Purine derivatives as anticancer agents

Abstract

Compounds are provided according to formula (I): Formula (I) and pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, tautomers and stereoisomers, and pharmaceutical compositions (wherein R A , R b , R c , R c’ , R 1 , R 2 , R 6 , m and n are as defined herein.) It is contemplated that the compounds disclosed herein are useful for the prevention and treatment of a variety of conditions. TIFF2024511996000343.tif48165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 162,460, filed March 17, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Ubiquitin is a small, highly conserved protein composed of 76 amino acids that is post-transcriptionally attached to target proteins, including itself, through a three-step concerted enzymatic reaction. This covalent bond, or isopeptide bond, occurs primarily between the C-terminal glycine of ubiquitin and the ε-amino group of lysine residue(s) on the target protein (Pickart, C.M., Annu. Rev. Biochem., 2001:503-33). The functional outcome of ubiquitination is determined by the number and linkage topology of ubiquitin molecules conjugated to the target protein. For example, proteins displaying Lys48-linked polyubiquitin chains are generally targeted to the proteasome for degradation, whereas monoubiquitinated or polyubiquitin chains linked through other lysines regulate several non-proteolytic functions, including cell cycle regulation (Nakayama, K.I. et al., Nat. Rev. Cancer, 6(5):369-81(2006)), DNA repair (Bergink, S., et al., Nature 458(7237):461-7(2009)), transcription (Conaway, R.C., et al., Science 296(5571):1254-8(2002)), and endocytosis (Mukhopadhyay, D., et al., Science 315(5809):201-5(2007)). Like other post-translational modifications, ubiquitination is a reversible process counteracted by a family of enzymes known as deubiquitinases (DUBs). These enzymes are cysteine ​​proteases or metalloproteases that hydrolyze ubiquitin isopeptide bonds (Komander, D., et al., Nat. Rev. Mol. Cell Biol. 10(8):550-63(2007)). The human genome encodes nearly 100 DUBs.

[0003] DUBs and their substrate proteins are often deregulated in cancer. Targeting specific DUB family members can result in antitumor activity by enhancing the ubiquitination and subsequent degradation of oncogenic substrates involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment (Hussain, S. et al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes, and tumor suppressors," Cell Cycle 8, 1688-1697 (2009)). Consequently, several members of the DUB family are involved in processes related to human diseases, including cancer and neurodegeneration. Among these, USP1 (ubiquitin-specific protease 1) has attracted increasing interest as a novel therapeutic target given its role in DNA damage response.

[0004] USP1 is a cysteine ​​isopeptidase of the USP subfamily of deubiquitinases (DUBs). (Nijman, S.M.B., et al., "The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway." Mol. Cell 17, 331-339 (2005)) Full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593, and Asp751. (Villamil, M.A., et al., "Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1." Biochem. 51, 9112-9113 (2012)) USP1 is relatively inactive by itself, and full enzymatic activity is achieved only when associated with USP1-associated factor 1 (UAF1) in a heterodimeric complex, which also binds and regulates the activities of USP12 and USP46. (Cohn, M.A., et al., "A UAF1-Containing Multisubunit Protein Complex." Regulates the Fanconi Anemia Pathway.”Mol.Cell 28,786-797(2007)).

[0005] USP1 deubiquitinates various cellular targets involved in different processes related to cancer. For example, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen), a key protein in translesion synthesis (TLS), and FANCI / FANCD2 (Fanconi anemia complementation group D2), a key protein complex in the Fanconi anemia (FA) pathway (Nijman, S.M.B. et al., "The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway," Mol. Cell. 17, 331-339 (2005); Huang, T.T. et al., "Regulation of monoubiquitinated PCNA by DUB autocleavage," Nat. Cell. Biol. 8, 339-347 (2006)). These DNA damage response (DDR) pathways are essential for repairing DNA damage, including that induced by DNA cross-linking agents such as cisplatin, mitomycin C (MMC), diepoxybutane, ionizing radiation, and UV light. Furthermore, USP1 promotes cancer cell stem cell maintenance by increasing the stability of inhibitor of endothelial cell (ID) proteins. Therefore, USP1 inhibition may antagonize cancer cell growth by inducing cell cycle arrest and reducing cancer stem cell maintenance through reduced ID protein stability. (Williams, SA et al., "USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma," Cell 146:918-30 (2011); Lee, JK et al., "USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance," Neuro Oncol. 18:37-47 (2016)) The compounds GW7647 and pimozide have been described as inactivators of USP1. However, both compounds are limited by potency and off-target pharmacology, in part due to significant activity against unrelated targets. Another small molecule inhibitor of USP1, C527, reported by D'Andrea et al. in WO 2011 / 137320, sensitizes cells to both the crosslinker mitomycin C and the topoisomerase 1 inhibitor camptothecin. However, C527 exhibits low micromolar inhibition of related USPs as well as different DUBs (i.e., UCHL-1 and UCHL-3). Another small molecule USP1-UAF1 inhibitor (ML323) has been more recently described (Dexheimer et al., J. Med. Chem. 2014, 57, 8099-8110; Liang et al., Nature Chem. Bio. 2015, 10, 298-304; US9802904B2). Additional USP1 inhibitors are also described in WO2017087837, WO2020132269, WO2020139988, and WO2021163530. The above indicates that there is an unmet need for new selective inhibitors of USP1, and further indicates that inhibition of USP1 by small molecule inhibitors may be a potential treatment for cancer and other disorders. For these reasons, there remains a significant need for potent small molecule inhibitors of USP1. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2011 / 137320 [Patent Document 2] U.S. Patent No. 9,802,904 [Patent Document 3] International Publication No. 2017 / 087837 [Patent Document 4] International Publication No. 2020 / 132269 [Patent Document 5] International Publication No. 2020 / 139988

Patent document 6

Non-licensed literature

[0007] [Non-licensed document 1] Pickart, CM, Annu. Rev. Biochem., 2001: 503-33 [Non-licensed document 2] Nakayama,KIet al.,Nat.rev.Cancer,6(5):369-81(2006) [Non-licensed document 3] Bergink,S.,et al.,Nature 458(7237):461-7(2009)

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Non-licensed literature 9

[0008] In one embodiment, a compound of formula (I) During the ceremony, [ka] Ring B is a 5- to 6-membered monocyclic aryl or heteroaryl; Ring A is C6-C 10 Aryl, 5-10 membered heteroaryl, -C3-C 10 cycloalkyl, and 3- to 10-membered heterocyclyl; R 1 is an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 3- to 10-membered heterocyclyl; R 2 is H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 heteroalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 is selected from cycloalkyl and arylalkyl, wherein each hydrogen of alkyl, haloalkyl, heteroalkyl, hydroxylalkyl, and arylalkyl can be independently replaced with a deuterium atom; R 6is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkynyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 6- to 10-membered heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, and -OC(=O)N(R a6 )2, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a6 are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R A are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, -OR A1 , -N(R A1 )2 is selected, Each R A1 is independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, and C3-C9 cycloalkyl; Each R bare independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR b1 , -N(R b1 )2, -C(=O)R b1 , -C(=O)OR b1 , -NR b1 C(=O)R b1 , -NR b1 C(=O)OR b1 , -C(=O)N(R b1 )2, -OC(=O)N(R b1 )2, -S(=O)R b1 , -S(=O)2R b1 , -SR b1 , -S(=O)(=NR b1 )R b1 , -NR b1 S(=O)2R b1 and -S(=O)2N(R b1 )2 or two R b together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, and R b wherein each alkyl, carbosilyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R b1 is independently selected from H, —C1-C6 alkyl (wherein each hydrogen can be independently replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R c and R c’is independently selected from H, -D, -C1-C6 alkyl (e.g., -Me), -C1-C6 heteroalkyl, and -C1-C6 haloalkyl, or R c and R c’ together with the atom to which they are attached can form -C3-C9 cycloalkyl (e.g., cyclopropyl) or carbonyl; n is 0, 1, 2 or 3; Compounds are provided wherein m is 0, 1, 2, or 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0009] In some embodiments, the compound of formula (II) is During the ceremony, [ka] X 1 is selected from CH and N; X 2 is selected from CH and N; R 3 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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 )Ra3 , -NR a3 S(=O)2R a3 and -S(=O)2N(R a3 )2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; R 4 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a3 and R a4are independently selected from H, —C1-C6 alkyl (each hydrogen can be replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0010] In some embodiments, a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is provided.

[0011] In some embodiments, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0012] In some embodiments, the pharmaceutical composition comprises a second therapeutic agent.

[0013] In some embodiments, there is provided a method for treating or preventing a disease or disorder associated with the inhibition of USP1, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0014] In some embodiments, there is provided a method of treating a disease or disorder associated with the inhibition of USP1, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0015] In some embodiments, there is provided a method for inhibiting USP1, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] In some embodiments, provided are methods for treating or preventing cancer in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0017] In some embodiments, provided are methods for treating cancer in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0018] In some embodiments, a method for treating or preventing a disease or disorder associated with DNA damage is provided, comprising administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need of treatment for a disease or disorder associated with DNA damage. In some embodiments, the disease is cancer.

[0019] In some embodiments, provided are methods for treating a disease or disorder associated with DNA damage, comprising administering to a patient in need of treatment for a disease or disorder associated with DNA damage an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0020] In some embodiments, provided are methods for inhibiting, modulating, or reducing DNA repair activity carried out by USP1, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. DETAILED DESCRIPTION OF THE INVENTION

[0021] 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.

[0022] 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.

[0023] Chemical Substance 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 detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, 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.

[0024] 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 mixtures 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 invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0025] As used herein, "enantiomeric excess" ("ee") or "% enantiomeric excess" ("%ee") of a composition refers to the excess of one enantiomer compared 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%.

[0026] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0027] As used herein, "diastereomeric excess" ("de") or "% diastereomeric excess" ("% de") of a composition refers to an excess of one diastereomer compared to 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%.

[0028] 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%.

[0029] 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 can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, and the nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C.18 O, or 15 N) can 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.

[0030] During the ceremony, [ka] is a single bond that does not specify the stereochemistry of the moiety directly attached to it.

[0031] 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.

[0032] 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 is also understood that any of the moieties defined below can be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as set forth below. Unless otherwise specified, the term "substituted" shall be defined as set forth below. It is further understood that the terms "group" and "radical" can be considered interchangeable as 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 analog" means one analog or more than one analog.

[0033] The term "unsaturated bond" refers to a double or triple bond.

[0034] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0035] The term "saturated" refers to a moiety that does not contain double or triple bonds, i.e., the moiety contains only single bonds.

[0036] The addition of 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.

[0037] The term "azido" refers to the radical -N3.

[0038] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0039] "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.

[0040] "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.

[0041] "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.

[0042] "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 1-2 In 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 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (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 Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i Pr(-CH(CH3)2), n Pr(-CH2CH2CH3), n Bu(-CH2CH2CH2CH3), or i Bu(-CH2CH(CH3)2).

[0043] "Alkylene" refers to an alkyl group in which two hydrogens are removed to give a divalent radical, which can 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. For example, exemplary substituted alkylene groups 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 substituted or unsubstituted with one or more substituents described herein.

[0044] "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, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 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.

[0045] "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 in 2-butynyl) or terminal (such as in 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 alkynyl 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.

[0046] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, which 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, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl groups are saturated groups 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 1-3In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 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, and -CHNH. 2、 Examples include -CH2NH(CH3), -CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2NH(CH3), and -CH2CH2N(CH3)2.

[0047] "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, an aryl group has 14 ring carbon atoms ("C 14"Aryl" includes, for example, anthracyl. "Aryl" also includes ring systems in which the aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such instances, 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.

[0048] 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.

[0049] Representative examples of substituted aryl include the following: [ka] R 56 and R 57 may be hydrogen, and one of R 56 and R 57 At least one of the following 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. 58R 59 , 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 N, O, or S groups. 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.

[0050] "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.

[0051] "Heteroaryl" refers to a radical of a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10-membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such instances, 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 the 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; in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can have the point of attachment on either ring, i.e., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0052] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 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 an 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.

[0053] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0054] 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 10aryl, and 5- to 10-membered heteroaryl.

[0055] 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 a bond spanning more than one ring means that the substituent can be attached at any position on either ring.

[0056] A "heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0057] 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 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6Carbocyclyl 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.

[0058] As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the 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 such instances, the number of carbon atoms continues to designate the number of carbon atoms 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 3-14In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0059] 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 3-6 In some embodiments, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Monocyclic cycloalkyl). 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 3-6Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8).

[0060] 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 ("C 7-9Bicyclic 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.

[0061] 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. Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0062] "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, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). 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 the heterocyclyl ring defined above is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring or ring system, or the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such instances, 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.

[0063] 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, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). 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, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). 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, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). 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.

[0064] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, 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 fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0065] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, such as, 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 (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0066] "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 having 1 to 5, especially 1 to 3, heteroatoms, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl; etc.

[0067] "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, -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). 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.

[0068] 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.

[0069] The term hydroxyalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced by an —OH group.

[0070] 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.

[0071] The term "aryloxy" refers to an -O-aryl radical. In some embodiments, the aryloxy group is phenoxy.

[0072] The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkoxy" includes haloalkoxy groups where the halo is fluorine. In some embodiments, haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0073] "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., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0074] 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 hydroxyl, or unsubstituted C-C haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF, -OCHCF, -OCHPh, -OCH-cyclopropyl, -OCHCHOH, and -OCHCHNMe.

[0075] "Amino" refers to the radical -NH2.

[0076] An "oxo group" refers to -C(=O)-.

[0077] "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 R 38 The groups are linked to form an alkylene group.

[0078] 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 includes both mono- and di-substituted amino groups.

[0079] 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 are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3001, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. 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 , Rbb , R cc and R dd is as defined herein; R aa Each instance of -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 The 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 1-10Alkyl, -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 bb The 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 The 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(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)(OR ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2、-C 1-6Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, 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 -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, wherein 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, C3-10 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 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 1-6alkyl), -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)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 2-6Alkynyl, 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.

[0080] 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'-dithiobenzyloxyl acylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanide, 3-methyl-3-nitrobutanide, o-nitrocinnamide, N-acetylmethyl anion derivatives, o-nitrobenzenezenamide, and o-(benzoyloxymethyl)benzamide.

[0081] Carbamate groups (e.g., -C(=O)OR aa), nitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethyl 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-Bu meoc), 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, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrilebenzyl 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-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl 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, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 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, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 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, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0082] 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 (M 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-trimethylbenzenesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthalinyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenylfamide.

[0083] 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-tetramethyldisilylazacylate. Clopentane 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-pyrrolin-3-yl) Amines, 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-dimethylthio Methyleneamine, 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).

[0084] 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.

[0085] 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, 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), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formic acid, benzoylformic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid Oroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, phenoxyacetic acid, p-chlorophenoxyacetic acid, 3-phenylpropionate, 4-oxopentanoic acid (levulinic acid), 4,4-(ethylenedithio)pentanoic acid (levulinoyldithioacetal), pivalic acid, adamantic acid, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoic acid, 4-azidobutyric acid, 4-nitro-4-methylpentanoic acid, o-(dibromomethyl)benzoic acid, 2-formylbenzenesulfonic acid , 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyric acid, monosuccinic acid, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoic acid, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfonate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0086] 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 )Raa , -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.

[0087] The term "leaving group" is given its ordinary meaning in the field 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 embodiments, 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 be a phosphinoxide (e.g., formed during the photochemical reaction) or an internal leaving group such as an epoxide or 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.

[0088] "Carboxy" refers to the radical -C(=O)OH.

[0089] "Cyano" refers to the radical -CN.

[0090] "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.

[0091] "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.

[0092] "Hydroxy" refers to the radical --OH.

[0093] "Nitro" refers to the radical -NO2.

[0094] "Thioketo" refers to the group ═S.

[0095] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen (e.g., a carbon atom or nitrogen atom) present on the group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reaction, etc. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein, that result in the formation of a stable compound. The present invention contemplates any and all such combinations 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.

[0096] 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, 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, 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(=NRff ) 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, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents can be joined to form =O or =S; R ee Each instance of -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff Each instance of is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- 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.

[0097] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electron 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, glycerylates, lactates, tartrates, glycolates, etc.).

[0098] Nitrogen atoms can be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa , -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.

[0099] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0100] Other definitions The term "about," as used herein, includes the recited number ±10%. Thus, "about 10" means 9 to 11. As will be understood by one of ordinary skill in the art, references herein to "about" a value or parameter include (and describe) instances directed to the value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0101] As used herein, "USP1" and "ubiquitin-specific processing protease 1" refer to any naturally occurring polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses "full-length," unprocessed USP1 polypeptides as well as any form of USP1 that results from processing within a cell (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein can be isolated from various sources, such as human tissue types or another source, or prepared by recombinant or synthetic methods. Human USP1 sequences are known and include, for example, the sequence published as UniProt No. 094782 (including isoforms). As used herein, the term "human USP1 protein" refers to a USP1 protein comprising the amino acid sequence set forth in SEQ ID NO: 1 in U.S. Provisional Patent Application No. 62 / 857,986, filed June 6, 2019.

[0102] USP1 is a deubiquitinating enzyme that acts as part of a complex with UAF1. The "deubiquitinase activity" of USP1 includes its deubiquitinating ability as part of the USP1-UAF1 complex.

[0103] The term "specifically binds" to a protein or domain of a protein is a term well understood in the art, and methods for determining such specific binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a protein or domain of a protein more frequently, more rapidly, for a longer period of time, and / or with a higher affinity than alternative proteins or domains. It should be understood that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain. Thus, "specific binding" or "preferential binding" does not necessarily require exclusive binding (although it can include it). Generally, although not necessarily, reference to binding refers to preferential binding. For example, a USP1 inhibitor that specifically binds to USP1, UAF1, and / or the USP1-UAF1 complex may not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or may bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with lower affinity compared to its binding to USP1.

[0104] The terms "reduce" or "reducing" or "inhibition" or "inhibiting" refer to a decrease or cessation of any phenotypic trait, or a decrease or cessation of the incidence, degree, or likelihood of that trait. "Reduce" or "inhibit" refers to a decrease, reduction, or cessation of an activity, function, and / or amount compared to a reference. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall decrease of 20% or more. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall decrease of 50% or more. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or more. In some embodiments, the amount is inhibited or decreased over a period of time compared to a control over the same period of time.

[0105] In some embodiments, inhibiting the USP1 protein refers to inhibiting one or more activities or functions of the USP1 protein. It should be understood that one or more activities or functions of the USP1 protein can be inhibited in vitro or in vivo. Non-limiting examples of USP1 activities and functions include deubiquitinase activity and the formation of a complex with UAF1, and are described herein. Exemplary levels of inhibition of one or more activities of the USP1 protein include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition.

