (s, 1H). Step 4: Synthesis of tert-butyl 4-((5-bromobenzo[d]thiazol-2-yl)methyl)-4-methylpiperidine-1-carboxylate Prepared by general procedure Scheme 4.1 Step 1B. Yield: 4.8 g (81.05%). 1 H NMR (500 MHz, CDCl3) δ (ppm) 1.08 (s, 3H), 1.43 (s, 9H), 1.46 (m, 2H), 1.57 (m, 2H), 3.04 (s, 2H), 3.23 (m, 2H), 3.66 (m, 2H), 7.44 (d, 1H), 7.67 (d, 1H), 8.12 (s, 1H). Step 5: Synthesis of 5-bromo-2-((4-methylpiperidin-4-yl)methyl)benzo[d]thiazole To a solution of tert-butyl 4-[(5-bromo-1,3-benzothiazol-2-yl)methyl]-4-methyl-piperidine-1-carboxylate (5.4 g, 12.69 mmol) in EtO (20.00 mL) was added 4.0 M hydrogen chloride solution in dioxane (24.00 g, 658.24 mmol, 30.00 mL) at 21 °C. The resulting mixture was continued to stir for 6 h. The resulting mixture was evaporated to dryness and used in the next step without further purification. 5-Bromo-2-[(4-methyl-4-piperidyl)methyl]-1,3-benzothiazole (4.5 g, crude, 2HCl) was obtained as a beige solid. LCMS(ESI):[M] + m / z: calculated 325.2; found 326.2; Rt = 2.325 min. Step 6: Synthesis of 5-bromo-2-((1,4-dimethylpiperidin-4-yl)methyl)benzo[d]thiazole Formaldehyde, a 37% w / w aqueous solution (1.01 g, 12.43 mmol, 931.63 μL, 37% purity) stabilized with 7-8% MeOH, and acetic acid (2.04 g, 33.90 mmol, 1.94 mL) were added to a solution of 5-bromo-2-[(4-methyl-4-piperidyl)methyl]-1,3-benzothiazole (4.5 g, 11.30 mmol, 2HCl) and anhydrous sodium acetate (1.85 g, 22.60 mmol, 1.21 mL) in MeOH. The resulting mixture was stirred at 21 °C for 1 h, after which sodium cyanoborohydride (1.42 g, 22.60 mmol) was added to it. Stirring was then continued for 8 h. The solvent was then removed under reduced pressure, and the residue was partitioned between 10% aqueous NaOH (20 mL) and DCM (40 mL). The organic layer was separated and evaporated to give 5-bromo-2-[(1,4-dimethyl-4-piperidyl)methyl]-1,3-benzothiazole (4.3 g, crude) as a yellow gum. LCMS(ESI):[M] + m / z: calculated 339.2; found 340.2; Rt = 2.474 min. Step 7: Synthesis of 2-((1,4-dimethylpiperidin-4-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1 Step 2. Yield: 4.5 g crude. LCMS(ESI):[M] + m / z: calculated 386.2; found 387.2; Rt = 2.490 min. Step 8: Synthesis of (S)-tert-butyl 6-(2-((1,4-dimethylpiperidin-4-yl)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 4.1, step 3. Yield: 7.5 g crude. LCMS(ESI):[M] + m / z: calculated 455.2; found 456.2; Rt = 3.572 min. Step 9: Synthesis of (S)-2-((1,4-dimethylpiperidin-4-yl)methyl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole To a solution of tert-butyl (3S)-6-[2-[(1,4-dimethyl-4-piperidyl)methyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate (7.5 g, 16.46 mmol) in DCM (18.66 mL) was added TFA (9.38 g, 82.30 mmol, 6.34 mL) in one portion, and the resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with aqueous NaOH (30%). Water was extracted with DCM (3 × 50 mL). The combined organics were dried over NaSO and evaporated to give a residue that was used in the next step without further purification. LCMS(ESI):[M] + m / z: calculated 355.2; found 356.2; Rt = 1.424 min. Step 10: Synthesis of 2-((1,4-dimethylpiperidin-4-yl)methyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole Prepared by general procedure Scheme 4.1, step 5. Yield: 0.77 g (15.31%). LCMS(ESI):[M] + m / z: calculated 357.2; found 358.2; Rt = 0.665 min. 3TTT.S)-N,N-Dimethyl-1-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)propan-2-amine [ka] Step 1: Synthesis of (S)-N,N-dimethyl-1-(3-nitrophenoxy)propan-2-amine Sodium hydride (in oil dispersion) 60% dispersion in mineral oil (405.15 mg, 10.13 mmol, 60% purity) was added to DMSO (7 mL), and the resulting mixture was stirred for 30 minutes. A solution of (2S)-2-(dimethylamino)propan-1-ol (950 mg, 9.21 mmol) in DMSO (2.5 mL) was added dropwise to the previous mixture, and the resulting mixture was stirred for 30 minutes. 