Methods for selectively degrading proteins

Abstract

The present disclosure relates to method for selectively degrading proteins in a cell. the present disclosure further relates to methods for treating a disease or disorder characterized by cyclin E amplification or overexpression

Description

WSGR Attorney Docket No. 64600-710.601METHODS FOR SELECTIVELY DEGRADING PROTEINS CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 741,748, filed January 3, 2025, which application is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to methods for selectively degrading proteins in a cell. The present disclosure further relates to methods for ubiquitinating select lysine residues.BACKGROUND

[0003] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases.Heterodimerized with regulatory subunits known as cyclins, CDKs become fully activated and regulate key cellular processes including cell cycle progression and cell division (Morgan, D. O., Annu Rev Cell Dev Biol, 1997.13: 261-91). Uncontrolled proliferation is a hallmark of cancer cells. The deregulation of the CDK activity is associated with abnormal regulation of cell -cycle and is detected in virtually all forms of human cancers (Sherr, C. J., Science, 1996.274(5293): 1672-7).

[0004] CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in a variety of human cancers. CDK2 plays a crucial role in promoting Gl / S transition and S phase progression. In complex with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (pl 07, pl30, pRb), leading to de-repressionof E2F transcription factors, expression of Gl / S transition related genes and transition from G1 to S phase (Henley, S. A. and F. A. Dick, Cell Div, 2012, 7(1): p.10). This in turn enables activation of CDK2 / cyclin A, which phosphorylates endogenous substrates that permit DNA synthesis, replication and centrosome duplication (Ekholm, S. V. and S. I. Reed, Curr. Opin. Cell Biol., 2000. 12(6): 676-84). It has been reported that the CDK2 pathway influences tumorigenesis mainly through amplification and / or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors (e.g., p27), respectively (Xu, X., et al., Biochemistry, 1999.38(27): 8713-22).

[0005] CCNE1 copy -number gain and overexpression have been identified in ovarian, gastric, endometrial, breast and other cancers and been associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002.347(20): 1566- 75; Nakayama, N., et al., Cancer, 2010.116(11): 2621-34; Au-Yeung, G., etal., Clin Cancer Res, 2017.23(7): 1862-1874; Rosen, D. G., et al., Cancer, 2006.106(9): 1925- 32). Amplification and / or overexpression of CCNE1WSGR Attorney Docket No. 64600-710.601also reportedly contribute to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011.108(9): 3761-6; Herrera-Abreu, M. T., et al., Cancer Res, 2016.76(8): 2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, Y. N., et al., Proc Natl Acad Sci USA, 1999.96(8): 4325-9; Mendoza, N., et al., Cancer Res, 2003.63(5): 1020-4). Inhibition of CDK2 also reportedly restores sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in a preclinical model (Scaltriti, supra).

[0006] These data provide a rationale for considering CDK2 as a potential target for new drug development in cancer associated with deregulated CDK2 activity. In the last decade there has been increasing interest in the development of CDK selective inhibitors. Despite significant efforts, there are no approved agents targeting CDK2 to date (Cicenas, J., et al., Cancers (Basel), 2014.6(4): p.2224-42). Therefore, it remains a need to discover CDK inhibitors having novel activity profiles, in particular those targeting CDK2. This application is directed to this need and others.SUMMARY

[0007] For purposes of summarizing the invention and the advantages achieved over the prior art, certain objects and advantages of the invention are described herein. Not all such objects or advantages may be achieved in any particular embodiment of the invention. Thus, for example, those skilled in the art will recognize that the invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein.

[0008] All of these embodiments are intended to be within the scope of the present invention herein disclosed. These and other embodiments of the present invention will become readily apparent to those skilled in the art from the following detailed description of the preferred embodiments having reference to the attached figures, the invention not being limited to any particular preferred embodiment(s) disclosed.

[0009] In one aspect, disclosed herein is a method for selectively degrading a one or more proteins in a cell, comprising: (a) selecting one or more lysine residues for ubiquitinating on at least one target protein of a protein complex; (b) contacting the protein complex with a molecule to form a non-native ternary complex comprising the protein complex and a ligase, whereby the molecule induces proximity between the protein complex and the ligase thereby causingWSGR Attorney Docket No. 64600-710.601ubiquitinating of at least one of the selected lysine residues; and (c) selectively degrading at least one protein in the protein complex containing the ubiquitinated selected lysine residues.

[0010] In some embodiments, ubiquitinating at least one of the selected lysine residues comprises trans-ubiquitination. In some embodiments, trans-ubiquitination comprises an ubiquitin ligase specific to the target protein.

[0011] In some embodiments, the molecule comprises a bifunctional molecule.

[0012] In some embodiments, the one or more lysine residues comprise solvent-exposed lysine residues. In some embodiments, the target protein is selected from CDK2, CCNE1, and CCNE2. In some embodiments, the selected lysine residue comprises CDK2 K250, CDK2 K291, or CCNE1 KI 45.