[0106] As used herein, the term "loss-of-function" mutation refers to a mutation that results in the absence of a gene, reduced expression of a gene, or the production of a gene product (e.g., a protein) with reduced or no activity. Loss-of-function mutations include, for example, missense mutations, nucleotide insertions, nucleotide deletions, and gene deletions. Loss-of-function mutations also include dominant-negative mutations. Thus, cancer cells having a loss-of-function mutation in the gene encoding BRCA1 include cancer cells containing missense mutations in the gene encoding BRCA1, as well as cancer cells lacking the gene encoding BRCA1.

[0107] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts.

[0108] 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 disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other 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, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0109] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or non-human animals, e.g., mammals such as 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.

[0110] Disease, disorder, and condition are used interchangeably herein.

[0111] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a specified disease, disorder, or condition and reduce the severity of the disease, disorder, or condition, or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment"). In some embodiments, the compounds provided herein are contemplated for use in therapeutic treatment methods in which the action 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 slow or delay in the progression of the disease, disorder, or condition. In alternative embodiments, the compounds provided herein are contemplated for use in prophylactic treatment methods in which the action 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.

[0112] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by one skilled in the art, the effective amount of the compounds disclosed herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment. An effective amount encompasses therapeutic and prophylactic treatment (i.e., encompasses a "therapeutically effective amount" and a "prophylactically effective amount").

[0113] 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 treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the 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 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 efficacy of another therapeutic agent.

[0114] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the 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 efficacy of another prophylactic agent.

[0115] The term "container" therefore refers to any container and closure suitable for storing, shipping, dispensing, and / or handling pharmaceutical products.

[0116] The term "insert" or "package insert" means the information that accompanies a drug product that provides instructions for how to administer the product, along with the safety and effectiveness data necessary to enable physicians, pharmacists, and patients to make informed decisions regarding the product's use. The package insert is generally considered the drug product's "label."

[0117] compound As generally described herein, provided are compounds (e.g., compounds of Formula (I), (II), or compounds of Table 1, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof) that are ubiquitin-specific processing protease 1 (USP1) inhibitors useful for treating diseases and disorders associated with USP1 (e.g., cancer).

[0118] Provided herein are compounds of formula (I). Unless the context otherwise requires, references throughout this specification to "compounds of formula (I)" or "compounds of formula (I)" refer to all embodiments of formula (I), including, for example, compounds of (I), (II), as well as compounds in Table 1.

[0119] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is provided. In some embodiments, including any of the numbered embodiments described herein, the compound is provided as a free base or a pharmaceutically acceptable salt. In some embodiments, including any of the numbered embodiments described herein, the compound is provided as a free base. In some embodiments, including any of the numbered embodiments described herein, the compound is provided as a pharmaceutically acceptable salt.

[0120] In some embodiments, the compound of formula (I) is During the ceremony, [ka] Ring B is a 5- to 6-membered monocyclic aryl or heteroaryl; Ring A is C6-C 10 Aryl, 5-10 membered heteroaryl, -C3-C 10 cycloalkyl, and 3- to 10-membered heterocyclyl; R 1 is an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 3- to 10-membered heterocyclyl; R 2 is H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 heteroalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 is selected from cycloalkyl and arylalkyl, wherein each hydrogen of alkyl, haloalkyl, heteroalkyl, hydroxylalkyl, and arylalkyl can be independently replaced with a deuterium atom; R 6 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkynyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 6- to 10-membered heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, and -OC(=O)N(R a6 )2, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a6 are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R A are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10Cycloalkyl, -OR A1 , -N(R A1 )2 is selected, Each R A1 is independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, and C3-C9 cycloalkyl; Each R b are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR b1 , -N(R b1 )2, -C(=O)R b1 , -C(=O)OR b1 , -NR b1 C(=O)R b1 , -NR b1 C(=O)OR b1 , -C(=O)N(R b1 )2, -OC(=O)N(R b1 )2, -S(=O)R b1 , -S(=O)2R b1 , -SR b1 , -S(=O)(=NR b1 )R b1 , -NR b1 S(=O)2R b1 and -S(=O)2N(R b1 )2 or two R b together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, and R b wherein each alkyl, carbosilyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R b1is independently selected from H, —C1-C6 alkyl (wherein each hydrogen can be independently replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R c and R c’ is independently selected from H, -D, -C1-C6 alkyl (e.g., -Me), -C1-C6 heteroalkyl, and -C1-C6 haloalkyl, or R c and R c’ together with the atom to which they are attached can form -C3-C9 cycloalkyl (e.g., cyclopropyl) or carbonyl; n is 0, 1, 2 or 3; Compounds are provided wherein m is 0, 1, 2, or 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0121] In some embodiments, the compound of formula (I) is During the ceremony, [ka] Ring B is a 5- to 6-membered monocyclic aryl or heteroaryl; Ring A is C6-C 10 Aryl, 5-10 membered heteroaryl, -C3-C 10 cycloalkyl, and 3- to 10-membered heterocyclyl; R 1 is an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 3- to 10-membered heterocyclyl; R 2 is H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 heteroalkyl, -C1-C6 hydroxyalkyl, -C3-C 10is selected from cycloalkyl and arylalkyl, wherein each hydrogen of alkyl, haloalkyl, heteroalkyl, hydroxylalkyl, and arylalkyl can be independently replaced with a deuterium atom; R 6 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkynyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 6- to 10-membered heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, and -OC(=O)N(R a6 )2, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a6 are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R A are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, -OR A1 , -N(R A1 )2 is selected, Each R A1is independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, and C3-C9 cycloalkyl; Each R b are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR b1 , -N(R b1 )2, -C(=O)R b1 , -C(=O)OR b1 , -NR b1 C(=O)R b1 , -NR b1 C(=O)OR b1 , -C(=O)N(R b1 )2, -OC(=O)N(R b1 )2, -S(=O)R b1 , -S(=O)2R b1 , -SR b1 , -S(=O)(=NR b1 )R b1 , -NR b1 S(=O)2R b1 and -S(=O)2N(R b1 )2 or two R b together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, and R b wherein each alkyl, carbosilyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R b1 are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R c and R c’ is independently selected from H, -D, -C1-C6 alkyl (e.g., -Me), -C1-C6 heteroalkyl, and -C1-C6 haloalkyl, or R c and R c’ together with the atom to which they are attached can form -C3-C9 cycloalkyl (e.g., cyclopropyl) or carbonyl; n is 0, 1, 2 or 3; Compounds are provided wherein m is 0, 1, 2, or 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0122] In Formula (I), Formula (II), and the exemplary compounds and intermediates disclosed herein, the moiety [ka] are alternative and interchangeable, [ka] It can be expressed as:

[0123] As generally defined herein, Ring B is a 5-6 membered monocyclic aryl or heteroaryl. In some embodiments, Ring B is R b In some embodiments, ring B is substituted with 0, 1, 2, or 3 instances of R b In some embodiments, ring B is substituted with 0, 1, or 2 instances of R b In some embodiments, ring B is substituted with one or two instances of R b In some embodiments, ring B is substituted with one instance of R b is replaced in two cases:

[0124] In certain embodiments, Ring B is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, Ring B is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, and R b In some embodiments, Ring B is a 5-membered heteroaryl ring selected from pyrrolyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, each of which can be optionally substituted (e.g., R b In certain embodiments, Ring B is selected from pyrazolyl, isoxazolyl, and isothiazolyl. In some embodiments, Ring B is pyrazolyl (e.g., pyrazol-5-yl, pyrazol-4-yl). In other embodiments, Ring B is isoxazolyl (e.g., isoxazol-4-yl). In yet other embodiments, Ring B is isothiazolyl (e.g., isothiazol-4-yl).

[0125] In certain embodiments, Ring B is an optionally substituted 6-membered heteroaryl containing 1-3 nitrogen atoms. b is a 6-membered heteroaryl containing 1 to 3 nitrogen atoms substituted with 0, 1, 2 or 3 instances of:

[0126] In some embodiments, Ring B is selected from pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl, each of which can be optionally substituted (e.g., R b In some embodiments, Ring B is selected from pyridinyl and pyrimidinyl, each of which can be optionally substituted (e.g., R b (0, 1, 2, or 3 instances of

[0127] In certain embodiments, Ring B is selected from phenyl, pyridinyl, and pyrimidinyl, each of which can be optionally substituted (e.g., R b In some embodiments, ring B is an optionally substituted phenyl (e.g., 0, 1, 2, or 3 instances of R b In some embodiments, Ring B is an optionally substituted pyridinyl (e.g., substituted with 0, 1, 2, or 3 instances of R b In some embodiments, ring B can be optionally substituted (e.g., 0, 1, 2, or 3 instances of R b In other embodiments, Ring B is an optionally substituted pyrimidinyl (e.g., R b In some embodiments, ring B can be optionally substituted (e.g., 0, 1, 2, or 3 instances of R b In certain embodiments, Ring B is an optionally substituted pyrimidin-5-yl (e.g., R b (substituted in 0, 1, 2, or 3 instances of

[0128] As generally defined herein, each R b are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR b1 , -N(R b1 )2, -C(=O)R b1 , -C(=O)OR b1 , -NR b1 C(=O)Rb1 , -NR b1 C(=O)OR b1 , -C(=O)N(R b1 )2, -OC(=O)N(R b1 )2, -S(=O)R b1 , -S(=O)2R b1 , -SR b1 , -S(=O)(=NR b1 )R b1 , -NR b1 S(=O)2R b1 and -S(=O)2N(R b1 )2 or two R b together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, and R b Each alkyl, carbosilyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0129] In certain embodiments, each R b are independently -CN, halo, -C1-C6 alkenyl, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10ア Reel, -OR b1 and -N(R b1 )2 or 2R b together with the atom(s) to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2, or oxo; and each R b1 is independently selected from H, —C1-C6 alkyl (wherein each hydrogen can be independently replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, and —C3-C9 cycloalkyl.

[0130] In certain embodiments, each R b are independently halo (e.g., -Cl, -F), -CN, -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), -C6-C 10 Aryl (e.g., phenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH, -CH(OH)CF3), -C3-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -OR b1 and -N(R b1 )2 or two R b together with the atom(s) to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), and each R b1 are independently H, -C1-C6 alkyl (each hydrogen can be independently replaced by deuterium) (e.g., -Me, -CD3, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - tBu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0131] In some embodiments, each R b are independently -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - i Pr, -CH2N(CH3)CH2CF3, -CH2N(CH3)2, -CH2OH, -CH(OH)CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0, 1, 2 instances of -F, -Me, -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -O i -Pr, -OMe, -OCH2CH(CH3)3, -N(Me)2 and -NHMe, or two R b together with the atoms to which they are attached form a 1,3 dioxole substituted with 0, 1 or 2 instances of -F or -Me.

[0132] In certain embodiments, each R b are independently -CN, halo, -C1-C6 alkenyl, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10ア Reel, -OR b1 and -N(R b1 )2 or 2R b together with the atom(s) to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2, or oxo; and each R b1is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, and —C3-C9 cycloalkyl.

[0133] In certain embodiments, each R b are independently halo (e.g., -Cl, -F), -CN, -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), -C6-C 10 Aryl (e.g., phenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH), -C3-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -OR b1 and -N(R b1 )2 or two R b together with the atom(s) to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), and each R b1 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - tBu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0134] In some embodiments, each R b are independently -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - i Pr, -CH2N(CH3)CH2CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0 or 1 instance of -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -O i -Pr, -OMe, -OCH2CH(CH3)3, -N(Me)2 and -NHMe, or two R b together with the atoms to which they are attached form a 1,3 dioxole substituted with 0, 1 or 2 instances of -F or -Me.

[0135] In some embodiments, each R b are independently -CN, -C(=CH2)CH3, -F, - i It is selected from Pr, -CF3, cyclopropyl (substituted with 0 or 1 instance of -CN), -OCF3, -OCHF2, and -OMe.

[0136] In some embodiments, R b is -D.

[0137] In certain embodiments, R b is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R b is -Cl. In some embodiments, R b is -F. In some embodiments, R b is -Br. In some embodiments, R b is -I.

[0138] In some embodiments, R b is -CN.

[0139] In certain embodiments, R b is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu). In some embodiments, R b is -Me. In some embodiments, R b is -Et. In some embodiments, R b is -Pr. In some embodiments, R b is -iPr.

[0140] In certain embodiments, R b is -C1-C6 alkenyl (e.g., vinyl, propenyl). In some embodiments, R b is vinyl. In some embodiments, R b is propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl). In some embodiments, R b is prop-1-en-2-yl (-C(=CH2)CH3).

[0141] In some embodiments, R b is —C1-C6 heteroalkyl. In some embodiments, R b is methoxymethyl (—CH2OCH3). In some embodiments, R b is aminomethyl (e.g., —CHNHCHCH, —CHN(CH)CHCF, —CHN(CH)CHCH, —CHN(CH)—CHNH, —CHNHCH, —CHN(CH)). In some embodiments, R b is -CH2N(CH3)CH2CF3.

[0142] In some embodiments, R b is -C1-C6 haloalkyl. In some embodiments, R b is trifluoromethyl (-CF). In other embodiments, R b is difluoromethyl (-CHF2).

[0143] In some embodiments, R b is —C1-C6 hydroxyalkyl (e.g., —CH2OH, —CH2CH2OH, —CH(OH)CF3). In some embodiments, R b is hydroxymethyl (-CHOH).

[0144] In some embodiments, R b is -C3-C 10 and cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), each of which can be optionally substituted. In some embodiments, R b is an optionally substituted cyclopropyl (e.g., cyclopropyl substituted with 0, 1, or 2 instances of -F, -Me, or -CN, or cyclopropyl substituted with 0, 1, or 2 instances of -F, -Me, or -CN). In some embodiments, R b is cyclobutyl. In some embodiments, R b is cyclopentyl. In some embodiments, R b is cyclohexyl.

[0145] In some embodiments, R b is a 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.4]octanyl), each of which can be optionally substituted. In some embodiments, R b is oxetanyl. In some embodiments, R bis tetrahydropyranyl. In some embodiments, R b is tetrahydrofuranyl. In some embodiments, R b is azetidinyl (e.g., azetidinyl substituted with 0 or 1 instance of halo or methyl). In some embodiments, R b is pyrrolidinyl. In some embodiments, R b is piperidinyl. In some embodiments, R b is piperazinyl. In some embodiments, R b is morpholinyl. In some embodiments, R b is azepanyl. In some embodiments, R b is 6-oxa-1-azaspiro[3.3]heptanyl. In some embodiments, R b is 6-oxa-1-azaspiro[3.4]octanyl.

[0146] In some embodiments, R b is an optionally substituted -C-C 10 aryl (e.g., phenyl, naphthyl). In some embodiments, R b is an optionally substituted phenyl (eg, phenyl substituted with 0 or 1 instance of halo (eg, —Cl, —F)).

[0147] In some embodiments, R b is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R b is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0148] In some embodiments, R bis arylalkyl. In some embodiments, R b is benzyl.

[0149] In some embodiments, R b is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0150] In some embodiments, R b -OR b1 (e.g., hydroxy (—OH), methoxy, —OCD, difluoromethoxy (—OCHF), trifluoromethoxy (—OCF), —OCH(CH)CF, —OCHCF, ethoxy, propoxy, isopropoxy, —OCHCH(CH), cyclopropyloxy, cyclobutyloxy). In some embodiments, R b is hydroxy. In some embodiments, R b is methoxy. In some embodiments, R b is ethoxy. In some embodiments, R b is propoxy. In some embodiments, R b is isopropoxy. In some embodiments, R b is difluoromethoxy (-OCHF). In some embodiments, R b is trifluoromethoxy (-OCF). In some embodiments, R b is —OCH(CH)CF. In some embodiments, R b is —OCH CF . In some embodiments, R b is cyclopropyloxy.

[0151] In some embodiments, R b is -N(R b1 )2 (e.g., -NH2, -NHR b1 , -N(CH3)R b1 In some embodiments, R b is -NH. In some embodiments, Rb -NHR b1 (e.g., -NHMe, -NHEt, -NHPr, -NH i In some embodiments, R b is -N(CH3)R b1 (For example, -NMe2, -N(CH3)Et, -N(CH3)Pr, -N(CH3) i -Pr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl).

[0152] In some embodiments, R b is -C(=O)R b1 or -C(=O)OR b1 In some embodiments, R b is -C(=O)R b1 and R b1 is as described herein. In some embodiments, R b is —C(═O)alkyl. In some embodiments, R b -C(O)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) t Bu, -C(O) i Pr, -C(O)Pr, -C(O) i Bu, or —C(═O)OMe. In some embodiments, R b is acetyl (—C(═O)Me). In some embodiments, R b is -C(=O)OR b1 In some embodiments, R b is —COOH. In some embodiments, R b is COOMe.

[0153] In some embodiments, R b is -NR b1 C(=O)R b1 In certain embodiments, R b is -NHC(=O)R b1(For example, -NH, -NHC(=O)Me, -NH, -NHC(=O)Et, -NH, -NHC(=O)Pr, -NH, -NHC(=O) i Pr, -NH, -NHC(=O)Bu, -NH, -NHC(=O) t Bu, —NH, —NHC(═O)cyclopropyl, —NH, —NHC(═O)cyclobutyl). In some embodiments, R b is -N(CH3)C(=O)R b1 (For example, -N(CH3)C(=O)Me, -N(CH3)C(=O)Et, -N(CH3)C(=O)Pr, -N(CH3)C(=O) i Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O) t Bu, -N(CH3)C(=O)cyclopropyl, -N(CH3)C(=O)cyclobutyl.

[0154] In some embodiments, R b is -NR b1 C(=O)OR b1 In certain embodiments, R b is -NHC(=O)OR b1 (For example, -NH, -NHC(=O)OMe, -NH, -NHC(=O)OEt, -NH, -NHC(=O)OPr, -NH, -NHC(=O)O i Pr, -NH, -NHC(=O)OBu, -NH, -NHC(=O)O t Bu, —NH, —NHC(═O)Ocyclopropyl, —NH, —NHC(═O)Ocyclobutyl). In some embodiments, R b is -N(CH3)C(=O)OR b1 (For example, -N(CH3)C(=O)OMe, -N(CH3)C(=O)OEt, -N(CH3)C(=O)OPr, -N(CH3)C(=O)O i Pr, -N(CH3)C(=O)OBu, -N(CH3)C(=O)O t Bu, -N(CH3)C(=O)Ocyclopropyl, -N(CH3)C(=O)Ocyclobutyl).

[0155] In some embodiments, R bis -C(=O)N(R b1 )2 (e.g., -C(=O)NH2, -C(=O)NHR b1 , -C(=O)N(CH3)R b1 In some embodiments, R b is —C(═O)NH. In certain embodiments, R b is -C(=O)NHR b1 (e.g. -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t Bu, —C(═O)NHcyclopropyl, —C(═O)NHcyclobutyl). In certain embodiments, R b is -C(=O)N(CH3)R b1 (For example, -C(=O)NMe2, -C(=O)N(CH3)Et, -C(=O)N(CH3)Pr, -C(=O)N(CH3) i Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3) t -Bu, -C(=O)N(CH3)cyclopropyl, -C(=O)N(CH3)cyclobutyl).