1-Fluoro-3-nitro-benzene (1.30 g, 9.21 mmol, 980.65 μL) was added dropwise to the previous mixture, and the resulting mixture was stirred for 1.5 hours. The reaction mixture was quenched with aqueous NH4Cl (50 ml), and the resulting mixture was extracted with EtOAc (3 * 50 ml). The combined organic layers were washed with brine (3 * 40 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 0% to 50% MeOH in MTBE) to give (2S)-N,N-dimethyl-1-(3-nitrophenoxy)propan-2-amine (1.14 g, 5.07 mmol, 55.11% yield). LCMS(ESI):[M] + m / z: calculated 224.2; found 225.2; Rt = 0.758 min. Step 2: Synthesis of (S)-3-(2-(dimethylamino)propoxy)aniline (2S)-N,N-Dimethyl-1-(3-nitrophenoxy)propan-2-amine (1.14 g, 5.07 mmol) was dissolved in MeOH (20 mL), and palladium, 10% on carbon, type 487, dried (270.02 mg, 2.54 mmol) was added to it. The resulting mixture was evacuated and refilled with hydrogen three times. The reaction mixture was hydrogenated overnight at 1 atm (balloon). According to LCMS of an aliquot, 25% of the starting material remained. 200 mg of 10% Pd / C was added to the reaction mixture, and the resulting mixture was evacuated and refilled with hydrogen three times. The reaction mixture was hydrogenated overnight at 1 atm (balloon). The catalyst was filtered, and the filtrate was concentrated in vacuo to give 3-[(2S)-2-(dimethylamino)propoxy]aniline (948 mg, 4.88 mmol, 96.16% yield). LCMS(ESI):[M] + m / z: calculated 194.2; found 195.2; Rt = 0.203 min. Step 3: Synthesis of (S)-N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-amine 3-[(2S)-2-(dimethylamino)propoxy]aniline (817 mg, 4.21 mmol) was dissolved in MeCN (11.25 mL), and bis(pinacolato)diboron (1.17 g, 4.63 mmol) was added thereto, followed by tert-butyl nitrite, technical grade 90% (650.50 mg, 6.31 mmol, 750.28 μL). The resulting mixture was heated at 80 °C (oil bath) overnight. 12% starting material remained by LCMS. An additional portion of tert-butyl nitrite, technical grade 90% (650.50 mg, 6.31 mmol, 750.28 μL) and bis(pinacolato)diboron (1.17 g, 4.63 mmol) was added to the reaction mixture, and the resulting mixture was heated at 80 °C overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (50 ml) and the resulting solution was washed with 3% HCl solution (2*10 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give (2S)-N,N-dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-amine (1.62 g, crude). LCMS(ESI):[M] + m / z: calculated 305.2; found 306.2; Rt = 0.901 min. Step 4: Synthesis of (S)-tert-butyl 6-(3-((S)-2-(dimethylamino)propoxy)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 7.1, step 2. Yield: 0.16 g (8.05%). CC conditions: The crude product was purified on silica gel using MTBE / MeOH 0-50% as the eluent mixture. LCMS(ESI):[M] + m / z: calculated 374.2; found 375.2; Rt = 1.075 min. Step 5: Synthesis of (S)-N,N-dimethyl-1-(3-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)propan-2-amine Prepared by general procedure Scheme 7.1, step 3. Yield: 152 mg crude. LCMS(ESI):[M] + m / z: calculated 274.2; found 275.2; Rt = 0.414 min. Step 6: Synthesis of (S)-N,N-dimethyl-1-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)propan-2-amine Prepared by general procedure Scheme 7.1, step 4. Yield: 121 mg crude. LCMS(ESI):[M] + m / z: calculated 276.2; found 277.2; Rt = 0.666 min. Intermediate 1. 