[0156] In some embodiments, R b is -OC(=O)N(R b1 )2. In certain embodiments, R b is -OC(=O)NHR b1 (e.g. -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, —OC(═O)NHcyclopropyl, —OC(═O)NHcyclobutyl). In certain embodiments, R b is -OC(=O)N(CH3)R b1 (For example, -OC(=O)NMe2, -OC(=O)N(CH3)Et, -OC(=O)N(CH3)Pr, -OC(=O)N(CH3) i Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3) tBu, -OC(=O)N(CH3)cyclopropyl, -OC(=O)N(CH3)cyclobutyl).

[0157] In some embodiments, R b is -S(=O)R b1 In certain embodiments, R b is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i Pr). In certain embodiments, R b is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0158] In some embodiments, R b is -S(=O)2R b1 In certain embodiments, R b is -S(=O)2 alkyl (e.g., -S(=O)2 Me, -S(=O)2 Et, -S(=O)2 Pr, -S(=O)2 i Pr). In certain embodiments, R b is -S(=O)2cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, R b is S(=O)2 aryl (e.g., S(=O)2 phenyl).

[0159] In some embodiments, R b -SR b1 In certain embodiments, R b is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i Pr). In certain embodiments, R b is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R b is -Saryl (e.g., Sphenyl).

[0160] In some embodiments, R b is -S(=O)(=NR b1 )R b1 In certain embodiments, R b is -S(=O)(=NH)R b1 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R b is -S(=O)(=NCH3)R b1 (For example, -S(=O)(=NCH3)Me, -S(=O)(=NCH3)Et, -S(=O)(=NCH3)Pr, -S(=O)(=NCH3) i Pr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3) t -Bu, -S(=O)(=NCH3)cyclopropyl, -S(=O)(=NCH3)cyclobutyl).

[0161] In some embodiments, R b is -NR b1 S(=O)2R b1 In certain embodiments, R b is -NHS(=O)2 alkyl (e.g., -NHS(=O)2 Me, -NHS(=O)2 Et, -NHS(=O)2 Pr, -NHS(=O)2 i Pr). In certain embodiments, R b is -NHS(=O)2cycloalkyl (e.g., -NHS(=O)2cyclopropyl, -NHS(=O)2cyclobutyl, -NHS(=O)2cyclopentyl, -NHS(=O)2cyclohexyl). In certain embodiments, R b is -N(CH3)S(=O)2 alkyl (e.g., -N(CH3)S(=O)2Me, -N(CH3)S(=O)2Et, -N(CH3)S(=O)2Pr, -N(CH3)S(=O)2i Pr). In certain embodiments, R b is —N(CH3)S(═O)2 cycloalkyl (e.g., —N(CH3)S(═O)2 cyclopropyl, —N(CH3)S(═O)2 cyclobutyl, —N(CH3)S(═O)2 cyclopentyl, —N(CH3)S(═O)2 cyclohexyl).

[0162] In some embodiments, R b is -S(=O)2N(R b1 )2 (e.g., -S(=O)2NH2, -S(=O)2NHR b1 , -S(=O)2N(CH3)R b1 In some embodiments, R b is —S(═O)NH. In some embodiments, R b is -S(=O)2NHR b1 (For example, -S(=O)2NHMe, -S(=O)2NHEt, -S(=O)2NHPr, -S(=O)2NH i In some embodiments, R b is -S(=O)2N(CH3)R b1 (For example, -S(=O)2NMe2, -S(=O)2N(CH3)Et, -S(=O)2N(CH3)Pr, -S(=O)2N(CH3) i -Pr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0163] In some embodiments, two R b together with the atom to which they are attached form an optionally substituted 4- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl. In some cases, the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2. In some cases, two R bThe ring formed by the group is an optionally substituted 1,3 dioxole (eg, a dioxole substituted with 0, 1, or 2 instances of -F or -Me).

[0164] As generally defined herein, each R b1 is independently selected from H, —C1-C6 alkyl (each hydrogen can be independently replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0165] In some embodiments, each R b1 are independently H, -C1-C6 alkyl (each hydrogen can be independently replaced by deuterium) (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, R is selected from the group consisting of -C1-C6 heteroalkyl (e.g., -Bu, -sec-Bu, -iso-Bu), -C1-C6 heteroalkyl (e.g., -CHOMe), -C1-C6 haloalkyl (e.g., -CHF2, -CF3, -CH(CH3)CF3, -CH2CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). b1 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0166] In some embodiments, each R b1are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0167] In some embodiments, each R b1 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, R is selected from the group consisting of -C1-C6 heteroalkyl (e.g., -Bu, -sec-Bu, -iso-Bu), -C1-C6 heteroalkyl (e.g., -CHOMe), -C1-C6 haloalkyl (e.g., -CHF2, -CF3, -CH(CH3)CF3, -CH2CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). b1 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0168] In some embodiments, each R b1 are independently H.

[0169] In some embodiments, each R b1 are independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, each R b1is independently -Me. In some embodiments, each R b1 is independently -Et. In some embodiments, each R b1 is independently -Pr. In some embodiments, each R b1 is, independently, - i It is Pr.

[0170] In some embodiments, each R b1 are independently H.

[0171] In some embodiments, each R b1 are independently -C1-C6 alkyl (each hydrogen can be independently replaced by deuterium) (e.g., -Me, -CD3, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, each R b1 is independently -Me. In some embodiments, each R b1 is independently -CD3. In some embodiments, each R b1 is independently -Et. In some embodiments, each R b1 is independently -Pr. In some embodiments, each R b1 is, independently, - i It is Pr.

[0172] In some embodiments, each R b1 is independently —C1-C6 heteroalkyl. In some embodiments, each R b1 is independently methoxymethyl (—CHOCH). In some embodiments, each R b1 are independently aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH)).

[0173] In some embodiments, each R b1 is independently —C1-C6 haloalkyl. In some embodiments, each R b1is independently trifluoromethyl (—CF). In other embodiments, each R b1 is independently difluoromethyl (-CHF). In some embodiments, R b1 is —CHF. In some embodiments, each R b1 is —CH(CH)CF. In some embodiments, each R b1 is -CH2CF3.

[0174] In some embodiments, each R b1 is independently —C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each R b1 is independently cyclopropyl. In some embodiments, each R b1 is independently cyclobutyl. In some embodiments, each R b1 is independently cyclopentyl. In some embodiments, each R b1 is independently cyclohexyl.

[0175] In some embodiments, each R b1 is independently 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0176] In some embodiments, R b1 is independently heteroaryl. In some embodiments, R b1 is independently a 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S). In some embodiments, R b1is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R b1 is independently a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). b1 is independently thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, R b1 is independently pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R b1 is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R b1 is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, R b1 is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R b1 is independently pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).

[0177] In some embodiments, R b1 is independently aryl. In some embodiments, R b1 is independently a 6- to 10-membered mono- or bicyclic aryl. In some embodiments, R b1 is independently phenyl.

[0178] In some embodiments, each R b1is independently cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, each R b1 is independently heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0179] In some embodiments, each R b1 is independently arylalkyl. In some embodiments, each R b1 is independently benzyl.

[0180] In some embodiments, each R b1 is independently heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0181] In some embodiments, the compound of formula (II) is During the ceremony, [ka] X 1 is selected from CH and N; X 2 is selected from CH and N; R 3 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; R 4 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a3 and R a4 are independently selected from H, —C1-C6 alkyl (each hydrogen can be replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0182] In some embodiments, the compound of formula (II) is During the ceremony, [ka] X 1 is selected from CH and N; X 2 is selected from CH and N; R 3 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; R 4 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R a3 and R a4are independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0183] In certain embodiments, X 1 is CH. In other embodiments, X 1 is N.

[0184] In certain embodiments, X 2 is CH. In other embodiments, X 2 is N. In some embodiments, X 1 is N and X 2 is CH. In some embodiments, X 1 is CH and X 2 is CH. In some embodiments, X 1 is N and X 2 is N. In some embodiments, X 1 is CH and X 2 is N.

[0185] In some embodiments, [ka] The part represented by [ka] is selected from.

[0186] As generally defined herein, each R 3are independently H, -D, halo, -CN, -C1-C6 alkyl (each hydrogen can be replaced by deuterium), -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0187] In some embodiments, each R 3 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, -OR a3 and -N(R a3)2, wherein each aryl, alkyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2, or oxo; and each R a3 is independently selected from H, —C1-C6 alkyl (each hydrogen can be replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, and —C3-C9 cycloalkyl.

[0188] In some embodiments, each R 3 are independently H, -D, halo (e.g., -F, -Cl), -CN, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH), -C3-C 10 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -C6-C 10 aryl (e.g., phenyl), -OR a3 and -N(R a3 )2, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., —F, —Cl), and each R a3 are independently H, -C1-C6 alkyl (each hydrogen can be replaced by deuterium) (e.g., -Me, -Et, -Pr, - i Pr, -n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0189] In some embodiments, each R 3 are independently H, -D, -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - i Pr, -CH2N(CH3)CH2CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0 or 1 instance of -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -OCH2F, -O i Pr, -OMe, -OEt, -OCD3, -OCH2CH(CH3)3, -N(Me)2 and -NHMe and -NH i Pr is selected from.

[0190] In some embodiments, each R 3 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 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)Ra3 , -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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0191] In some embodiments, each R 3 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, -OR a3 and -N(R a3 )2, wherein each aryl, alkyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2, or oxo; and each R a3 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, and —C3-C9 cycloalkyl.

[0192] In some embodiments, each R 3 are independently H, -D, halo (e.g., -F, -Cl), -CN, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - tBu), -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH), -C3-C 10 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -C6-C 10 aryl (e.g., phenyl), -OR a3 and -N(R a3 )2, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., —F, —Cl), and each R a3 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0193] In some embodiments, each R 3 are independently H, -D, -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - iPr, -CH2N(CH3)CH2CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0 or 1 instance of -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -O i Pr, -OMe, -OCH2CH(CH3)3, -N(Me)2 and -NHMe and -NH i Pr is selected from.

[0194] In some embodiments, R 3 is H. In some embodiments, R 3 is -D.

[0195] In certain embodiments, R 3 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 3 is -Cl. In some embodiments, R 3 is -F. In some embodiments, R 3 is -Br. In some embodiments, R 3 is -I.

[0196] In some embodiments, R 3 is -CN.

[0197] In certain embodiments, R 3 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t In some embodiments, R 3 is -Me. In some embodiments, R 3 is -Et. In some embodiments, R 3 is -Pr. In some embodiments, R 3 is -iPr. In some embodiments, R 3 is -C(CH3)CH2CH3.

[0198] In certain embodiments, R 3 is -C1-C6 alkenyl (e.g., vinyl, propenyl). In some embodiments, R 3 is vinyl. In some embodiments, R 3 is propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl). In some embodiments, R 3 is prop-1-en-2-yl (-C(=CH2)CH3).

[0199] In some embodiments, R 3 is —C1-C6 heteroalkyl. In some embodiments, R 3 is methoxymethyl (—CH2OCH3). In some embodiments, R 3 is aminomethyl (e.g., —CHNH, —CHNHCH, —CHNHCHCH, —CHN(CH)). In some embodiments, R 3 is —CHN(CH)CHCH. In some embodiments, R 3 is -CH2N(CH3)CH2CF3.

[0200] In some embodiments, R 3 is -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3). In some embodiments, R 3 is trifluoromethyl (-CF). In other embodiments, R 3 is difluoromethyl (-CHF). In other embodiments, R 3 is -CH2CF3.

[0201] In some embodiments, R 3 is —C1-C6 hydroxyalkyl (e.g., —CH2OH, —CH2CH2OH), —CH(OH)CF3). In some embodiments, R 3 is hydroxymethyl (-CHOH).

[0202] In some embodiments, R 3 is an optionally substituted -C-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 3 is an optionally substituted cyclopropyl (e.g., substituted with 0 or 1 instance of —CN). In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.

[0203] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.4]octanyl). In some embodiments, R 3 is oxetanyl. In some embodiments, R 3 is tetrahydropyranyl. In some embodiments, R 3 is tetrahydrofuranyl. In some embodiments, R 3 is azetidinyl. In certain embodiments, the azetidinyl is optionally substituted (e.g., substituted with 0 or 1 instance of -F or -Me). In some embodiments, R 3 is pyrrolidinyl. In some embodiments, R 3 is piperidinyl. In some embodiments, R 3 is piperazinyl. In some embodiments, R 3 is morpholinyl. In some embodiments, R 3 is azepanyl. In some embodiments, R 3is 6-oxa-1-azaspiro[3.3]heptanyl. In some embodiments, R 3 is 6-oxa-1-azaspiro[3.4]octanyl.

[0204] In some embodiments, R 3 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 3 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0205] In some embodiments, R 3 is arylalkyl. In some embodiments, R 3 is benzyl.

[0206] In some embodiments, R 3 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0207] In some embodiments, R 3 is an optionally substituted -C-C 10 aryl (e.g., phenyl, naphthyl). In some embodiments, R 3 is an optionally substituted phenyl (e.g., phenyl substituted with 0 or 1 instance of halo (e.g., -Cl, -F)). In certain embodiments, R 3 is 2-Cl-phenyl.

[0208] In some embodiments, R 3 -OR a3(e.g., hydroxy (-OH), methoxy, -OCD, difluoromethoxy (-OCHF), fluoromethoxy (-OCHF), trifluoromethoxy (-OCF), -OCH(CH)CF, -OCHCF, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, -OCHCH(CH)). In some embodiments, R 3 is hydroxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is isopropoxy. In some embodiments, R 3 is difluoromethoxy (-OCHF). In some embodiments, R 3 is trifluoromethoxy (-OCF). In some embodiments, R 3 is —OCH(CH)CF. In some embodiments, R 3 is —OCH CF . In some embodiments, R 3 is cyclopropyloxy. In some embodiments, R 3 is -OCH2CH(CH3)3.

[0209] In some embodiments, R 3 is -N(R a3 )2 (e.g., -NH2, -NHR a3 , -N(CH3)R a3 In some embodiments, R 3 is -NH. In some embodiments, R 3 -NHR a3 (e.g., -NHMe, -NHEt, -NHPr, -NH i In some embodiments, R 3 is -N(CH3)R a3 (For example, -NMe2, -N(CH3)Et, -N(CH3)Pr, -N(CH3) i-Pr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl).

[0210] In some embodiments, R 3 is -C(=O)R a3 or -C(=O)OR a3 In some embodiments, R 3 is -C(=O)R a3 and R a3 is as described herein. In some embodiments, R 3 is —C(═O)alkyl. In some embodiments, R 3 -C(O)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) t Bu, -C(O) i Pr, -C(O)Pr, -C(O) i Bu, or —C(═O)OMe. In some embodiments, R 3 is acetyl (—C(═O)Me). In some embodiments, R 3 is -C(=O)OR a3 In some embodiments, R 3 is —COOH. In some embodiments, R 3 is COOMe.

[0211] In some embodiments, R 3 is -NR a3 C(=O)R a3 In certain embodiments, R 3 is -NHC(=O)R a3 (For example, -NH, -NHC(=O)Me, -NH, -NHC(=O)Et, -NH, -NHC(=O)Pr, -NH, -NHC(=O) i Pr, -NH, -NHC(=O)Bu, -NH, -NHC(=O) t Bu, —NH, —NHC(═O)cyclopropyl, —NH, —NHC(═O)cyclobutyl). In some embodiments, R 3 is -N(CH3)C(=O)R a3(For example, -N(CH3)C(=O)Me, -N(CH3)C(=O)Et, -N(CH3)C(=O)Pr, -N(CH3)C(=O) i Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O) t Bu, -N(CH3)C(=O)cyclopropyl, -N(CH3)C(=O)cyclobutyl.

[0212] In some embodiments, R 3 is -NR a3 C(=O)OR a3 In certain embodiments, R 3 is -NHC(=O)OR a3 (For example, -NH, -NHC(=O)OMe, -NH, -NHC(=O)OEt, -NH, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t Bu, -NHC(=O)Ocyclopropyl, -NHC(=O)Ocyclobutyl). In some embodiments, R 3 is -N(CH3)C(=O)OR a3 (For example, -N(CH3)C(=O)OMe, -N(CH3)C(=O)OEt, -N(CH3)C(=O)OPr, -N(CH3)C(=O)O i Pr, -N(CH3)C(=O)OBu, -N(CH3)C(=O)O t Bu, -N(CH3)C(=O)Ocyclopropyl, -N(CH3)C(=O)Ocyclobutyl).

[0213] In some embodiments, R 3 is -C(=O)N(R a3 )2 (e.g., -C(=O)NH2, -C(=O)NHR a3 , -C(=O)N(CH3)R a3 In some embodiments, R 3 is —C(═O)NH. In certain embodiments, R 3 is -C(=O)NHR a3 (e.g. -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O)NHi Pr, -C(=O)NHBu, -C(=O)NH t Bu, —C(═O)NHcyclopropyl, —C(═O)NHcyclobutyl). In certain embodiments, R 3 is -C(=O)N(CH3)R a3 (For example, -C(=O)NMe2, -C(=O)N(CH3)Et, -C(=O)N(CH3)Pr, -C(=O)N(CH3) i Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3) t -Bu, -C(=O)N(CH3)cyclopropyl, -C(=O)N(CH3)cyclobutyl).

[0214] In some embodiments, R 3 is -OC(=O)N(R a3 )2. In certain embodiments, R 3 is -OC(=O)NHR a3 (e.g. -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, —OC(═O)NHcyclopropyl, —OC(═O)NHcyclobutyl). In certain embodiments, R 3 is -OC(=O)N(CH3)R a3 (For example, -OC(=O)NMe2, -OC(=O)N(CH3)Et, -OC(=O)N(CH3)Pr, -OC(=O)N(CH3) i Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3) t Bu, -OC(=O)N(CH3)cyclopropyl, -OC(=O)N(CH3)cyclobutyl).

[0215] In some embodiments, R 3 is -S(=O)R a3 In certain embodiments, R 3 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) iPr). In certain embodiments, R 3 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0216] In some embodiments, R 3 is -S(=O)2R a3 In certain embodiments, R 3 is -S(=O)2 alkyl (e.g., -S(=O)2 Me, -S(=O)2 Et, -S(=O)2 Pr, -S(=O)2 i Pr). In certain embodiments, R 3 is -S(=O)2cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, R 3 is S(=O)2 aryl (e.g., S(=O)2 phenyl).

[0217] In some embodiments, R 3 -SR a3 In certain embodiments, R 3 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i Pr). In certain embodiments, R 3 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 3 is -Saryl (e.g., Sphenyl).

[0218] In some embodiments, R 3 is -S(=O)(=NR a3 )R a3 In certain embodiments, R 3 is -S(=O)(=NH)R a3 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) iPr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 3 is -S(=O)(=NCH3)R a3 (For example, -S(=O)(=NCH3)Me, -S(=O)(=NCH3)Et, -S(=O)(=NCH3)Pr, -S(=O)(=NCH3) i Pr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3) t -Bu, -S(=O)(=NCH3)cyclopropyl, -S(=O)(=NCH3)cyclobutyl).