2-Amino-3-methyl-quinoline-6-carboxylic acid [ka] Step 1: Synthesis of 6-bromo-3-methyl-quinolin-2-amine A mixture of 6-bromo-2-chloro-3-methyl-quinoline (10 g, 38.98 mmol), acetamide (40.00 g, 677.19 mmol), and potassium carbonate, anhydrous, 99% (30.00 g, 217.07 mmol, 13.10 mL) was stirred at 210° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water. The formed precipitate was collected by filtration, washed with water, and dried at 70° C. overnight to give 6-bromo-3-methyl-quinolin-2-amine (12 g, crude). LCMS(ESI):[M+3H] + m / z: calculated 239.0; found 239.0; Rt = 0.863 min. Step 2: Synthesis of methyl 2-amino-3-methyl-quinoline-6-carboxylate Crude 6-bromo-3-methyl-quinolin-2-amine (18 g, 75.92 mmol), TEA (9.22 g, 91.10 mmol, 12.70 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.28 mmol) were dissolved in MeOH (300 mL). The reaction mixture was stirred at 125 °C and 40 atm under carbon dioxide (2.28 g, 75.92 mmol, 2.11 mL) for 16 h. The solvent was evaporated, and the mixture was poured into water (200 mL) and extracted with EtOAc (2 * 200 mL). The combined organic layers were dried over Na2SO4 and evaporated to give methyl 2-amino-3-methyl-quinoline-6-carboxylate (5.2 g, 24.05 mmol, 31.68% yield). 1 H NMR (dmso, 400 MHz): δ (ppm) 2.27 (s, 3H), 3.91 (s, 3H), 6.78 (s, 2H), 7.52 (m, 1H), 7.93 - 7.99 (m, 2H), 8.32 (s, 1H). LCMS(ESI):[M+H] + m / z: calculated 217.1; found 218.2; Rt = 0.812 min. Step 3: Synthesis of 2-amino-3-methyl-quinoline-6-carboxylic acid To a stirred solution of methyl 2-amino-3-methyl-quinoline-6-carboxylate (5.2 g, 24.05 mmol) in THF (20 mL) / HO (15 mL) was added lithium hydroxide monohydrate, 98% (2.32 g, 55.31 mmol, 1.54 mL), and the resulting mixture was stirred at 25 °C for 4 h. The THF was evaporated. The residue (aqueous) was acidified with sodium hydrogen sulfate to a slightly acidic pH. The product was extracted with EtOAc (2 * 100 mL) and dried over NaSO. Evaporation of EtOAc gave 2-amino-3-methyl-quinoline-6-carboxylic acid (3.7 g, 18.30 mmol, 76.09% yield). 1H NMR (dmso, 400 MHz): δ (ppm) 2.27 (s, 3H), 6.78 (s, 2H), 7.52 - 7.55 (d, 1H), 7.93 (s, 1H), 7.96 - 7.99 (d, 1H), 8.32 (s, 1H). LCMS(ESI):[M+H] + m / z: calculated 203.2; found 203.2; Rt = 0.564 min. Example 1. Compound 95 N-(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(1-methylpiperidin-4-yl)quinolin-7-yl)piperidin-1-yl)-2-oxoacetamide [ka] Step 1: Synthesis of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate Di-tert-butyl dicarbonate (4.29 g, 19.65 mmol, 4.51 mL) was added dropwise to a solution of 2-(4-piperidyl)ethanol (3.1 g, 18.71 mmol, HCl) and TEA (4.73 g, 46.78 mmol, 6.52 mL) in DCM (30 mL). The resulting solution was stirred at 26 °C for 14 h and diluted with water. The organic layer was separated, dried over NaSO, filtered, and evaporated to give tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.76 g, crude). 1 H NMR (400 MHz, CDCl3) δ (ppm) 1.01 (m, 2H), 1.27 (s, 1H), 1.45 (s, 9H), 1.52 (m, 2H), 1.61 (m, 2H), 2.55 (m, 1H), 2.72 (m, 2H), 3.69 (m, 2H), 4.09 (m, 2H). Step 2: Synthesis of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.76 g, 16.40 mmol) in DCM (100 mL) was added Dess-Martin periodinane (8.35 g, 19.68 mmol), and the reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was evaporated, and 100 mL of water and 50 mL of MTBE were added. The precipitate formed was filtered. The organic layer was separated, and the aqueous layer was extracted with 2 * 50 mL of MTBE. The organic layers were combined, washed with aqueous NaHCO3 (2 * 100 mL), then dried over Na2SO4 and concentrated to give a congested mixture of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (3.76 g, crude), which was used in the next step. 1 H NMR (500 MHz, CDCl3) δ (ppm) 1.44 (s, 9H), 1.58 (m, 2H), 2.03 (m, 1H), 2.37 (m, 2H), 2.72 (m, 2H), 3.20 (m, 2H), 4.04 (m, 2H), 9.77 (m, 1H). Step 3: Synthesis of tert-butyl 4-(7-bromoquinolin-3-yl)piperidine-1-carboxylate A solution of potassium hydroxide (167.86 mg, 2.99 mmol, 82.12 μL) in EtOH (50 mL) was added dropwise to a mixture of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (2 g, 8.80 mmol) and 2-amino-4-bromobenzaldehyde (1.76 g, 8.80 mmol) in EtOH (50 mL). The mixture was heated to reflux and then maintained at reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated to remove EtOH, then water was added and the mixture was extracted with DCM (3x50 ml), and the combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography (Interchim 80 g SiO, 0-100% hexane-MTBE, flow rate = 70 mL / min, cv = 49.8) to give tert-butyl 4-(7-bromo-3-quinolyl)piperidine-1-carboxylate (1.5 g, 3.83 mmol, 43.57% yield). LCMS(ESI):[M] + m / z: calculated 391.2; found 392.2; Rt = 1.572 min. Step 4: Synthesis of 7-bromo-3-(piperidin-4-yl)quinoline tert-Butyl 4-(7-bromo-3-quinolyl)piperidine-1-carboxylate (1.4 g, 3.58 mmol) was dissolved in a mixture of DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at 22 °C for 16 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in water, basified with NaHCO and extracted with DCM (3 times). The combined DCM layers were dried over NaSO, filtered, and evaporated to give 7-bromo-3-(4-piperidyl)quinoline (0.7 g, 2.40 mmol, 67.19% yield). The resulting product was used in the next step without further purification. LCMS(ESI):[M] + m / z: calculated 291.2; found 292.2; Rt = 0.896 min. Step 5: Synthesis of 7-bromo-3-(1-methylpiperidin-4-yl)quinoline A 37% w / w aqueous formaldehyde solution (836.19 mg, 10.30 mmol, 772.10 μL, 37% purity) stabilized with 7-8% MeOH was added to a mixture of 7-bromo-3-(4-piperidyl)quinoline (0.6 g, 2.06 mmol) and sodium cyanoborohydride (647.42 mg, 10.30 mmol) in MeOH (19.51 mL), followed by concentration. The residue was treated with an aqueous solution of NaHCO3, and the desired product was extracted with 2 x 30 mL of DCM, dried over Na2SO4, and concentrated in vacuo to give 7-bromo-3-(1-methyl-4-piperidyl)quinoline (0.53 g, crude). LCMS(ESI):[M] + m / z: calculated 305.2; found 306.2; Rt = 0.803 min. Step 6: Synthesis of 3-(1-methylpiperidin-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline Prepared by general procedure Scheme 7.1 Step 1. Yield: 0.45 g crude. LCMS(ESI):[M] + m / z: calculated 352.2; found 353.2; Rt = 0.869 min. Step 7: Synthesis of (S)-tert-butyl 3-methyl-6-(3-(1-methylpiperidin-4-yl)quinolin-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate Prepared by general procedure Scheme 7.1, step 2. Yield: 0.6 g crude. LCMS(ESI):[M] + m / z: calculated 421.2; found 422.2; Rt = 1.023 min. Step 8: Synthesis of (S)-7-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-3-(1-methylpiperidin-4-yl)quinoline Prepared by general procedure Scheme 7.1, step 3. Yield: 0.3 g crude. LCMS(ESI):[M] + m / z: calculated 321.2; found 322.2; Rt = 0.651 min. Step 9: Synthesis of 7-((2R,5S)-5-methylpiperidin-2-yl)-3-(1-methylpiperidin-4-yl)quinoline Prepared by general procedure Scheme 7.1, step 4. Yield: 0.21 g crude. LCMS(ESI):[M] + m / z: calculated 323.2; found 324.2; Rt = 0.502 min. Step 10: Synthesis of N-(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(1-methylpiperidin-4-yl)quinolin-7-yl)piperidin-1-yl)-2-oxoacetamide (Compound 95) Prepared by general procedure Scheme 7.1 Step 5A. Yield: 9.6 mg (2.64%). HPLC conditions: Column: SunFire C18 100*19mm, 5 micrometers; 0.6-8.6 min 0-100% MeCN+FA 30ml / min; (loading pump 4ml / min MeCN). Compound 95: 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 1.03 - 1.38 (m, 8H), 1.70 - 1.85 (m, 4H), 2.07 - 2.40 (m, 8H), 2.72 - 2.95 (m, 4H), 3.51 - 4.08 (m, 2H), 5.37 - 5.77 (m, 4H), 7.43 - 7.60 (m, 2H), 7.88 - 8.15 (m, 4H), 8.83 (s, 1H), 10.54 - 10.59 (m, 1H). LCMS(ESI):[M] + m / z: calculated 514.2; found 515.2; Rt = 1.892 min. Example 2. Compound 46 2-Methoxy-5-(2-((2R,5S)-5-methyl-2-(2-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide)nicotinamide [ka] Step 1: Synthesis of 1-methyl-2,5,6,7-tetrahydro-1H-azepine-4-carboxylic acid A 37% w / w aqueous formaldehyde solution (672.67 mg, 8.29 mmol, 621.11 µL, 37% purity) stabilized with 7-8% MeOH was added to a solution of 1-tert-butoxycarbonyl-2,3,4,7-tetrahydroazepine-5-carboxylic acid (800 mg, 3.32 mmol) in formic acid (12.20 g, 225.31 mmol, 10 mL, 85% purity). The resulting mixture was stirred at 80 °C for 14 h. The volatiles were then removed under reduced pressure to leave 1-methyl-2,3,4,7-tetrahydroazepine-5-carboxylic acid (0.8 g, crude). LCMS(ESI):[M] + m / z: calculated 155.2; found 156.2; Rt = 0.188 min. Step 2: Synthesis of 1-methyl-2,5,6,7-tetrahydro-1H-azepine-4-carbonyl chloride Oxalyl chloride (3.27 g, 25.77 mmol, 2.25 mL) was added to a solution of 1-methyl-2,3,4,7-tetrahydroazepine-5-carboxylic acid (0.8 g, 5.15 mmol) in DCM (20 mL). The resulting mixture was stirred at 25° C. for 3 hours. The solvent was then removed under reduced pressure. The residue was dissolved in chloroform (20 mL) and again concentrated in vacuo to give 1-methyl-2,3,4,7-tetrahydroazepine-5-carbonyl chloride (0.95 g, 4.52 mmol, 87.72% yield, HCl). 1 H NMR (500 MHz, CDCl3) δ (ppm) 1.49 (m, 1H), 2.05 (m, 1H), 2.21 (m, 1H), 2.83 (s, 3H), 2.92 (m, 1H), 3.33 (m, 1H), 3.76 (m, 1H), 4.28 (m, 2H), 8.02 (m, 1H). Step 3: Synthesis of (2R,5S)-tert-butyl 2-(3-amino-4-mercaptophenyl)-5-methylpiperidine-1-carboxylate Hydrazine hydrate (6.32 g, 126.33 mmol, 6.16 mL) was added to a solution of tert-butyl (2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-piperidine-1-carboxylate (4.2 g, 12.63 mmol) in EtOH (50 mL). The resulting mixture was stirred at 78 °C for 72 hours. The volatiles were then removed under reduced pressure, and the residue was diluted with water (50 ml) and extracted with MTBE (2 × 40 ml). The combined organic layers were dried over NaSO and concentrated under reduced pressure to leave tert-butyl (2R,5S)-2-(3-amino-4-sulfanyl-phenyl)-5-methyl-piperidine-1-carboxylate (4 g, 12.40 mmol, 98.19% yield). LCMS(ESI): [M(disulfide)-Boc] + m / z: calculated 542.2; found 543.2; Rt = 1,800 min. Step 4: Synthesis of (2R,5S)-tert-butyl 5-methyl-2-(2-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)benzo[d]thiazol-5-yl)piperidine-1-carboxylate A solution of 1-methyl-2,3,4,7-tetrahydroazepine-5-carbonyl chloride (274 mg, 1.30 mmol, HCl) in DCM (2 mL) was added dropwise to a solution of tert-butyl (2R,5S)-2-(3-amino-4-sulfanyl-phenyl)-5-methyl-piperidine-1-carboxylate (420.54 mg, 1.30 mmol) in DCM (3 mL) under argon, and the resulting mixture was stirred at 25° C. for 24 hours. The volatiles were then removed under reduced pressure and the residue was subjected to HPLC (50-50-100% 0-1-6 min HO / MeCN / 0.1% NHOH, flow rate: 30 ml / min; column: XBridge BEH C18 100 x 19 mm, 5 um) to give tert-butyl (2R,5S)-5-methyl-2-[2-(1-methyl-2,3,4,7-tetrahydroazepin-5-yl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (25 mg, 56.61 μmol, 4.34% yield). LCMS(ESI):[M] + m / z: calculated 441.2; found 442.2; Rt = 1.264 min. Step 5: Synthesis of 2-methoxy-5-(2-((2R,5S)-5-methyl-2-(2-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamido)nicotinamide (Compound 46) TFA (148.00 mg, 1.30 mmol, 0.1 mL) was added to a solution of tert-butyl (2R,5S)-5-methyl-2-[2-(1-methyl-2,3,4,7-tetrahydroazepin-5-yl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylate (25 mg, 56.61 μmol) in DCM (1 mL). The resulting mixture was stirred at 25° C. for 3 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in DMF (1 mL). 