[0219] In some embodiments, R 3 is -NR a3 S(=O)2R a3 In certain embodiments, R 3 is -NHS(=O)2 alkyl (e.g., -NHS(=O)2 Me, -NHS(=O)2 Et, -NHS(=O)2 Pr, -NHS(=O)2 i Pr). In certain embodiments, R 3 is -NHS(=O)2cycloalkyl (e.g., -NHS(=O)2cyclopropyl, -NHS(=O)2cyclobutyl, -NHS(=O)2cyclopentyl, -NHS(=O)2cyclohexyl). In certain embodiments, R 3 is -N(CH3)S(=O)2 alkyl (e.g., -N(CH3)S(=O)2Me, -N(CH3)S(=O)2Et, -N(CH3)S(=O)2Pr, -N(CH3)S(=O)2 i Pr). In certain embodiments, R 3 is —N(CH3)S(═O)2 cycloalkyl (e.g., —N(CH3)S(═O)2 cyclopropyl, —N(CH3)S(═O)2 cyclobutyl, —N(CH3)S(═O)2 cyclopentyl, —N(CH3)S(═O)2 cyclohexyl).

[0220] In some embodiments, R 3 is -S(=O)2N(Ra3 )2 (e.g., -S(=O)2NH2, -S(=O)2NHR a3 , -S(=O)2N(CH3)R a3 In some embodiments, R 3 is —S(═O)NH. In some embodiments, R 3 is -S(=O)2NHR a3 (For example, -S(=O)2NHMe, -S(=O)2NHEt, -S(=O)2NHPr, -S(=O)2NH i In some embodiments, R 3 is -S(=O)2N(CH3)R a3 (For example, -S(=O)2NMe2, -S(=O)2N(CH3)Et, -S(=O)2N(CH3)Pr, -S(=O)2N(CH3) i -Pr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0221] As generally defined herein, each R a3 are independently selected from H, —C1-C6 alkyl (each hydrogen can be replaced by deuterium), —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0222] In some embodiments, each R a3 are independently H, -C1-C6 alkyl (each hydrogen can be replaced by deuterium) (e.g., -Me, -CD3, Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - tBu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0223] In some embodiments, each R a3 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0224] In some embodiments, each R a3 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0225] In some embodiments, each R a3 are independently H.

[0226] In some embodiments, each R a3 are independently -C1-C6 alkyl (each hydrogen can be replaced by deuterium) (e.g., -Me, -CD3, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, each R a3 is independently -Me. In some embodiments, each R a3 is independently -Et. In some embodiments, each R a3is independently -Pr. In some embodiments, each R a3 is, independently, - i It is Pr.

[0227] In some embodiments, each R a3 is independently —C1-C6 heteroalkyl. In some embodiments, each R a3 is independently methoxymethyl (—CHOCH). In some embodiments, each R a3 are independently aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH)).

[0228] In some embodiments, each R a3 is independently —C1-C6 haloalkyl. In some embodiments, each R a3 is independently trifluoromethyl (—CF). In other embodiments, each R a3 is independently difluoromethyl (-CHF). In some embodiments, each R a3 is independently CHF. In some embodiments, each R a3 is —CH(CH)CF. In some embodiments, each R a3 is -CH2CF3.

[0229] In some embodiments, each R a3 is independently —C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each R a3 is independently cyclopropyl. In some embodiments, each R a3 is independently cyclobutyl. In some embodiments, each R a3 is independently cyclopentyl. In some embodiments, each R a3 is independently cyclohexyl.

[0230] In some embodiments, each R a3is independently 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0231] In some embodiments, R a3 is independently heteroaryl. In some embodiments, R a3 is independently a 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S). In some embodiments, R a3 is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R a3 is independently a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). a3 is independently thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, R a3 is independently pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R a3 is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R a3 is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, R a3 is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R a3is independently pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).

[0232] In some embodiments, R a3 is independently aryl. In some embodiments, R a3 is independently a 6- to 10-membered mono- or bicyclic aryl. In some embodiments, R a3 is independently phenyl.

[0233] In some embodiments, each R a3 is independently cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, each R a3 is independently heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0234] In some embodiments, each R a3 is independently arylalkyl. In some embodiments, each R a3 is independently benzyl.

[0235] In some embodiments, each R a3 is independently heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0236] As generally defined herein, each R 4 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10Aryl, 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, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0237] In some embodiments, each R 4 are independently H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C6 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, -OR a4 and -N(R a4 )2, wherein each aryl, alkyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl), -OH, -CN, -Me, -Et, -NH2, or oxo; and each R a4 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, and —C3-C9 cycloalkyl.

[0238] In some embodiments, each R 4are independently H, -D, halo (e.g., -F, -Cl), -CN, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH), -C3-C 10 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -C6-C 10 aryl (e.g., phenyl), -OR a4 and -N(R a4 )2, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., -F, -Cl) or -Me; and each R a4 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0239] In some embodiments, each R 4 are independently H, -D, -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - iPr, -CH2N(CH3)CH2CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0, 1 or 2 instances of -CN, -F, or -Me), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -O i Pr, -OMe, -OCH2CH(CH3)3, -N(Me)2 and -NHMe and -NH i Pr is selected from.

[0240] In some embodiments, each R 4 are independently H, -D, halo (e.g., -F, -Cl), -CN, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), -C1-C6 alkenyl (e.g., vinyl, propenyl), -C1-C6 heteroalkyl (e.g., -CH2NHCH2CH3, -CH2N(CH3)CH2CH3, -CH2N(CH3)2), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 hydroxyalkyl (e.g., -CH2OH), -C3-C 10 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3- to 10-membered heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-aspiro[3.4]octanyl), -C6-C 10 aryl (e.g., phenyl), -OR a4 and -N(R a4 )2, wherein each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo (e.g., —F, —Cl), and each R a4 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - nBu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and —C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0241] In some embodiments, each R 4 are independently H, -D, -CN, -C(=CH2)CH3, -C(CH3)CH2CH3, -Cl, -F, -Me, - i Pr, -CH2N(CH3)CH2CF3, -CF3, -CH2CF3, cyclopropyl (substituted with 0 or 1 instance of -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF3, -OCH2CF3, -OCHF2, -O i Pr, -OMe, -OCH2CH(CH3)3, -N(Me)2 and -NHMe and -NH i Pr is selected from.

[0242] In certain embodiments, R 4 is selected from H and -OMe.

[0243] In some embodiments, R 4 is H. In some embodiments, R 4 is -D.

[0244] In certain embodiments, R 4 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Br. In some embodiments, R 4 is -I.

[0245] In some embodiments, R 4 is -CN.

[0246] In certain embodiments, R 4 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t In some embodiments, R 4 is -Me. In some embodiments, R 4 is -Et. In some embodiments, R 4 is -Pr. In some embodiments, R 4 is -iPr. In some embodiments, R 4 is -C(CH3)CH2CH3.

[0247] In certain embodiments, R 4 is -C1-C6 alkenyl (e.g., vinyl, propenyl). In some embodiments, R 4 is vinyl. In some embodiments, R 4 is propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl). In some embodiments, R 4 is prop-1-en-2-yl (-C(=CH2)CH3).

[0248] In some embodiments, R 4 is —C1-C6 heteroalkyl. In some embodiments, R 4 is methoxymethyl (—CH2OCH3). In some embodiments, R 4 is aminomethyl (e.g., —CHNH, —CHNHCH, —CHNHCHCH, —CHN(CH)). In some embodiments, R 4 is —CHN(CH)CHCH. In some embodiments, R 4 is -CH2N(CH3)CH2CF3.

[0249] In some embodiments, R 4is -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3). In some embodiments, R 4 is trifluoromethyl (-CF). In other embodiments, R 4 is difluoromethyl (-CHF). In other embodiments, R 4 is -CH2CF3.

[0250] In some embodiments, R 4 is —C1-C6 hydroxyalkyl (e.g., —CH2OH, —CH2CH2OH). In some embodiments, R 4 is hydroxymethyl (-CHOH).

[0251] In some embodiments, R 4 is an optionally substituted -C-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 4 is an optionally substituted cyclopropyl (e.g., substituted with 0, 1, or 2 instances of -CN, -F, or -Me). In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is cyclohexyl.

[0252] In some embodiments, R 4 is an optionally substituted 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.4]octanyl). In some embodiments, R 4 is oxetanyl. In some embodiments, R 4 is tetrahydropyranyl. In some embodiments, R 4is tetrahydrofuranyl. In some embodiments, R 4 is azetidinyl. In certain embodiments, the azetidinyl is optionally substituted (e.g., substituted with 0 or 1 instance of -F or -Me). In some embodiments, R 4 is pyrrolidinyl. In some embodiments, R 4 is piperidinyl. In some embodiments, R 4 is piperazinyl. In some embodiments, R 4 is morpholinyl. In some embodiments, R 4 is azepanyl. In some embodiments, R 4 is 6-oxa-1-azaspiro[3.3]heptanyl. In some embodiments, R 4 is 6-oxa-1-azaspiro[3.4]octanyl.

[0253] In some embodiments, R 4 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 4 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0254] In some embodiments, R 4 is arylalkyl. In some embodiments, R 4 is benzyl.

[0255] In some embodiments, R 4 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0256] In some embodiments, R4 is an optionally substituted -C-C 10 aryl (e.g., phenyl, naphthyl). In some embodiments, R 4 is an optionally substituted phenyl (e.g., phenyl substituted with 0 or 1 instance of halo (e.g., -Cl, -F)). In certain embodiments, R 4 is 2-Cl-phenyl.

[0257] In some embodiments, R 4 -OR a4 (e.g., hydroxy (—OH), methoxy, difluoromethoxy (—OCHF), trifluoromethoxy (—OCF), —OCH(CH)CF, —OCHCF, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, —OCHCH(CH)). In some embodiments, R 4 is hydroxy. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is isopropoxy. In some embodiments, R 4 is difluoromethoxy (-OCHF). In some embodiments, R 4 is trifluoromethoxy (-OCF). In some embodiments, R 4 is —OCH(CH)CF. In some embodiments, R 4 is —OCH CF . In some embodiments, R 4 is cyclopropyloxy. In some embodiments, R 4 is -OCH2CH(CH3)3.

[0258] In some embodiments, R 4 is -N(R a4 )2 (e.g., -NH2, -NHR a4 , -N(CH3)R a4In some embodiments, R 4 is -NH. In some embodiments, R 4 -NHR a4 (e.g., -NHMe, -NHEt, -NHPr, -NH i In some embodiments, R 4 is -N(CH3)R a4 (For example, -NMe2, -N(CH3)Et, -N(CH3)Pr, -N(CH3) i -Pr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl).

[0259] In some embodiments, R 4 is -C(=O)R a4 or -C(=O)OR a4 In some embodiments, R 4 is -C(=O)R a4 and R a4 is as described herein. In some embodiments, R 4 is —C(═O)alkyl. In some embodiments, R 4 -C(O)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) t Bu, -C(O) i Pr, -C(O)Pr, -C(O) i Bu, or —C(═O)OMe. In some embodiments, R 4 is acetyl (—C(═O)Me). In some embodiments, R 4 is -C(=O)OR a4 In some embodiments, R 4 is —COOH. In some embodiments, R 4 is COOMe.

[0260] In some embodiments, R 4 is -NR a4 C(=O)R a4 In certain embodiments, R 4 is -NHC(=O)Ra4 (e.g. -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) i Pr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 4 is -N(CH3)C(=O)R a4 (For example, -N(CH3)C(=O)Me, -N(CH3)C(=O)Et, -N(CH3)C(=O)Pr, -N(CH3)C(=O) i Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O) t Bu, -N(CH3)C(=O)cyclopropyl, -N(CH3)C(=O)cyclobutyl.

[0261] In some embodiments, R 4 is -NR a4 C(=O)OR a4 In certain embodiments, R 4 is -NHC(=O)OR a4 (e.g. -NHC(=O)OMe, -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t Bu, -NHC(=O)Ocyclopropyl, -NHC(=O)Ocyclobutyl). In some embodiments, R 4 is -N(CH3)C(=O)OR a4 (For example, -N(CH3)C(=O)OMe, -N(CH3)C(=O)OEt, -N(CH3)C(=O)OPr, -N(CH3)C(=O)O i Pr, -N(CH3)C(=O)OBu, -N(CH3)C(=O)O t Bu, -N(CH3)C(=O)Ocyclopropyl, -N(CH3)C(=O)Ocyclobutyl).

[0262] In some embodiments, R 4 is -C(=O)N(R a4 )2 (e.g., -C(=O)NH2, -C(=O)NHRa4 , -C(=O)N(CH3)R a4 In some embodiments, R 4 is —C(═O)NH. In certain embodiments, R 4 is -C(=O)NHR a4 (e.g. -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t Bu, —C(═O)NHcyclopropyl, —C(═O)NHcyclobutyl). In certain embodiments, R 4 is -C(=O)N(CH3)R a4 (For example, -C(=O)NMe2, -C(=O)N(CH3)Et, -C(=O)N(CH3)Pr, -C(=O)N(CH3) i Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3) t -Bu, -C(=O)N(CH3)cyclopropyl, -C(=O)N(CH3)cyclobutyl).

[0263] In some embodiments, R 4 is -OC(=O)N(R a4 )2. In certain embodiments, R 4 is -OC(=O)NHR a4 (e.g. -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, —OC(═O)NHcyclopropyl, —OC(═O)NHcyclobutyl). In certain embodiments, R 4 is -OC(=O)N(CH3)R a4 (For example, -OC(=O)NMe2, -OC(=O)N(CH3)Et, -OC(=O)N(CH3)Pr, -OC(=O)N(CH3) i Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3) t Bu, -OC(=O)N(CH3)cyclopropyl, -OC(=O)N(CH3)cyclobutyl).

[0264] In some embodiments, R 4 is -S(=O)R a4 In certain embodiments, R 4 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i Pr). In certain embodiments, R 4 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0265] In some embodiments, R 4 is -S(=O)2R a4 In certain embodiments, R 4 is -S(=O)2 alkyl (e.g., -S(=O)2 Me, -S(=O)2 Et, -S(=O)2 Pr, -S(=O)2 i Pr). In certain embodiments, R 4 is -S(=O)2cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, R 4 is S(=O)2 aryl (e.g., S(=O)2 phenyl).

[0266] In some embodiments, R 4 -SR a4 In certain embodiments, R 4 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i Pr). In certain embodiments, R 4 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 4 is -Saryl (e.g., Sphenyl).

[0267] In some embodiments, R 4is -S(=O)(=NR a4 )R a4 In certain embodiments, R 4 is -S(=O)(=NH)R a4 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 4 is -S(=O)(=NCH3)R a4 (For example, -S(=O)(=NCH3)Me, -S(=O)(=NCH3)Et, -S(=O)(=NCH3)Pr, -S(=O)(=NCH3) i Pr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3) t -Bu, -S(=O)(=NCH3)cyclopropyl, -S(=O)(=NCH3)cyclobutyl).

[0268] In some embodiments, R 4 is -NR a4 S(=O)2R a4 In certain embodiments, R 4 is -NHS(=O)2 alkyl (e.g., -NHS(=O)2 Me, -NHS(=O)2 Et, -NHS(=O)2 Pr, -NHS(=O)2 i Pr). In certain embodiments, R 4 is -NHS(=O)2cycloalkyl (e.g., -NHS(=O)2cyclopropyl, -NHS(=O)2cyclobutyl, -NHS(=O)2cyclopentyl, -NHS(=O)2cyclohexyl). In certain embodiments, R 4 is -N(CH3)S(=O)2 alkyl (e.g., -N(CH3)S(=O)2Me, -N(CH3)S(=O)2Et, -N(CH3)S(=O)2Pr, -N(CH3)S(=O)2 i Pr). In certain embodiments, R 4is —N(CH3)S(═O)2 cycloalkyl (e.g., —N(CH3)S(═O)2 cyclopropyl, —N(CH3)S(═O)2 cyclobutyl, —N(CH3)S(═O)2 cyclopentyl, —N(CH3)S(═O)2 cyclohexyl).

[0269] In some embodiments, R 4 is -S(=O)2N(R a4 )2 (e.g., -S(=O)2NH2, -S(=O)2NHR a4 , -S(=O)2N(CH3)R a4 In some embodiments, R 4 is —S(═O)NH. In some embodiments, R 4 is -S(=O)2NHR a4 (For example, -S(=O)2NHMe, -S(=O)2NHEt, -S(=O)2NHPr, -S(=O)2NH i In some embodiments, R 4 is -S(=O)2N(CH3)R a4 (For example, -S(=O)2NMe2, -S(=O)2N(CH3)Et, -S(=O)2N(CH3)Pr, -S(=O)2N(CH3) i -Pr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0270] As generally defined herein, each R a4 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0271] In some embodiments, each R a4 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - nBu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0272] In some embodiments, each R a4 are independently H.

[0273] In some embodiments, each R a4 are independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, each R a4 is independently -Me. In some embodiments, each R a4 is independently -Et. In some embodiments, each R a4 is independently -Pr. In some embodiments, each R a4 is, independently, - i It is Pr.

[0274] In some embodiments, each R a4 is independently —C1-C6 heteroalkyl. In some embodiments, each R a4 is independently methoxymethyl (—CHOCH). In some embodiments, each R a4 are independently aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH)).

[0275] In some embodiments, each R a4 is independently —C1-C6 haloalkyl. In some embodiments, each R a4 is independently trifluoromethyl (—CF). In other embodiments, each R a4is independently difluoromethyl (-CHF). In some embodiments, each R a4 is —CH(CH)CF. In some embodiments, each R a4 is -CH2CF3.

[0276] In some embodiments, each R a4 is independently —C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each R a4 is independently cyclopropyl. In some embodiments, each R a4 is independently cyclobutyl. In some embodiments, each R a4 is independently cyclopentyl. In some embodiments, each R a4 is independently cyclohexyl.

[0277] In some embodiments, each R a4 is independently 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0278] In some embodiments, R a4 is independently heteroaryl. In some embodiments, R a4 is independently a 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S). In some embodiments, R a4 is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R a4is independently a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). a4 is independently thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, R a4 is independently pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R a4 is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R a4 is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, R a4 is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R a4 is independently pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).

[0279] In some embodiments, R a4 is independently aryl. In some embodiments, R a4 is independently a 6- to 10-membered mono- or bicyclic aryl. In some embodiments, R a4 is independently phenyl.

[0280] In some embodiments, each R a4 is independently cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, each R a4is independently heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0281] In some embodiments, each R a4 is independently arylalkyl. In some embodiments, each R a4 is independently benzyl.

[0282] In some embodiments, each R a4 is independently heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0283] In certain embodiments, [ka] The part represented by [ka] is.

[0284] In some embodiments, [ka] The part represented by [ka] is selected from.

[0285] In some embodiments, [ka] The part represented by [ka] is. R 3 is as defined herein.

[0286] In some embodiments, R 3 is cyclopropyl, -OCH2CF3, -OCF3, -OCHF2, - i It is selected from Pr and -OMe.

[0287] In some embodiments, [ka] The part represented by [ka] (R 3 is as defined herein).

[0288] In some embodiments, R 3 -Cl, - i It is selected from: -Pr, -C(=CH2)CH3, -OCHF2, -OCF3, -2-Cl-phenyl, -CF3 and cyclopropyl.

[0289] As generally defined herein, each R c and R c’ is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, and —C1-C6 haloalkyl, or R c and R c’ can, together with the atom to which they are attached, form a -C3-C9 cycloalkyl or carbonyl.

[0290] In some embodiments, R c and R c’ are each independently selected from H and -Me, or taken together form a carbonyl group or a cyclopropyl group.

[0291] In some embodiments, R c is H and Rc’ is -Me.

[0292] In certain embodiments, R c and R c’ are each independently H.

[0293] In certain embodiments, R c and R c’ are each independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu). In some embodiments, R c and R c’ are each independently -Me. In some embodiments, R c and R c’ are each independently -Et. In some embodiments, R c and R c’ are each independently -Pr. In some embodiments, R c and R c’ are each independently -iPr.

[0294] In some embodiments, R c and R c’ are each independently -C1-C6 heteroalkyl. In some embodiments, R c and R c’ are each independently methoxymethyl (—CH2OCH3). In some embodiments, R c and R c’ are each independently hydroxymethyl (—CHOH). In some embodiments, R c and R c’ are each independently aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH)). In some embodiments, R c and R c’ are each independently —CHN(CH)CHCH.

[0295] In some embodiments, R c and R c’ are each independently -C1-C6 haloalkyl. In some embodiments, R c and R c’ are each independently trifluoromethyl (-CF). In other embodiments, R c and R c’ are each independently difluoromethyl (-CHF2).

[0296] In some embodiments, R c and R c’ together with the carbon to which they are attached to form a carbonyl group (C(=O)).

[0297] In some embodiments, R c and R c’ taken together with the carbon to which they are attached form -C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). In some embodiments, R c and R c’ together with the carbon to which they are attached form a cyclopropyl. In some embodiments, R c and R c’ together with the carbon to which they are attached form a cyclobutyl. In some embodiments, R c and R c’ together with the carbons to which they are attached form cyclopentyl. In some embodiments, R c and R c’ together with the carbon to which they are attached to form cyclohexyl.

[0298] As generally defined herein, ring A is a C6-C 10 Aryl, 5-10 membered heteroaryl, -C3-C 10 It is selected from cycloalkyl, and 3- to 10-membered heterocyclyl.

[0299] In certain embodiments, Ring A is selected from phenyl, pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl), thiophenyl (e.g., thiophen-2-yl), cyclohexyl, piperidinyl (e.g., piperidin-4-yl, piperidin-2-yl), and piperazinyl.

[0300] In some embodiments, ring A is a 6-membered heteroaryl containing 1 to 3 nitrogen atoms (e.g., pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl). In some embodiments, ring A is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, ring A is pyridin-2-yl.

[0301] In some embodiments, ring A is C6-C 10 and aryl (e.g., phenyl, naphthyl). In some embodiments, ring A is phenyl.

[0302] In some embodiments, ring A is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S (e.g., furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl). In some embodiments, ring A is thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, ring A is thiophen-2-yl.

[0303] In some embodiments, ring A is C3-C 10 and cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). In some embodiments, Ring A is cyclohexyl.

[0304] In other embodiments, ring A is a 3-10 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl). In some embodiments, ring A is selected from piperidinyl and piperazinyl. In some embodiments, ring A is piperidinyl (e.g., piperidin-4-yl, piperidin-1-yl). In some embodiments, ring A is piperazinyl (e.g., piperazin-4-yl).

[0305] In some embodiments, [ka] The part represented by [ka] is selected from.

[0306] In certain embodiments, [ka] The part represented by [ka] is.

[0307] In certain embodiments, [ka] The part represented by [ka] is.

[0308] In some embodiments, [ka] The part represented by [ka] is selected from.

[0309] As generally defined herein, n is 0, 1, 2, or 3. In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0310] As generally defined herein, each R A are independently -D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, -OR A1 , -N(R A1 ) and each R A1 is independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, and C3-C9 cycloalkyl. A are independently -D, halo (e.g., -F, -Cl), -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu), -OH and -O-C1-C6 alkyl (e.g., -OMe, -OEt, -OPr, -O i Pr, -O n Bu, -O t In some embodiments, each R A is independently selected from -F, -Cl, -Me, -OH, and -OMe.

[0311] As generally defined herein, R 1 is an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 3- to 10-membered heterocyclyl.

[0312] In certain embodiments, R 1 is R 5 In some embodiments, the heteroaryl or heterocyclyl is a 5- to 10-membered heteroaryl or a 3- to 10-membered heterocyclyl substituted with 0, 1, 2, or 3 instances of R 5 In some embodiments, the heteroaryl or heterocyclyl is substituted with 0, 1, or 2 instances of R 5 In some embodiments, the heteroaryl or heterocyclyl is substituted with one or two instances of R 5 In some embodiments, the heteroaryl or heterocyclyl is substituted with one instance of R 5 is replaced in two cases:

[0313] In some embodiments, R 1 is a 3-7 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from O, N, and S (e.g., azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl). In some embodiments, R 1 is a 5-membered monocyclic heterocyclyl (e.g., tetrahydrofuranyl, pyrrolidinyl). In some embodiments, R 1 is pyrrolidinyl (e.g., pyrrolidin-1-yl).

[0314] In certain embodiments, R 1 teeth, [ka] is selected from.

[0315] In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In some embodiments, R 1 is R 5 In some embodiments, R1 is R 5 In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 is R 5 In some embodiments, R 1 is R 5 In some embodiments, R 1 is R 5 It is replaced in three cases:

[0316] In certain embodiments, R 1 is an optionally substituted 5-membered monocyclic heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In some embodiments, R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thiophenyl, oxazolyl, thiadiazolyl, and oxadiazolyl, each of which is selected from R 5 In some embodiments, R 1 is pyrrolyl (e.g., pyrrol-2-yl). In some embodiments, R 1 is pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl). In some embodiments, R 1 is pyrazol-1-yl. In some embodiments, R 1 is imidazolyl (e.g., imidazol-2-yl, imidazol-4-yl, imidazol-5-yl). In some embodiments, R 1 is imidazol-2-yl. In some embodiments, R 1 is thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R 1 is furanyl (e.g., furan-2-yl, furan-3-yl). In some embodiments, R 1is thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, R 1 is oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl). In some embodiments, R 1 is thiadiazolyl. In some embodiments, R 1 is oxadiazolyl. In some embodiments, R 1 is R 5 In some embodiments, R 1 is R 5 In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 is R 5 In some embodiments, R 1 is R 5 In some embodiments, R 1 is R 5 It is replaced in three cases:

[0317] In certain embodiments, R 1 is selected from optionally substituted imidazolyl (e.g., imidazol-2-yl) and pyrazolyl (e.g., pyrazol-1-yl). In some embodiments, imidazolyl and pyrazolyl are ... 5 In some embodiments, imidazolyl and pyrazolyl are substituted with one, two, or three instances of R 5 is replaced in one or two instances.

[0318] In some embodiments, R 1 is R 5 In some embodiments, R is imidazolyl (e.g., imidazol-2-yl) substituted with 0, 1, 2, or 3 instances of 1 is R 5 In some embodiments, R is imidazolyl (e.g., imidazol-2-yl) substituted with 0, 1, or 2 instances of1 is unsubstituted imidazolyl. In some embodiments, R 1 is R 5 In some embodiments, R is an imidazolyl substituted with one instance of 1 is R 5 In some embodiments, R is an imidazolyl (e.g., imidazol-2-yl) substituted with two instances of 1 is R 5 In three cases, imidazolyl is substituted (eg, imidazol-2-yl).

[0319] In some embodiments, R 1 is R 5 In some embodiments, R is a pyrazolyl (e.g., pyrazol-1-yl) substituted with 0, 1, 2, or 3 instances of 1 is R 5 In some embodiments, R is a pyrazolyl (e.g., pyrazol-1-yl) substituted with 0, 1, or 2 instances of 1 is unsubstituted pyrazolyl. In some embodiments, R 1 is R 5 In some embodiments, R is a pyrazolyl substituted with one instance of 1 is R 5 In some embodiments, R is a pyrazolyl (e.g., pyrazol-1-yl) substituted with two instances of 1 is R 5 In three cases, substituted pyrazolyl (e.g., pyrazol-1-yl) is

[0320] As generally defined herein, each R 5 are independently halo, -CN, -C1-C6 alkyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a5 , -N(R a5 )2, -C(=O)Ra5 , -C(=O)OR a5 , -NR a5 C(=O)R a5 , -NR a5 C(=O)OR a5 , -C(=O)N(R a5 )2, -OC(=O)N(R a5 )2, -S(=O)R a5 , -S(=O)2R a5 , -SR a5 , -S(=O)(=NR a5 )R a5 , -NR a5 S(=O)2R a5 and -S(=O)2N(R a5 )2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0321] In certain embodiments, R 5 is halo (e.g., -F, -Cl, -Br), -CN, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3, -CH2CH2F, -CH2CHF2), -OC1-C6 alkyl (e.g., -OMe, -OEt, -OPr, -O i Pr, -O n Bu, -O t Bu), -C3-C 10 and selected from cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) and 3- to 10-membered heterocyclyl (e.g., azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl), each alkyl, cycloalkyl, and heterocyclyl being substituted by 0, 1, or 2 instances of -Me, -OMe, -OH, -CN, halo (e.g., -F, -Cl).

[0322] In certain embodiments, R5 -CN, -F, -Cl, -Br, -Me, -Et, - i It is selected from Pr, -CF3, -CH2CH2F, -CH2CHF2, -OMe, -OEt, -CH2CH2OMe, -CH2CH2OH, cyclopropyl, oxetanyl and azetidinyl (e.g., N-methyl-azetidin-3-yl).

[0323] In certain embodiments, R 5 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 5 is -Cl. In some embodiments, R 5 is -F. In some embodiments, R 5 is -Br. In some embodiments, R 5 is -I.

[0324] In some embodiments, R 5 is -CN.

[0325] In certain embodiments, R 5 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu). In some embodiments, R 5 is -Me. In some embodiments, R 5 is -Et. In some embodiments, R 5 is -Pr. In some embodiments, R 5 is -iPr.

[0326] In some embodiments, R 5 is —C1-C6 heteroalkyl. In some embodiments, R 5 is methoxymethyl (—CH2OCH3). In some embodiments, R 5 is -CHCHOMe. In some embodiments, R 5is aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH). In some embodiments, R 5 is -CH2N(CH3)CH2CH3.

[0327] In some embodiments, R 5 is -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CH2F, -CH2CHF2). In some embodiments, R 5 is trifluoromethyl (-CF). In other embodiments, R 5 is difluoromethyl (-CHF). In some embodiments, R 5 is -CH2CH2F. In other embodiments, R 5 is -CH2CHF2.

[0328] In some embodiments, R 5 is —C1-C6 hydroxyalkyl (e.g., —CH2OH, —CH2CH2OH). In some embodiments, R 5 is hydroxyethyl (-CH2CH2OH).

[0329] In some embodiments, R 5 is -C3-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is cyclobutyl. In some embodiments, R 5 is cyclopentyl. In some embodiments, R 5 is cyclohexyl.

[0330] In some embodiments, R 5is a 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.4]octanyl). 5 is oxetanyl. In some embodiments, R 5 is tetrahydropyranyl. In some embodiments, R 5 is tetrahydrofuranyl. In some embodiments, R 5 is azetidinyl (e.g., N-methylazetidin-3-yl). In some embodiments, R 5 is pyrrolidinyl. In some embodiments, R 5 is piperidinyl. In some embodiments, R 5 is piperazinyl. In some embodiments, R 5 is morpholinyl. In some embodiments, R 5 is azepanyl. In some embodiments, R 5 is 6-oxa-1-azaspiro[3.3]heptanyl. In some embodiments, R 5 is 6-oxa-1-azaspiro[3.4]octanyl.

[0331] In some embodiments, R 5 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 5 is heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0332] In some embodiments, R 5 is arylalkyl. In some embodiments, R5 is benzyl.

[0333] In some embodiments, R 5 is heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0334] In some embodiments, R 5 -OR a5 (e.g., hydroxy (—OH), methoxy, difluoromethoxy (—OCHF), trifluoromethoxy (—OCF), —OCH(CH)CF, —OCHCF, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 5 is hydroxy. In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is isopropoxy. In some embodiments, R 5 is difluoromethoxy (-OCHF). In some embodiments, R 5 is trifluoromethoxy (-OCF). In some embodiments, R 5 is —OCH(CH)CF. In some embodiments, R 5 is —OCH CF . In some embodiments, R 5 is cyclopropyloxy.

[0335] In some embodiments, R 5 is -N(R a5 )2 (e.g., -NH2, -NHR a5 , -N(CH3)R a5 In some embodiments, R 5 is -NH. In some embodiments, R 5 -NHR a5(e.g., -NHMe, -NHEt, -NHPr, -NH i In some embodiments, R 5 is -N(CH3)R a5 (For example, -NMe2, -N(CH3)Et, -N(CH3)Pr, -N(CH3) i -Pr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl).

[0336] In some embodiments, R 5 is -C(=O)R a5 or -C(=O)OR a5 In some embodiments, R 5 is -C(=O)R a5 and R a5 is as described herein. In some embodiments, R 5 is —C(═O)alkyl. In some embodiments, R 5 -C(O)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) t Bu, -C(O) i Pr, -C(O)Pr, -C(O) i Bu, or —C(═O)OMe. In some embodiments, R 5 is acetyl (—C(═O)Me). In some embodiments, R 5 is -C(=O)OR a5 In some embodiments, R 5 is —COOH. In some embodiments, R 5 is COOMe.

[0337] In some embodiments, R 5 is -NR a5 C(=O)R a5 In certain embodiments, R 5 is -NHC(=O)R a5 (For example, -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) iPr, -NHC(=O)Bu, -NHC(=O) t In some embodiments, R 5 is -N(CH3)C(=O)R a5 (For example, -N(CH3)C(=O)Me, -N(CH3)C(=O)Et, -N(CH3)C(=O)Pr, -N(CH3)C(=O) i Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O) t Bu, -N(CH3)C(=O)cyclopropyl, -N(CH3)C(=O)cyclobutyl.

[0338] In some embodiments, R 5 is -NR a5 C(=O)OR a5 In certain embodiments, R 5 is -NHC(=O)OR a5 (e.g. -NHC(=O)OMe, -NHC(=O)OEt, -NHC(=O)OPr, -NHC(=O)O i Pr, -NHC(=O)OBu, -NHC(=O)O t Bu, -NHC(=O)Ocyclopropyl, -NHC(=O)Ocyclobutyl). In some embodiments, R 5 is -N(CH3)C(=O)OR a5 (For example, -N(CH3)C(=O)OMe, -N(CH3)C(=O)OEt, -N(CH3)C(=O)OPr, -N(CH3)C(=O)O i Pr, -N(CH3)C(=O)OBu, -N(CH3)C(=O)O t Bu, -N(CH3)C(=O)Ocyclopropyl, -N(CH3)C(=O)Ocyclobutyl).

[0339] In some embodiments, R 5 is -C(=O)N(R a5 )2 (e.g., -C(=O)NH2, -C(=O)NHR a5 , -C(=O)N(CH3)R a5 In some embodiments, R 5is —C(═O)NH. In certain embodiments, R 5 is -C(=O)NHR a5 (e.g. -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O)NH i Pr, -C(=O)NHBu, -C(=O)NH t Bu, —C(═O)NHcyclopropyl, —C(═O)NHcyclobutyl). In certain embodiments, R 5 is -C(=O)N(CH3)R a5 (For example, -C(=O)NMe2, -C(=O)N(CH3)Et, -C(=O)N(CH3)Pr, -C(=O)N(CH3) i Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3) t -Bu, -C(=O)N(CH3)cyclopropyl, -C(=O)N(CH3)cyclobutyl).

[0340] In some embodiments, R 5 is -OC(=O)N(R a5 )2. In certain embodiments, R 5 is -OC(=O)NHR a5 (e.g. -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O)NH i Pr, -OC(=O)NHBu, -OC(=O)NH t Bu, —OC(═O)NHcyclopropyl, —OC(═O)NHcyclobutyl). In certain embodiments, R 5 is -OC(=O)N(CH3)R a5 (For example, -OC(=O)NMe2, -OC(=O)N(CH3)Et, -OC(=O)N(CH3)Pr, -OC(=O)N(CH3) i Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3) t Bu, -OC(=O)N(CH3)cyclopropyl, -OC(=O)N(CH3)cyclobutyl).

[0341] In some embodiments, R 5 is -S(=O)Ra5 In certain embodiments, R 5 is -S(=O)alkyl (e.g., -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) i Pr). In certain embodiments, R 5 is -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0342] In some embodiments, R 5 is -S(=O)2R a5 In certain embodiments, R 5 is -S(=O)2 alkyl (e.g., -S(=O)2 Me, -S(=O)2 Et, -S(=O)2 Pr, -S(=O)2 i Pr). In certain embodiments, R 5 is -S(=O)2cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, R 5 is S(=O)2 aryl (e.g., S(=O)2 phenyl).

[0343] In some embodiments, R 5 -SR a5 In certain embodiments, R 5 is -S alkyl (e.g., -SMe, -SEt, -SPr, -S i Pr). In certain embodiments, R 5 is -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In certain embodiments, R 5 is -Saryl (e.g., Sphenyl).

[0344] In some embodiments, R 5 is -S(=O)(=NR a5 )R a5 In certain embodiments, R5 is -S(=O)(=NH)R a5 (For example, -S(=O)(=NH)Me, -S(=O)(=NH)Et, -S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t In some embodiments, R 5 is -S(=O)(=NCH3)R a5 (For example, -S(=O)(=NCH3)Me, -S(=O)(=NCH3)Et, -S(=O)(=NCH3)Pr, -S(=O)(=NCH3) i Pr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3) t -Bu, -S(=O)(=NCH3)cyclopropyl, -S(=O)(=NCH3)cyclobutyl).

[0345] In some embodiments, R 5 is -NR a5 S(=O)2R a5 In certain embodiments, R 5 is -NHS(=O)2 alkyl (e.g., -NHS(=O)2 Me, -NHS(=O)2 Et, -NHS(=O)2 Pr, -NHS(=O)2 i Pr). In certain embodiments, R 5 is -NHS(=O)2cycloalkyl (e.g., -NHS(=O)2cyclopropyl, -NHS(=O)2cyclobutyl, -NHS(=O)2cyclopentyl, -NHS(=O)2cyclohexyl). In certain embodiments, R 5 is -N(CH3)S(=O)2 alkyl (e.g., -N(CH3)S(=O)2Me, -N(CH3)S(=O)2Et, -N(CH3)S(=O)2Pr, -N(CH3)S(=O)2 i Pr). In certain embodiments, R 5is —N(CH3)S(═O)2 cycloalkyl (e.g., —N(CH3)S(═O)2 cyclopropyl, —N(CH3)S(═O)2 cyclobutyl, —N(CH3)S(═O)2 cyclopentyl, —N(CH3)S(═O)2 cyclohexyl).