2-[(5-carbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (17.60 mg, 73.59 μmol) and TEA (57.28 mg, 566.09 μmol, 78.90 μL) were added to the solution, followed by HATU (30.13 mg, 79.25 μmol), and the resulting reaction mixture was stirred at 25° C. for 3 hours. It was then subjected to HPLC (40-40-90% 0-1-6 min HO / MeOH / 0.1% NHOH, flow rate: 30 ml / min; column: XBridge BEH C18 100 x 19 mm, 5 um) to give 2-methoxy-5-[[2-oxo-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-2,3,4,7-tetrahydroazepin-5-yl)-1,3-benzothiazol-5-yl]-1-piperidyl]acetyl]amino]pyridine-3-carboxamide (13 mg, 23.10 μmol, 40.81% yield). Compound 46: 1H NMR(DMSO-d6, 600 MHz): δ (ppm) 1.02 - 1.06 (m, 3H), 1.32 - 1.40 (m, 1H), 1.68 - 1.92 (m, 4H), 2.07 - 2.31 (m, 4H), 2.45 (m, 2H), 2.82 (m, 2H), 3.49 - 4.05 (m, 5H), 5.27 - 5.69 (m, 1H), 6.94 - 6.96 (m, 1H), 7.34 - 7.41 (d, 1H), 7.68 (d, 1H), 7.75 (s, 1H), 7.85 (m, 1H), 7.99 - 8.03 (d, 1H), 8.41 - 8.58 (m, 2H), 11.11 (s, 1H). LCMS(ESI):[M] + m / z: calculated 562.2; observed 563.2; Rt = 2.806 min Example 3. Compound 5 2-Methoxy-5-[[2-oxo-2-[(2R,5S)-5-methyl-2-[2-[1-(trideuteriomethyl)-4-piperidyl]-1,3-benzothiazol-5-yl]-1-piperidyl]acetyl]amino]pyridine-3-carboxamide [ka] Step 1: Synthesis of tert-butyl (2R,5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methyl-piperidine-1-carboxylate To a mixture of tert-butyl (2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-piperidine-1-carboxylate (4.30 g, 12.9 mmol), CBr4 (4.30 g, 13.0 mmol), and DMF (20 mL), sodium 2-methylpropan-2-olate (5.2 g, 54.1 mmol) was added, and the mixture was stirred at 20° C. for 2 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL*2), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (2R,5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methyl-piperidine-1-carboxylate (3.5 g, 65.8% yield) as a yellow oil. LCMS (ESI) [M+H] + m / z calculated: 411.1, observed: 355.0 (t-Bu decomposition mass). Step 2: Synthesis of 2-bromo-5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazole A mixture of tert-butyl (2R,5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methyl-piperidine-1-carboxylate (1.00 g, 2.43 mmol), DCM (9 mL), and TFA (2 mL, 26.0 mmol) was stirred at 20 °C for 2 hours. The resulting mixture was adjusted to pH = 9 with saturated aqueous Na2CO3, and then the mixture was extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-bromo-5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazole (750 mg, crude) as a yellow solid. LCMS (ESI) [M+H] + m / z calculated 313.0, observed 312.9. Step 3: Synthesis of tert-butyl 4-[5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate To a mixture of 2-bromo-5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazole (650 mg, 2.09 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (850 mg, 2.75 mmol) in EtOH (12 mL) and HO (5 mL) was added Pd(PPh) (260 mg, 0.225 mmol) and KCO (910 mg, 6.58 mmol). The resulting mixture was stirred at 95 °C under microwave irradiation for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® silica flash column, 0-10% MeOH in DCM / MeOH, flow rate: 30 mL / min, 254 nm) to give tert-butyl 4-[5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.0 g, crude) as a yellow oil. LCMS (ESI) [M+H] + m / z calculated 414.2, observed 414.1. Step 4: Synthesis of tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate To a mixture of tert-butyl 