[0346] In some embodiments, R 5 is -S(=O)2N(R a5 )2 (e.g., -S(=O)2NH2, -S(=O)2NHR a5 , -S(=O)2N(CH3)R a5 In some embodiments, R 5 is —S(═O)NH. In some embodiments, R 5 is -S(=O)2NHR a5 (For example, -S(=O)2NHMe, -S(=O)2NHEt, -S(=O)2NHPr, -S(=O)2NH i In some embodiments, R 5 is -S(=O)2N(CH3)R a5 (For example, -S(=O)2NMe2, -S(=O)2N(CH3)Et, -S(=O)2N(CH3)Pr, -S(=O)2N(CH3) i -Pr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0347] As generally defined herein, each R a5 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

[0348] In some embodiments, each R a5 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - nBu, - t and -C1-C6 haloalkyl (e.g., -Bu, -sec-Bu, -iso-Bu) and -C1-C6 haloalkyl (e.g., -CHF2, -CF3, -CH(CH3)CF3, -CH2CF3).

[0349] In some embodiments, each R a5 are independently H.

[0350] In some embodiments, each R a5 are independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t In some embodiments, each R a5 is independently -Me. In some embodiments, each R a5 is independently -Et. In some embodiments, each R a5 is independently -Pr. In some embodiments, each R a5 is, independently, - i It is Pr.

[0351] In some embodiments, each R a5 teeth 、 In some embodiments, each R a5 is independently methoxymethyl (—CHOCH). In some embodiments, each R a5 is independently hydroxymethyl (—CHOH). In some embodiments, each R a5 are independently aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH)).

[0352] In some embodiments, each R a5 is independently —C1-C6 haloalkyl. In some embodiments, each R a5 is independently trifluoromethyl (—CF). In other embodiments, each R a5is independently difluoromethyl (-CHF). In some embodiments, each R a5 is —CH(CH)CF. In some embodiments, each R a5 is -CH2CF3.

[0353] In some embodiments, each R a5 is independently —C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each R a5 is independently cyclopropyl. In some embodiments, each R a5 is independently cyclobutyl. In some embodiments, each R a5 is independently cyclopentyl. In some embodiments, each R a5 is independently cyclohexyl.

[0354] In some embodiments, each R a5 is independently 3- to 10-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0355] In some embodiments, R a5 is independently heteroaryl. In some embodiments, R a5 is independently a 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S). In some embodiments, R a5 is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, a 6 membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R a5is independently a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). a5 is independently thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, R a5 is independently pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R a5 is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R a5 is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, R a5 is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R a5 is independently pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).

[0356] In some embodiments, R a5 is independently aryl. In some embodiments, R a5 is independently a 6-10 membered mono- or bicyclic aryl. In some embodiments, R a5 is independently phenyl.

[0357] In some embodiments, each R a5 is independently cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, each R a5is independently heterocyclylalkyl (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0358] In some embodiments, each R a5 is independently arylalkyl. In some embodiments, each R a5 is independently benzyl.

[0359] In some embodiments, each R a5 is independently heteroarylalkyl (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0360] In some embodiments, R 1 teeth, [ka] is selected from.

[0361] In some embodiments, R 1 teeth, [ka] is selected from.

[0362] In some embodiments, R 1 teeth, [ka] is selected from.

[0363] As generally defined herein, R 2 is H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 heteroalkyl, -C1-C6 hydroxyalkyl, -C3-C 10It is selected from cycloalkyl and arylalkyl, and each hydrogen of alkyl, haloalkyl, heteroalkyl, hydroxylalkyl and arylalkyl can be independently replaced with a deuterium atom.

[0364] In some embodiments, R 2 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CHF2, -CH2CF3), -C1-C6 heteroalkyl (e.g., -CH2CH2OMe), -C3-C 10 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), and each hydrogen of alkyl, haloalkyl, and heteroalkyl can be independently replaced with a deuterium atom.

[0365] In certain embodiments, R 2 -Me, -Et, -CH2CHF2, -CH2CF3, cyclobutyl and -CH2CH2OMe,

[0366] In some embodiments, R is selected from C1-C6 alkyl, wherein one or more of the hydrogen atoms of the alkyl are replaced with deuterium atoms (e.g., -CD3, -CD2CD3). 2 is -CD3.

[0367] In some embodiments, R 2 is H or -Me.

[0368] In certain embodiments, R 2 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu). In some embodiments, R 2 is -Me. In some embodiments, R 2is -Et. In some embodiments, R 2 is -Pr. In some embodiments, R 2 is -iPr.

[0369] In certain embodiments, R 2 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t In some embodiments, R is a methyl group, and ... 2 is -CD3.

[0370] In some embodiments, R 2 is —C1-C6 heteroalkyl. In some embodiments, R 2 is methoxymethyl (—CH2OCH3). In some embodiments, R 2 is aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH). In some embodiments, R 2 is -CH2N(CH3)CH2CH3.

[0371] In some embodiments, R 2 is -C1-C6 haloalkyl. In some embodiments, R 2 is trifluoromethyl (-CF). In other embodiments, R 2 is difluoromethyl (-CHF2).

[0372] In some embodiments, R 2 is —C1-C6 hydroxyalkyl (e.g., —CH2OH, —CH2CH2OH). In some embodiments, R 2 is hydroxymethyl (-CHOH).

[0373] In some embodiments, R 2is arylalkyl. In some embodiments, R 2 is benzyl.

[0374] As generally defined herein, R 6 is H, -D, halo, -CN, -C1-C6 alkyl, -C1-C6 alkynyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -C3-C 10 Cycloalkyl, 3-10 membered heterocyclyl, -C6-C 10 Aryl, 6- to 10-membered heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 )2, -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 )2, and -OC(=O)N(R a6 )2, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position.

[0375] In certain embodiments, R 6 is H, -D, -CN, halo (e.g., -F, -Cl), -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu), -C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3), -C1-C6 alkynyl (e.g., -CCH, -CC-CH3, -CC-cyclopropyl), -C6-C 10 aryl (e.g., phenyl substituted with 0 to 1 instance of C1-C6 alkyl), -C(=O)N(R a6 )2 (e.g., -C(=O)NMe2, -C(=O)NHMe, -C(=O)NH2), -C3-C 10cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 6- to 10-membered heteroaryl (e.g., pyridinyl), -N(R a6 )2 (e.g., -NH2, -NMe2, -NHMe), -OH, and -O(C1-C6 alkyl) (e.g., -OMe).

[0376] In some embodiments, R 6 is H, -D, -CN, -F, -Cl, -Me, -Et, -Pr, - i Pr, - n Bu, - t Bu, -CF3, -CHF2, phenyl (e.g., 2- i In some embodiments, R is selected from the group consisting of -C(=O)NMe, -C(=O)NHMe, -C(=O)NH, -NH, -NMe, -NHMe, -OH, and -OMe. 6 is selected from H, —Cl, —Me, and —CF. In some embodiments, R 6 is H.

[0377] In some embodiments, R 6 is D.

[0378] In certain embodiments, R 6 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -F. In some embodiments, R 6 is -Br. In some embodiments, R 6 is -I.

[0379] In some embodiments, R 6 is -CN.

[0380] In certain embodiments, R 6 is -C1-C6 alkyl (e.g., -Me, -Et, -Pr, -i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu). In some embodiments, R 6 is -Me. In some embodiments, R 6 is -Et. In some embodiments, R 6 is -Pr. In some embodiments, R 6 is -iPr.

[0381] In some embodiments, R 6 is —C1-C6 heteroalkyl. In some embodiments, R 6 is methoxymethyl (—CH2OCH3). In some embodiments, R 6 is hydroxymethyl (—CHOH). In some embodiments, R 6 is aminomethyl (e.g., —CHNH, —CHNHCH, —CHN(CH). In some embodiments, R 6 is -CH2N(CH3)CH2CH3.

[0382] In some embodiments, R 6 is -C1-C6 haloalkyl. In some embodiments, R 6 is trifluoromethyl (-CF). In other embodiments, R 6 is difluoromethyl (-CHF2).

[0383] In some embodiments, R 6 is -C3-C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 is cyclohexyl.

[0384] In some embodiments, R 6 is hydroxy (—OH). In certain embodiments, R 6 is —O(C1-C6 alkyl) (e.g., methoxy, ethoxy, propoxy, isopropoxy). In some embodiments, R 6 is methoxy. In some embodiments, R 6 is ethoxy. In some embodiments, R 6 is propoxy. In some embodiments, R 6 is isopropoxy.

[0385] As generally defined herein, each R a6 is independently selected from H, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl. In some embodiments, R a6 are independently H, -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - i Pr, - n Bu, -sec-Bu, -iso-Bu, - t Bu), —C1-C6 haloalkyl (e.g., —CF3, —CHF2, —CH2CF3, —CH(CH3)CF3), and C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

[0386] In some embodiments, the compound is selected from the compounds in Table 1.

[0387] In some embodiments, provided is a pharmaceutical composition comprising a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof as defined herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

[0388] In various embodiments, the compounds of the present disclosure are USP1 inhibitors that reduce the level of USP1 protein and / or inhibit or reduce at least one biological activity of USP1 protein.

[0389] In some embodiments, compounds of the present disclosure specifically bind to USP1 protein. In some embodiments, compounds of the present disclosure specifically bind to USP1 protein in a USP1-UAF1 complex. In some embodiments, compounds of the present disclosure specifically bind to USP1 mRNA. In some embodiments, compounds of the present disclosure specifically bind to USP1 protein (alone or in a USP1-UAF1 complex) or USP1 mRNA. In some embodiments, compounds of the present disclosure specifically bind to UAF1 (alone or in a USP1-UAF1 complex) and inhibit or reduce the formation or activity of the USP1-UAF1 complex.

[0390] In some embodiments, compounds of the present disclosure decrease the formation of the USP1-UAF1 complex. In some embodiments, compounds of the present disclosure decrease the activity of the USP1-UAF1 complex. In some embodiments, compounds of the present disclosure decrease the deubiquitinase activity of USP1. In some embodiments, compounds of the present disclosure increase monoubiquitinated PCNA. In some embodiments, compounds of the present disclosure increase monoubiquitinated FANCD2. In some embodiments, compounds of the present disclosure increase monoubiquitinated FANCI.

[0391] In some embodiments, compounds of the present disclosure do not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or bind to deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with an affinity that is reduced by at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold compared to the affinity for USP1 (i.e., the KD of the USP1 inhibitor for other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) is at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold). Certain compounds of the present disclosure were evaluated for USP1-UAF1 activity in the ubiquitin rhodamine assay, as described in Biological Example 1.

[0392] Table 1 shows the IC of exemplary compounds against USP1-UAF1. 50 Values ​​(μM) are shown (column 4). For column 4, "a" indicates an IC<30 nM 50 "b" indicates IC values ​​of 30 nM or greater but less than 100 nM. 50 The IC value is shown, and "c" is an IC value of 100 nM or more but less than 10 μM. 50 values, and "d" indicates IC ≥ 10 μM. 50 Indicates the value.

[0393] Table 1 also shows the IC in the viability assay for a non-isogenic pair of BRCA1 mutant (column 5—MDA-MB-436) and BRCA1 WT (column 6—HCC1954) cell lines. 50 These values ​​indicate the effect of compound treatment on cell survival. In columns 5 and 6, "aa" and "aaa" values ​​indicate IC<100 nM in mutant and wild-type cell lines, respectively. 50 The values ​​of "bb" and "bbb" indicate IC values ​​of 100 nM or more and less than 250 nM in mutant and wild-type cell lines, respectively. 50The values ​​of "cc" and "ccc" indicate IC values ​​of 250 nM or more and less than 10 μM in mutant and wild-type cell lines, respectively. 50 The values ​​of "dd" and "ddd" indicate IC values ​​of 10 μM or higher in mutant and wild-type cell lines, respectively. 50 Shows.

[0394] Table 1 also shows the IC of exemplary compounds in the αLISA assay measuring monoubiquitinated PCNA in BRCA1 mutant cell lines. 50 Values ​​are shown (MDA-MB-436, column 7). In column 7, values ​​of "A" indicate IC<100 nM. 50 "B" indicates an IC of 100 nM or more but less than 250 nM. 50 indicates an IC value of 250 nM or more and less than 10 μM. 50 indicates an IC value of 10 μM or higher. 50 Shows.

[0395] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. Compounds marked with (or) or (rel) are single enantiomers for which the absolute stereochemistry has been arbitrarily assigned (e.g., based on the chiral SFC elution described in the Examples section). Compounds marked with (and) or (rac) are mixtures of enantiomers in which the relative stereochemistry is as shown. Compounds marked with (abs) are single enantiomers in which the absolute stereochemistry is as shown. [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

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

[0396] 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 can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, and the nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) can 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.

[0397] Pharmaceutical Compositions In some embodiments, 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 Formula (I), (II) or a compound in Table 1), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0398] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient, together with a compound provided herein, which does not destroy its pharmacological activity and which is non-toxic when administered in dosages sufficient to deliver a therapeutic amount of the compound.

[0399] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may 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, trimethylsilyl 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 the compounds of the formulae described herein.

[0400] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared by methods well known in the pharmaceutical arts and contain at least one active compound.

[0401] In some embodiments, with respect to pharmaceutical compositions, the carrier is a parenteral carrier, an oral or a topical carrier.

[0402] In some embodiments, provided is a compound described herein (e.g., a compound of Formula (I), (II) or a compound of Table 1), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) (or a pharmaceutical composition thereof) for use as a medicine or medicament (e.g., a medicament for treating a disease or disorder associated with USP1 in a subject in need thereof). In some embodiments, the disease is a proliferative disease. In further embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, pancreatic cancer, or lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0403] In some embodiments, provided is a compound described herein (e.g., a compound of Formula (I), (II) or a compound of Table 1), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) (or a pharmaceutical composition thereof) for use in treating a disease or disorder associated with USP1 in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In further embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, pancreatic cancer, or lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0404] In some embodiments, provided is a compound described herein (e.g., a compound of Formula (I), (II), or a compound of Table 1), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (or a pharmaceutical composition thereof) for use in the manufacture of a medicament (e.g., a medicament for treating a disease or disorder associated with USP1 in a subject in need thereof). In some embodiments, the disease is a proliferative disease. In further embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, pancreatic cancer, or lung cancer (e.g., non-small cell lung cancer (NSCLC)). Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of compound actually administered is typically determined by a physician according to 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.

[0405] The pharmaceutical compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral administration or injection. The pharmaceutical compositions provided herein may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. Optionally, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to improve the stability of the formulated compound or its delivery form. The term parenteral, as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intraspinal, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0406] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable for use as single dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is usually a minor component (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 serve to form the desired dosage form.

[0407] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, etc.

[0408] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As mentioned 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, etc. Pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween® 80, etc.) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, can be used. 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 contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants, commonly used in the formulation of pharmaceutically acceptable dosage forms such as 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.

[0409] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s), generally in amounts 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 is typically combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance dermal penetration of the active ingredient or the stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0410] 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.

[0411] The pharmaceutical compositions provided herein may also 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.

[0412] 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 a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents well known in the art.

[0413] The above ingredients for orally administrable, injectable or topically administrable, rectally administrable, and nasally administrable compositions are merely representative. Other materials, 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.

[0414] The compounds disclosed 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.

[0415] When the compositions provided herein 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%, and more preferably about 5-95%, of the dose normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds provided herein as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds provided herein in a single composition.

[0416] Also provided are pharmaceutically acceptable acid addition salts of the compounds described herein (eg, compounds of Formula (I), (II) or compounds of Table 1).

[0417] Acids that can 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, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, paratoluenesulfonate, and the like.

[0418] The compounds described herein can be administered, for example, by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or subcutaneously, or orally, bucally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, at dosages ranging from about 0.5 to about 100 mg per kg of body weight, alternatively at dosages of 1 mg to 1000 mg per dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions provided herein are administered about 1 to about 6 times per day, or alternatively, as a continuous infusion. Such administration can be used as chronic or acute therapy. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical formulations contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0419] Lower or higher dosages 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 patient's age, body weight, general health, sex, diet, time of administration, rate of excretion, concurrent drug use, the severity and course of the disease, condition, or symptom, the patient's disposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0420] When patient's condition improves, if necessary, the maintenance dose of compound, composition or combination provided herein can be administered.After that, depending on symptoms, when symptoms are reduced to desired level, dosage or administration frequency, or both, can be reduced to the level that maintains improved condition.However, patient may need to be intermittently treated for a long period of time depending on the recurrence of disease symptoms.

[0421] Treatment and Use In some embodiments, the compounds described herein can be used to inhibit the activity of USP1 protein. For example, in some embodiments, the method for inhibiting USP1 protein comprises contacting USP1 protein with a compound disclosed herein. Contacting can occur in vitro or in vivo.

[0422] In some embodiments, the compounds described herein can be used to treat a "USP1 protein-mediated" disorder (e.g., a USP1 protein-mediated cancer), a "USP1-associated" disorder (e.g., a USP1-associated cancer), or a "USP1-related" disorder (e.g., a USP1-associated cancer). A "USP1 protein-mediated," "USP1-associated" disorder, or "USP1-related" disorder is any pathological condition in which the USP1 protein is known to play a role, including any cancer that requires USP1 for cell proliferation and survival. In some embodiments, a "USP1 protein-mediated," "USP1-associated" disorder, or "USP1-related" disorder is a proliferative disease such as cancer. The method includes administering to a patient in need of treatment for a USP1 protein-mediated disorder an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

[0423] In some embodiments, a method for treating a disease or disorder associated with modulation of USP1 is provided. The method comprises administering to a patient in need of treatment for a disease or disorder associated with modulation of USP1 an effective amount of a compound of Formula (I), (II), or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the disease or disorder is cancer. In some embodiments, the compound or composition is administered in combination with a second therapeutic agent.

[0424] In some embodiments, methods for treating or preventing cancer are provided, comprising administering to a patient in need of cancer treatment an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0425] In some embodiments, methods of treating cancer are provided, comprising administering to a patient in need of cancer treatment an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0426] In some embodiments, a method for treating or preventing a disease or disorder associated with DNA damage is provided. The method comprises administering to a patient in need of treatment for a disease or disorder associated with DNA damage an effective amount of a compound of Formula (I), (II), or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the disease is cancer.

[0427] In some embodiments, a method for treating a disease or disorder associated with DNA damage is provided, comprising administering to a patient in need of treatment for a disease or disorder associated with DNA damage an effective amount of a compound of Formula (I), (II) or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0428] In some embodiments, there is provided a method for inhibiting, modulating, or reducing DNA repair activity carried out by USP1, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0429] In some embodiments, there is provided (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, for use as a medicament.