4-[5-[(2R,5S)-5-methyl-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.08 g, 2.61 mmol), TEA (1.08 mL, 7.75 mmol) in DCM (10 mL) was slowly added 4-methylbenzenesulfonyl chloride (605 mg, 3.17 mmol). The resulting mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by adding water (50 mL) and extracted with DCM (100 mL * 3). The combined organic layer was washed with saturated aqueous NH4Cl (50 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® silica flash column, 0-20% EtOAc in petroleum ether / EtOAc, flow rate = 30 mL / min, 254 nm) to afford tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (750 mg, 50.6% yield) as a white solid. LCMS (ESI) [M+H] + m / z: calculated 568.2, observed 568.3. Step 5: Synthesis of tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]piperidine-1-carboxylate A mixture of tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (710 mg, 1.25 mmol) and Pd / C (600 mg, 10 wt% Pd containing 50 wt% water) in MeOH (10 mL) was stirred under hydrogen (in a balloon) at 45 °C for 48 h. The resulting mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (600 mg, crude) as a yellow solid. LCMS (ESI) [M+H] + m / z: calculated value 570.2, observed value 514.2 (t-Bu decomposition mass). Step 6: Synthesis of 2-(4-piperidyl)-5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazole A mixture of tert-butyl 4-[5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazol-2-yl]piperidine-1-carboxylate (600 mg, 0.906 mmol), DCM (6 mL), and TFA (0.7 mL, 9.09 mmol) was stirred at 20 °C for 2 h. The resulting mixture was adjusted to pH = 8 with NH3-HO (12 N). The resulting mixture was quenched by adding water (50 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(4-piperidyl)-5-[(2R,5S)-5-methyl-1-(p-tolylsulfonyl)-2-piperidyl]-1,3-benzothiazole (600 mg, crude) as a yellow solid, which was used in the next step without further purification. L...

Claims

【Request Item 1】 【Chemistry 1-1】 [Chemistry 1-2] [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] [Chemistry 1-8] [Chemistry 1-9] 【Chemistry 1-10】 【Chemistry 1-11】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. 3. The pharmaceutical composition of claim 2, further comprising a second therapeutic agent.

4. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of claim 1, 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.

5. 5. The composition or pharmaceutical composition of claim 4, wherein the composition or pharmaceutical composition is administered in combination with a second therapeutic agent.

6. The pharmaceutical composition of claim 3 for treating an MTAP deficiency and / or an MTA accumulation disease in a subject in need thereof.

7. The composition or pharmaceutical composition according to any one of claims 4 to 6, wherein the disease is a proliferative disease.

8. The composition or pharmaceutical composition according to claim 7, wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

9. 9. The composition or pharmaceutical composition of claim 8, wherein the cancer is 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 or sarcoma of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon.

10. 10. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2 or 3, for use in a method of treating cancer in a subject in need thereof, said method comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject, wherein the MTA level 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 deficiency and / or MTA accumulation in the test sample compared to the reference indicates that the cancer in the subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering said composition or pharmaceutical composition to said subject identified in step b).

Images