[0430] In some embodiments, there is provided (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, for use in treating or preventing a disease associated with inhibition of USP1. In some embodiments, the disease is cancer.

[0431] In some embodiments, there is provided (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, for use in treating a disease or disorder associated with the inhibition of USP1.

[0432] In some embodiments, there is provided (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer.

[0433] In some embodiments, there is provided a pharmaceutical composition comprising: (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, or (b) an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, for use in the treatment of cancer.

[0434] In some embodiments, there is provided (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, for use in treating or preventing a disease or disorder associated with DNA damage. In some embodiments, the disease or disorder is cancer.

[0435] In some embodiments, there is provided a pharmaceutical composition comprising (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, for use in treating a disease or disorder associated with DNA damage. In some embodiments, the disease or disorder is cancer.

[0436] In some embodiments, provided is (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, for use in a method of inhibiting or reducing DNA repair activity regulated by USP1.

[0437] In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I), (II) or Table 1, or a compound of Formula (I), (II) or Table 1, and a pharmaceutically acceptable carrier for use in the treatment of cancer.

[0438] In some embodiments, there is provided a use of (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating or preventing a disease associated with inhibition of USP1. In some embodiments, the disease or disorder is cancer.

[0439] In some embodiments, there is provided the use of (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating or preventing cancer.

[0440] In some embodiments, there is provided the use of (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating or preventing a disease or disorder associated with DNA damage. In some embodiments, the disease or disorder is cancer.

[0441] In some embodiments, there is provided a use of (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating a disease or disorder associated with DNA damage. In some embodiments, the disease or disorder is cancer.

[0442] In some embodiments, there is provided a use of (a) a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for inhibiting or reducing DNA repair activity regulated by USP1.

[0443] In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0444] In some embodiments, methods are provided for treating diseases or disorders associated with the modulation of USP1, including but not limited to cancer, comprising administering to a patient suffering from at least one of the diseases or disorders (a) an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or (b) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient, and one or more additional anti-cancer agent(s).

[0445] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) and other anticancer agent(s) are generally administered sequentially in any order by injection or orally. The administration regimen may vary depending on the stage of the disease, the patient's physical compatibility, the safety profile of the individual drugs, and the tolerability of the individual drugs, as well as other criteria known to the attending physician and physician(s) administering the combination. The compound disclosed herein and other anticancer agent(s) 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 can include administration of one drug more frequently than the other, with different doses for each drug administration during the treatment cycle.

[0446] In some embodiments, kits are provided that include one or more of the compounds disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), and a second therapeutic agent disclosed herein. Exemplary kits include (a) a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), and (b) at least one other therapeutic agent, such as those described above, whereby such kits may include a package insert or other labeling containing instructions for administration.

[0447] In some embodiments of the methods and uses described herein, the cancer is adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct cancer, bladder cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, ependymoma, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma, adrenal cortex, pancreatic islet cell carcinoma, primary central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, tendon sheath specific Alveolar sarcoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma / tumor family, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer (including intraocular melanoma), and retinoblastoma, gallbladder cancer, gastrointestinal carcinoid tumor, ovarian germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Hodgkin's disease, hypopharyngeal cancer, Kaposi's sarcoma, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin's lymphoma, Waldenstrom's disease Rehm's macroglobulinemia, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, Merkel cell carcinoma, metastatic squamous cell neck cancer with unknown primary, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity cancer, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, cystoid The cancer is selected from stalk carcinoma, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, transitional cell carcinoma (such as of the renal pelvis and ureter), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, malignant fibrous histiocytoma of bone, soft tissue sarcoma, Sézary syndrome, skin cancer, small intestine cancer, stomach (gastric) cancer, supratentorial primitive neuroectodermal and pineal tumor, cutaneous T-cell lymphoma, testicular cancer, malignant thymoma, thyroid cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor. In other embodiments, the cancer is non-small cell lung cancer.

[0448] In any of the embodiments, the cancer can be any cancer in any organ, for example, the cancer is selected from the group consisting of glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell carcinoma, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0449] In some embodiments, the cancer treated with the compounds disclosed herein is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue tumors, including rhabdoid and sarcoma; kidney cancer, bladder cancer, skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer, colon cancer, uterine cancer, nervous system cancer, head and neck cancer, pancreatic cancer, and cervical cancer.

[0450] In other embodiments, the cancer is selected from liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical, oropharyngeal, penile, anal, thyroid, or vaginal cancer or Epstein-Barr virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, and diffuse large B-cell lymphoma.

[0451] In some embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC)), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, pancreatic cancer, and lung cancer (e.g., non-small cell lung cancer (NSCLC)). In some embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC)), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, and lung cancer (e.g., non-small cell lung cancer (NSCLC)). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0452] In certain embodiments of the methods described herein, the cancer is a dedifferentiated ID-driven cancer. In other embodiments, the cancer is a cancer that is sensitive to USP1 inhibition. In yet other embodiments, the cancer is a cancer that is sensitive to USP1 inhibition due to a DNA damage pathway defect.

[0453] In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of a hematological cancer, a lymphatic cancer, and a DNA damage repair pathway deficient cancer.

[0454] In some embodiments, the compounds disclosed herein are used to treat cancer, and the cancer is a homologous recombination deficient cancer. In some embodiments, the compounds disclosed herein are used to treat cancer that does not have a defect in the homologous recombination pathway.

[0455] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer. In some embodiments, the DNA damage repair pathway deficient cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), and breast cancer (e.g., triple-negative breast cancer (TNBC)). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer. In some embodiments, the cancer is platinum-refractory ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer.

[0456] In some embodiments, the cancer is an HRR (homologous recombination repair) gene mutant cancer. In some embodiments, the cancer is an HRR (homologous recombination repair) gene mutant cancer selected from the group consisting of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L mutant cancer. In some embodiments, the cancer is an ATM mutant cancer. In some embodiments, the cancer is a BARD1 mutant cancer. In some embodiments, the cancer is a BRCA1 mutant cancer. In some embodiments, the cancer is a BRCA2 mutant cancer. In some embodiments, the cancer is a BRIP1 mutant cancer. In some embodiments, the cancer is a CDK12 mutant cancer. In some embodiments, the cancer is a CHEK1 mutant cancer. In some embodiments, the cancer is a CHEK2 mutant cancer. In some embodiments, the cancer is a FANCL mutant cancer. In some embodiments, the cancer is a PALB2 mutant cancer. In some embodiments, the cancer is a PPP2R2A mutant cancer. In some embodiments, the cancer is a RAD51B mutant cancer. In some embodiments, the cancer is a RAD51C mutant cancer. In some embodiments, the cancer is a RAD51D mutant cancer. In some embodiments, the cancer is a RAD54L mutant cancer.

[0457] In some embodiments, the cancer is a BRCA1 mutant cancer. In some embodiments, the BRCA1 mutation is a germline mutation. In some embodiments, the BRCA1 mutation is a somatic mutation. In some embodiments, the BRCA1 mutation results in a BRCA1 deficiency. In some embodiments, the cancer is a BRCA2 mutant cancer. In some embodiments, the BRCA2 mutation is a germline mutation. In some embodiments, the BRCA2 mutation is a somatic mutation. In some embodiments, the BRCA2 mutation results in a BRCA2 deficiency. In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 defective cancer. In some embodiments, the cancer is a BRCA2 defective cancer. In some embodiments, the cancer is a BRCA1 defective cancer and a BRCA2 defective cancer. In some embodiments, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 defective cancer and a BRCA2 mutant cancer. In some embodiments, the BRCA1 or BRCA2 mutant cancer or the BRCA1 or BRCA2 deficient cancer is selected from non-small cell lung cancer (NSCLC), osteosarcoma, prostate cancer, pancreatic cancer, ovarian cancer, and breast cancer. In some embodiments, the BRCA1 mutant cancer, BRCA2 mutant cancer, BRCA1 deficient cancer, or BRCA2 deficient cancer described herein is ovarian cancer, breast cancer, prostate cancer, or pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer. In some embodiments, the cancer is platinum-refractory ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is homologous recombination deficient. Homologous recombination deficiency can be measured by genomic instability (a positive homologous recombination deficiency (HRD) score) with or without a BRCA1 / 2 mutation.

[0458] In some embodiments, the cancer is a poly(ADP-ribose) polymerase ("PARP") inhibitor refractory or resistant cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1, BRCA2, or BRCA1 and BRCA2 mutant cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1, BRCA2, or BRCA1 and BRCA2 deficient cancer. In some embodiments, the PARP inhibitor refractory or resistant cancer is selected from cancers described herein. In some embodiments, the PARP inhibitor refractory or resistant cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), pancreatic cancer, and prostate cancer.

[0459] In some embodiments, the cancer has a mutation in the gene encoding the ataxia telangiectasia mutated (ATM) protein kinase or loss of ATM protein expression. In some embodiments, the cancer treated with the compounds disclosed herein is a cancer comprising cancer cells with a loss-of-function mutation in the gene encoding ATM (e.g., a cancer selected from the cancers described herein). In some embodiments, the ATM mutation is a germline mutation. In some embodiments, the ATM mutation is a somatic mutation. In some embodiments, the cancer is not an ATM mutant cancer. In some embodiments, the cancer is an ATM-deficient cancer. In some embodiments, the ATM-deficient cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC)), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), colorectal cancer, gastric cancer, endometrial cancer, urothelial cancer, cervical cancer, melanoma, esophageal cancer, head and neck cancer, mantle cell lymphoma, sarcoma, prostate cancer, pancreatic cancer, and lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0460] In some embodiments, the cancer comprises cancer cells with elevated levels of cross-lesion synthesis. This includes cancers that exhibit elevated PCNA monoubiquitination, with or without elevated levels of RAD18 and / or UBE2K. In some embodiments, the elevated levels of RAD18 and / or UBE2K are elevated RAD18 and / or UBE2K protein levels. In some embodiments, the elevated levels of RAD18 and / or UBE2K are elevated RAD18 and / or UBE2K mRNA levels. In some embodiments, elevated levels of RAD18 and / or UBE2K (e.g., RAD18 and / or UBE2K protein and / or RAD18 and / or UBE2K mRNA) are detected prior to administration (e.g., in a cancer sample obtained from the subject). Elevated cross-lesion synthesis due to PCNA monoubiquitination can also be measured without elevated RAD18 and / or UBE2K levels. In some embodiments, the subject's cancer has been tested for RAD18 and / or UBE2K protein or mRNA levels, or PCNA monoubiquitination, prior to initiating treatment with a USP1 inhibitor. In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer), ovarian cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), or prostate cancer.

[0461] In some embodiments, the cancer is a BRCA1 and / or BRCA2 mutant cancer, and the cancer comprises cells with increased crossover synthesis, as exemplified by increased PCNA monoubiquitination with or without elevated levels of RAD18 and / or UBE2K. In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer), ovarian cancer, or prostate cancer that is a BRCA1 and / or BRCA2 mutant cancer.

[0462] In some embodiments, the cancer is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue tumors, including rhabdoid and sarcoma; kidney cancer, bladder cancer, skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer, colon cancer, uterine cancer, nervous system cancer, head and neck cancer, pancreatic cancer, and cervical cancer.

[0463] Combination therapy In some embodiments, the compounds of the present disclosure are administered in a therapeutically effective amount in combination with one or more therapeutic agents (pharmaceutical combinations) or modalities, such as non-drug therapies.For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory substances.When the compounds of the present disclosure are administered in combination with other therapies, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the specific drug used, the condition being treated, etc.

[0464] In some embodiments, methods are provided for treating a disease or disorder associated with USP1 with a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with a second therapeutic agent. In some embodiments, methods are provided for treating a disease or disorder associated with USP1 with a compound of Formula (I), (II), or 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, methods are provided for treating a disease or disorder associated with USP1 with a compound of Formula (I), (II), or 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.

[0465] The term "combination" refers to either a fixed combination in a single dosage unit form, or a combined administration in which a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer 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 when these time intervals allow the combination partners to exhibit a coordinated, e.g., synergistic, effect. Single components can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration. As used herein, terms such as "co-administration" or "co-administration" 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 agents are not necessarily administered by the same route of administration or at the same time. As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining 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 compound disclosed herein (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer 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 compound disclosed herein (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), and a combination partner are administered to a patient simultaneously, concurrently, or sequentially as separate entities without specific time restrictions, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, eg, the administration of three or more therapeutic agents.

[0466] 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 the co-administration of these therapeutic agents in a substantially simultaneous manner, such as, for example, in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the use of each type of therapeutic agent sequentially, either at about the same time or at different times.

[0467] In certain embodiments, the compounds disclosed herein are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergy agents, anti-nausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

[0468] In some embodiments, methods of treating a disease or disorder associated with USP1 (e.g., cancer) include administering to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt thereof) and anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine ( Xeloda®), N4-pentoxycarbonyl-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 (Fluda ra (registered trademark), 5-fluorouracil (Adrucil (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®), methotrexate (Folex®), mitoxantrone (Novantrone®), Milotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (N and a common chemotherapeutic agent selected from the group consisting of olvadex®, teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinnorelbine (Navelbine®), in any order.

[0469] In some embodiments, methods are provided for treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, a compound disclosed herein (e.g., a compound of Formula (I), (II) or 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 are provided for treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a MAPK pathway inhibitor (e.g., BRAFi, panRAFi, MEKi, ERKi) to a patient in need thereof. In some embodiments, provided are methods for treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II) or 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 analogs thereof).

[0470] In some embodiments, provided is a method of enhancing chemotherapy treatment of cancer in a mammal undergoing treatment with an anti-cancer agent, the method comprising co-administering to the mammal an effective amount of a compound disclosed herein. In certain embodiments, provided are methods of treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a DNA damaging agent (e.g., actinomycin, amsacrine, an anthracycline, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamine oxaliplatin, ifosfamide, melphalan, macroretamine, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, teniposide, triethiethiophosphorformamide, and etoposide). In a preferred embodiment, the DNA damaging agent is cisplatin. In some embodiments, the DNA damaging agent is radiation or a biotherapeutic agent (e.g., an antibody).

[0471] In some embodiments, the anticancer drug is a reversible DNA binder (e.g., topotecan hydrochloride, irinotecan (CPT11-camptosar), rubitecan, exatecan, nalidixic acid, TAS-103, etoposide, acridines (e.g., amsacrine, aminocrine), actinomycins (e.g., actinomycin D), anthracyclines (e.g., doxorubicin, daunorubicin), benzophenones, XR 1 1576 / MLN576, benzopyridoindole, mitoxantrone, AQ4, etoposide, teniposide, epipodophyllotoxin, and bisintercalators such as triostin A and echinomycin), DNA alkylating agents (e.g., sulfur mustards, nitrogen mustards (e.g., mechlorethamine), chlorambucil, melphalan, ethylenimines (e.g., triethylenemelamine, carboquone, diaziquone), methyl methanesulfonate, busulfan, CC-1065, duocarmycins (e.g., duocarmycin A, duocarmycin SA), nitrosoureas (e.g., carmustine, lomustine, (2-chloroisothiazolinone, 2-chloroisothiazolinone, 2-chloroisothiazolinone, 2-chloroisothiazolinone), methyl ... and (ethyl)nitrosoureas), triazine antitumor agents such as triazenoimidazoles (e.g., dacarbazine, mitomycin C, and leinamycin), DNA strand breakers (e.g., doxorubicin and daunorubicin (which are also reversible DNA binders), other anthracyclines, enediene antitumor antibiotics such as bleomycin, tirapazamine, neocarzinostatin, esperamicin, calicheamicin, dynemicin A, hedercidin, C-1027, N1999A2, esperamicin, and zinostatin), and disruptors of DNA replication (e.g., 5-fluorodeoxyuridine).

[0472] In certain embodiments, the DNA damaging agent is radiation (e.g., radiation that induces DNA crosslinking within cells when applied to cells (e.g., ionizing radiation and ultraviolet (UV) radiation)). Ionizing radiation consists of subatomic particles or electromagnetic waves with enough energy to cause ionization by separating electrons from atoms or molecules. Ionization depends on the energy of the individual particles or waves that collide. Generally, ionizing particles or photons with energies greater than a few electron volts can be ionized. Non-limiting examples of ionizing particles are alpha particles, beta particles, and neutrons. The ability of photons to ionize atoms or molecules depends on their frequency. Short-wavelength radiation, such as high-frequency ultraviolet radiation, X-rays, and gamma rays, is ionizing. Ionizing radiation comes from radioactive materials, X-ray tubes, and particle accelerators.

[0473] In certain embodiments, the anticancer drug targets USP1-independent DNA repair mechanisms. Non-limiting examples of suitable DNA repair inhibitors include poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, ataxia telangiectasia and Rad3-related protein (ATR) inhibitors, ataxia telangiectasia mutated (ATM) inhibitors, checkpoint kinase 1 (CHK1) inhibitors, checkpoint kinase 2 (CHK2) inhibitors, and Wee1 inhibitors. BRCA1 / 2 status has been reported to predict the effectiveness of PARP inhibitors in clinical trials (Audeh et al. Lancet (2010) 376 (9737), 245-51). In general, BRCA1 / 2 mutant cancers show increased sensitivity to USP1 inhibitors. Thus, in some embodiments, in certain embodiments, methods are provided for treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a PARP inhibitor (e.g., olaparib, rucaparib, niraparib, talazoparib, and veliparib).

[0474] In certain embodiments, the anti-cancer agent or DNA damaging agent can be a biotherapeutic agent. Non-limiting examples of suitable biotherapeutic agents include rInterferon-a2a, rInterferon-oi2b, rInterleukin-2, rG-CSF, rGM-CSF, and rErythropoietin.

[0475] In certain embodiments, the anti-cancer agent may be an antibody, such as a monoclonal antibody. Non-limiting examples of suitable therapeutic monoclonal antibodies for use in the methods described herein include trastuzumab, anti-ErbB2 / HER2 for breast cancer, cetuximab, anti-ErbB1 / EGFR for colorectal cancer, and bevacizumab, which is anti-VEGF for colorectal, breast, and lung cancer (see G. Adams et al., Nature Biotechnology 23:1147-57 (2005)). Multi-targeted inhibitors, such as Sutent, which inhibit the TK activity of VEGFR, PDGFR, and FGFR, are also suitable for use in the methods of the present invention.

[0476] In certain embodiments, the anti-cancer agent may be a proteasome inhibitor, such as bortezomib.

[0477] Administration of the compounds disclosed herein can be achieved via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical modes of administration.

[0478] Some patients may experience allergic reactions to the compounds disclosed 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 certain embodiments, a method of treating a disease or disorder associated with USP1 (e.g., cancer) is provided, comprising administering to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II), or 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.

[0479] Some patients may experience nausea during and after administration of a compound disclosed herein and / or other anticancer agent(s). Therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting. In certain embodiments, provided is a method of treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering, in any order, a compound disclosed herein (e.g., a compound of Formula (I), (II), or 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) to a patient in need thereof.

[0480] Medications to alleviate pain experienced during treatment are often prescribed to make patients more comfortable. In certain embodiments, provided are methods of treating a disease or disorder associated with USP1 (e.g., cancer), comprising administering or co-administering to a patient in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (II), or 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®), and fentanyl (e.g., Duragesic®)), in any order.

[0481] 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 certain embodiments, a method of treating a disease or disorder associated with USP1 (e.g., cancer) comprises administering or co-administering, in any order, to a patient in need thereof, a compound disclosed herein (e.g., a compound of Formula (I), (II), or 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)).

[0482] The structures of active compounds identified by code numbers, generic or trade names can be obtained from the actual editions of standard abstracts "The Merck Index" or databases such as Patents International (e.g. IMS World Publications).

[0483] The compounds that can be used in combination with the compounds disclosed herein can be prepared and administered as described in the art, including but not limited to the above-cited documents.

[0484] In some embodiments, pharmaceutical compositions are provided that include at least one compound disclosed herein (e.g., a USP1 inhibitor, e.g., a compound of Formula (I), (II), or a compound in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), either alone or together with other anti-cancer agents, together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0485] In some embodiments, methods are provided for treating a human or animal subject having or diagnosed with a disease or disorder associated with USP1 (e.g., cancer), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) in combination with a second therapeutic agent.

[0486] In some embodiments, provided are methods for treating a disease or disorder associated with USP1 (e.g., cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) in combination with a second therapeutic agent.

[0487] In particular, the compositions are either formulated together as a combination therapy or administered separately.

[0488] In combination therapy, the compounds disclosed herein and other anti-cancer agent(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.

[0489] The compounds disclosed herein (e.g., compounds of Formula (I), (II), or Table 1, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof) can also be used in combination with known therapeutic processes, such as the administration of hormones, or, particularly, radiation. The compounds disclosed herein can be used as radiosensitizers, particularly for the treatment of tumors that are poorly sensitive to radiation therapy.

[0490] In certain instances, the compounds disclosed herein are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergy agents, anti-nausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

[0491] Patient Selection and Monitoring Determining whether a subject responds to treatment with a USP1 inhibitor In some embodiments, a method of determining whether a subject (i.e., a cancer patient (e.g., a USP1-associated cancer patient)) having or diagnosed with cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting the level of RAD18 and / or UBE2K (e.g., RAD18 and / or UBE2K protein and / or RAD18 and / or UBE2K mRNA) in a test cancer sample (e.g., in a cancer test sample obtained from a subject); and b) comparing the test cancer sample with a reference cell (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein an elevated level of RAD18 and / or UBE2K in the test cancer sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0492] In some embodiments, a method of determining whether a subject (i.e., a cancer patient (e.g., a USP1-associated cancer patient)) having or diagnosed with cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting a level of crossover synthesis in a test cancer sample (e.g., in a cancer test sample obtained from a subject); and (e.g., detecting a level of PCNA monoubiquitination); and b) comparing the test cancer sample with a reference cell (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein an increase in cross-damage synthesis (e.g., an increase in PCNA monoubiquitination levels) in the test cancer sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0493] In some embodiments, a method of determining whether a subject (i.e., a cancer patient (e.g., a USP1-associated cancer patient)) having or diagnosed with cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting a mutation (i.e., a loss function mutation) in a gene encoding ATM in a test cancer sample (e.g., in a cancer test sample obtained from a subject); and b) determining that the presence of a mutation in the gene encoding ATM in the test cancer sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0494] In some embodiments, a method of determining whether a subject (i.e., a cancer patient (e.g., a USP1-associated cancer patient)) having or diagnosed with cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting a germline or somatic mutation (e.g., a loss-of-function mutation) in the gene encoding BRCA1 in a test sample from the subject (e.g., in a cancer test sample or a blood test sample obtained from the subject); b) determining that the presence of a mutation in the gene encoding BRCA1 in the test sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0495] In some embodiments, a method of determining whether a subject having or diagnosed with cancer (e.g., a cancer patient) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprising: a) detecting a germline or somatic mutation (e.g., a loss-of-function mutation) in the gene encoding BRCA2 in a test sample from the subject (e.g., in a cancer test sample or a blood test sample obtained from the subject); b) determining that the presence of a mutation in the gene encoding BRCA2 in the test sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0496] In some embodiments, a method of determining whether a subject (i.e., a cancer patient (e.g., a USP1-associated cancer patient)) having or diagnosed with cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting a homologous recombination deficiency (e.g., as measured by a positive homologous recombination deficiency (HRD) score) in a test sample from the subject (e.g., in a cancer sample or a blood sample obtained from the subject); b) determining that the presence of a homologous recombination deficiency (e.g., a positive homologous recombination deficiency (HRD) score) in the test sample indicates that the subject will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0497] In some embodiments, the cancer is a cancer selected from the cancers disclosed herein. In some embodiments, the cancer is pancreatic cancer, breast cancer (e.g., triple-negative breast cancer (TNBC)), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)). In certain embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer (TNBC)), ovarian cancer (e.g., platinum-resistant ovarian cancer, platinum-refractory ovarian cancer), prostate cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0498] Determine whether the cancer responds to treatment with a USP1 inhibitor In some embodiments, a method of determining whether a cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting the level of RAD18 and / or UBE2K (e.g., RAD18 and / or UBE2K protein and / or RAD18 and / or UBE2K mRNA) in a cancer test sample (e.g., in a cancer sample obtained from a subject); and b) comparing the cancer test sample with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein elevated levels of RAD18 and / or UBE2K in the cancer test sample indicate that the cancer will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II) or a compound of Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

[0499] In some embodiments, a method of determining whether a cancer (e.g., a USP1-associated cancer) will respond to therapeutic treatment with a USP1 inhibitor (e.g., a compound of Formula (I), (II), or Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof), comprises: a) detecting a level of cross-damage synthesis in a test cancer sample (e.g., in a cancer sample obtained from a subject); and (e.g., detecting a lev...

Claims

1. A compound of formula (I) During the ceremony, 【Chemistry 260】 Ring B is a 5-6 membered monocyclic aryl or heteroaryl; Ring A is C ６ -C １０ Aryl, 5- to 10-membered heteroaryl, -C ３ -C １０ cycloalkyl, and 3- to 10-membered heterocyclyl; R １ is optionally substituted 5-10 membered heteroaryl or optionally substituted 3-10 membered heterocyclyl; R ２ But H, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ cycloalkyl and arylalkyl, each hydrogen of said alkyl, haloalkyl, heteroalkyl, hydroxylalkyl and arylalkyl can be independently replaced with a deuterium atom; R ６ H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkynyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, 6- to 10-membered heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ６ , -N(R ａ６ ) ２ , -C(=O)R ａ６ , -C(=O)OR ａ６ , -NR ａ６ C(=O)R ａ６ , -NR ａ６ C(=O)OR ａ６ , -C(=O)N(R ａ６ ) ２ and -OC(=O)N(R ａ６ ) ２ wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R ａ６ are independently H, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C ３ -C ９ selected from cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R Ａ are independently -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, -OR Ａ１ , -N(R Ａ１ ) ２ is selected from Each R Ａ１ are independently H, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl and C ３ -C ９ cycloalkyl; Each R ｂ are independently D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkenyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ｂ１ , -N(R ｂ１ ) ２ , -C(=O)R ｂ１ , -C(=O)OR ｂ１ , -NR ｂ１ C(=O)R ｂ１ , -NR ｂ１ C(=O)OR ｂ１ , -C(=O)N(R ｂ１ ) ２ , -OC(=O)N(R ｂ１ ) ２ , -S(=O)R ｂ１ , -S(=O) ２ R ｂ１ , -SR ｂ１ , -S(=O)(=NR ｂ１ ) R ｂ１ , -NR ｂ１ S (=O) ２ R ｂ１ And -S(=O) ２ N (R ｂ１ ) ２ or two R ｂ together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, R ｂ each alkyl, carbosilyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R ｂ１ are independently H, -C １ -C ６ Alkyl (wherein each hydrogen can be independently replaced by deuterium), -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C ３ -C ９ selected from cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl; Each R ｃ and R ｃ’ independently, H, -D, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl and -C １ -C ６ haloalkyl, or R ｃ and R ｃ’ together with the atoms to which they are attached, -C ３ -C ９ can form a cycloalkyl or carbonyl, n is 0, 1, 2 or 3; The compound, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, or 3.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1 or 2.

3. Each R ｂ are independently halo, -CN, -C １ -C ６ , -C １ -C ６ Alkyl, -C ６ -C １０ Aryl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -OR ｂ１ and -N(R ｂ１ ) ２ or two R ｂ together with the atom to which they are attached form a 4- to 7-membered carbocyclyl or a 4- to 7-membered heterocyclyl, each aryl, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo or -Me; ｂ１ are independently H, -C １ -C ６ Alkyl (wherein each hydrogen can be independently replaced by deuterium), -C １ -C ６ Haloalkyl and -C ３ -C ９ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from: cycloalkyl.

4. Each R ｂ are independently -CN, -C(=CH ２ ) CH ３ , -F, - ｉ Pr, -CF ３ , cyclopropyl (substituted with 0, 1 or 2 instances of -F, -Me, -CN), -OCF ３ , -OCHF ２ 4. The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from -OMe, -OMe, and -OMe.

5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring B is a 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

6. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring B is selected from phenyl, pyridinyl, and pyrimidinyl.

7. The compound is of formula (II) During the ceremony, 【Chemical 261】 X １ is selected from CH and N; X ２ is selected from CH and N; R ３ H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkenyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ３ , -N(R ａ３ ) ２ , -C(=O)R ａ３ , -C(=O)OR ａ３ , -NR ａ３ C(=O)R ａ３ , -NR ａ３ C(=O)OR ａ３ , -C(=O)N(R ａ３ ) ２ , -OC(=O)N(R ａ３ ) ２ , -S(=O)R ａ３ , -S(=O) ２ R ａ３ , -SR ａ３ , -S(=O)(=NR ａ３ ) R ａ３ , -NR ａ３ S (=O) ２ R ａ３ And -S(=O) ２ N (R ａ３ ) ２ wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; R ４ H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkenyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ４ , -N(R ａ４ ) ２ , -C(=O)R ａ４ , -C(=O)OR ａ４ , -NR ａ４ C(=O)R ａ４ , -NR ａ４ C(=O)OR ａ４ , -C(=O)N(R ａ４ ) ２ , -OC(=O)N(R ａ４ ) ２ , -S(=O)R ａ４ , -S(=O) ２ R ａ４ , -SR ａ４ , -S(=O)(=NR ａ４ ) R ａ４ , -NR ａ４ S (=O) ２ R ａ４ And -S(=O) ２ N (R ａ４ ) ２ wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; Each R ａ３ and R ａ４ are independently H, -C １ -C ６ Alkyl (each hydrogen can be replaced by deuterium), -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C ３ -C ９ The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl. 【Request 8】 【Chemical 262】 The part represented by 【Chemical 263】 8. The compound of claim 7, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

9. Each R ３ are independently H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkenyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, -OR ａ３ and -N(R ａ３ ) ２ wherein each aryl, alkyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo; and each R ａ３ are independently H, -C １ -C ６ Alkyl (each hydrogen can be replaced by deuterium), -C １ -C ６ Haloalkyl and -C ３ -C ９ 9. The compound of claim 7 or 8, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from: cycloalkyl.

10. Each R ３ are independently H, -D, -CN, -C(=CH ２ ) CH ３ , -C(CH ３ ) CH ２ CH ３ , -Cl, -F, -Me, - ｉ Pr, -CH ２ N (CH ３ ) CH ２ CF ３ , -CF ３ , -CH ２ CF ３ , cyclopropyl (substituted with 0 or 1 instance of -CN), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF ３ , -OCH ２ CF ３ , -OCHF ２ , -OCH ２ F, -O ｉ Pr, -OMe, -OEt, -OCD ３ , -OCH ２ CH (CH ３ ) ３ , -N(Me) ２ , -NHMe and -NH ｉ 9. The compound of claim 7 or 8, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

11. Each R ４ are independently H, -D, halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Alkenyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, -C ６ -C １０ Aryl, -OR ａ４ and -N(R ａ４ ) ２ wherein each aryl, alkyl, cycloalkyl, and heterocyclyl is substituted with 0, 1, 2, or 3 instances of halo or -Me; ａ４ are independently H, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl and -C ３ -C ９ 11. The compound of any one of claims 7 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from cycloalkyl.

12. Each R ４ are independently H, -D, -CN, -C(=CH ２ ) CH ３ , -C(CH ３ ) CH ２ CH ３ , -Cl, -F, -Me, - ｉ Pr, -CH ２ N (CH ３ ) CH ２ CF ３ , -CF ３ , -CH ２ CF ３ , cyclopropyl (substituted with 0, 1 or 2 instances of -CN, -F, or -Me), azetidinyl (substituted with 0 or 1 instance of -F), phenyl (substituted with 0 or 1 instance of halo), -OCF ３ , -OCH ２ CF ３ , -OCHF ２ , -O ｉ Pr, -OMe, -OCH ２ CH (CH ３ ) ３ , -N(Me) ２ and -NHMe and -NH ｉ 11. The compound of any one of claims 7 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from: Pr

13. Each R ４ The compound of any one of claims 7 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein is selected from H and -OMe.

14. R ｃ and R ｃ’ is each independently selected from H and -Me, or taken together form a cyclopropyl group, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

15. 【Catalogue 264】 The part represented by 【Chemistry 265】 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

16. 【Catalogue 266】 The part represented by 【Chemical 267】 15. The compound of any one of claims 1 to 14, wherein:

17. Each R Ａ are independently -D, halo, -C １ -C ６ Alkyl, —OH and —O—C １ -C ６ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

18. Each R Ａ is independently selected from -F, -Cl, -Me, -OH and -OMe, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

19. R １ is 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each of which is R ５ and each R ５ are independently halo, -CN, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Hydroxyalkyl, -C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR ａ５ , -N(R ａ５ ) ２ , -C(=O)R ａ５ , -C(=O)OR ａ５ , -NR ａ５ C(=O)R ａ５ , -NR ａ５ C(=O)OR ａ５ , -C(=O)N(R ａ５ ) ２ , -OC(=O)N(R ａ５ ) ２ , -S(=O)R ａ５ , -S(=O) ２ R ａ５ , -SR ａ５ , -S(=O)(=NR ａ５ ) R ａ５ , -NR ａ５ S (=O) ２ R ａ５ And -S(=O) ２ N (R ａ５ ) ２ wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted at any available position; and each R ａ５ are independently H, -C １ -C ６ Alkyl, -C １ -C ６ Heteroalkyl, -C １ -C ６ Haloalkyl, -C ３ -C ９ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from cycloalkyl, 3- to 7-membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5- to 6-membered heteroaryl, arylalkyl, and heteroarylalkyl.

20. R １ is a 5-membered monocyclic heteroaryl containing 1 to 3 heteroatoms selected from O, N, and S, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

21. R １ is imidazolyl or pyrazolyl, each of which is R ５ 21. The compound of claim 20, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0, 1, 2 or 3 instances of:

22. R ５ is -CN, -F, -Cl, -Br, -Me, -Et, - ｉ Pr, -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -OMe, -OEt, -CH ２ CH ２ OMe, -CH ２ CH ２ 22. The compound of any one of claims 19 to 21, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from OH, cyclopropyl, oxetanyl, and azetidinyl.

23. R １ but, 【Chemical 268】 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

24. R １ but, 【Chemical 269】 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

25. R ２ But, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Heteroalkyl, -C ３ -C １０ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein each hydrogen of said alkyl, said haloalkyl, and said heteroalkyl can be independently replaced with a deuterium atom.

26. R ２ But -CD ３ 26. The compound of claim 25, wherein:

27. R ２ The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

28. R ６ is H, -D, -CN, -F, -Cl, -Me, -Et, -Pr, - ｉ P, - ｎ Bu,- ｔ Bu, -CF ３ , -CHF ２ , phenyl, pyridinyl, -CC-CH ３ , —CC-cyclopropyl, —C(═O)NMe ２ , -C(=O)NHMe, -C(=O)NH ２ , -NH ２ , -NMe ２ 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the R is selected from -NHMe, -OH, and -OMe.

29. R ６ is H, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

30. The compound is 【Chemistry 270】 【Chemical 271】 【Chemical 272】 【Chemical 273】 【Chemical 274】 【Chemistry 275】 【Chemical 276】 【Chemical 277】 【Chemical 278】 【Chemical 279】 【Chemistry 280】 【Chemistry 281】 【Chemical 282】 【Chemistry 283】 【Chemical 284】 【Chemistry 285】 【Chemistry 286】 【Chemistry 287】 【Chemistry 288】 【Chemical 289】 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

31. 31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier.

32. 31. A composition for treating cancer in a patient in need thereof, comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

33. 32. The composition of claim 31 for treating cancer in a patient in need thereof.

34. The composition of claim 32 or 33, wherein the cancer is a cancer that is sensitive to USP1 inhibition.

35. 34. The composition of claim 32 or 33, wherein the cancer is a BRCA1 and / or BRCA2 mutant cancer.

36. The composition of claim 32 or 33, wherein the cancer is a BRCA1 and / or BRCA2 deficient cancer.

37. 34. The composition of claim 32 or 33, wherein the cancer is an ATM mutant cancer.

38. The composition of claim 32 or 33, wherein the cancer is a PARP inhibitor-resistant or refractory cancer.

39. The composition according to any one of claims 32 to 38, characterized in that the composition is administered to the patient in need of said treatment in combination with an additional therapeutic agent.

40. The cancer is selected from the group consisting of adrenal cortical carcinoma, AIDS-related lymphoma, AIDS-related malignant tumor, anal cancer, cerebellar astrocytoma, extrahepatic bile duct cancer, bladder cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, ependymoma, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma, adrenal cortex, pancreatic islet cell carcinoma, primary central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell sarcoma of tendon sheath, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer. , ependymoma, esophageal cancer, Ewing's sarcoma / tumor family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinoma, eye cancer (including intraocular melanoma), and retinoblastoma, gallbladder cancer, gastrointestinal carcinoid tumors, ovarian germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, Hodgkin's disease, hypopharyngeal cancer, hypothalamic and visual pathway gliomas, intraocular melanoma, Kaposi's sarcoma, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia , malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, metastatic squamous cell neck carcinoma with unknown primary site, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity cancer, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pheochromocytoma, hypoxemia ...

40. The composition of any one of claims 32 to 39, wherein the cancer is selected from pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, malignant fibrous histiocytoma of bone, soft tissue sarcoma, Sezary syndrome, skin cancer, small intestine cancer, stomach (gastric) cancer, supratentorial primitive neuroectodermal and pineal tumor, cutaneous T-cell lymphoma, testicular cancer, malignant thymoma, thyroid cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

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