[0013] In some embodiments, the method treats a disease or disorder that is resistant to CDK2 inhibition alone. In some embodiments, the method treats a disease or disorder characterized by CCNE1 or CCNE2 amplification or overexpression. In some embodiments, the method ablates the cyclin E upregulation resistance mechanism induced by kinase inhibitors.

[0014] In another aspect, disclosed herein is a method for ubiquitinating one or more select lysine residues, comprising: (a) identifying one or more ubiquitin -competent lysine residues on a target protein of a protein complex; (b) inducing a ubiquitin-competent ternary complex via a bifunctional molecule; and (c) ubiquitinating the one or more select lysine residues of the target protein.

[0015] In some embodiments, identifying one or more ubiquitin-competent lysine residues comprises predicting selectivity for a CDK2 lysine residue over a homologous lysine residue. In some embodiments, ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of CDK2 K250. In some embodiments, ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of CDK2 K291. In some embodiments, ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of cyclin E. In some embodiments, ubiquitinating the bifunctional molecule comprises a dual CDK2 and cyclin E affinity degrader. In some embodiments, the one or more ubiquitinated lysine residues are subsequently degraded via a proteasome pathway.

[0016] In another aspect, disclosed herein is a method for treating a disease or disorder that is unresponsive, or partially unresponsive, to CDK2 inhibition alone. In another aspect, disclosed herein is a method for treating a disease or disorder characterized by cyclin E amplification or overexpression.WSGR Attorney Docket No. 64600-710.601BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0018] FIG. 1 illustrates the dose-response curves for the degradation of CDK2 and Cyclin E1 by compounds of the disclosure, according to some embodiments herein.

[0019] FIG. 2A is a graph illustrating the lysine distance distributions for cyclin-dependent kinase (CDK) / Cyclin E1 complexes in the presence of a compound according to some embodiments herein.

[0020] FIG. 2B is a graph illustrating the lysine distance distributions for cyclin-dependent kinase (CDK) / Cyclin E1 complexes in the presence of a compound according to some embodiments herein.

[0021] FIG. 3 A is a graph illustrating the cellular target engagement across various CDKs and their associated cyclins in the presence of a compound according to some embodiments herein.

[0022] FIG. 3B is a Western Blot illustrating the degradation of CDK2 and Cyclin E1 in the presence of a compound according to some embodiments herein, and its CRBN analog.

[0023] FIG. 3C is a graph illustrating protein degradation as a function of compound concentration.

[0024] FIG. 3D is a graph illustrating protein degradation in the presence of a CRBN-incompetent analog compound.

[0025] FIG. 4A is a Western Blot showing the expression of CDK2 and Cyclin E1 in a SK-OV-3 cell line after being treated with a compound according to some embodiments herein.

[0026] FIG. 4B is a Western Blot showing the expression of Cyclin E1 in a CDK2 knocked-out cell line after being treated with a compound according to some embodiments herein.

[0027] FIG. 5 is an image of colony formation assays illustrating the dose-response effects of various cancer cell lines after being treated with a compound according to some embodiments herein.

[0028] FIG. 6 is a graph depicting the OVCAR-3 tumor size over time for mice treated with a control and a compound according to some embodiments herein.

[0029] FIG. 7A is a graph depicting target degradation and engagement of various CDKs in HEK293 cells with a compound according to some embodiments herein.WSGR Attorney Docket No. 64600-710.601

[0030] FIG. 7B is a Western Blot showing the expression of CDK2 and Cyclin E1 in a COV318 cell line after being treated with a compound according to some embodiments herein.

[0031] FIG. 7C is a Western Blot showing the expression of CDK2 and Cyclin E1 in a SK-OV-3 cell line after being treated with a compound according to some embodiments herein.

[0032] FIG. 7D is a Western Blot showing the expression of CDK2 and Cyclin E1 in a SK-OV-3 cell line with and without being treated by a neddylation inhibitor.

[0033] FIG.8A is an image of colony formation assays illustrating the dose-response effects of OVCAR3 and SKOV3 cell lines after being treated with a compound according to some embodiments herein.

[0034] FIG. 8B is a graph illustrates the dose-response curves of OVCAR3 and SKOV3 cell lines after being treated with a compound according to some embodiments herein at varying concentrations.

[0035] FIG. 8C is a graph illustrates the dose-response curves of OVCAR3 and SKOV3 cell lines after being treated with a compound at varying concentrations.

[0036] FIG. 9 are scatter plots representing the degradation of CDK2 and Cyclin E1 in mouse spleen tissue after being treated with a compound according to some embodiments herein.

[0037] FIG. 10 is a graph depicting OVCAR-3 tumor size over time for mice treated with a compound according to some embodiments herein.

[0038] FIG. 11A is a graph depicting HiBiT degradation profiles of various CDK complexes after being treated with a compound according to some embodiments herein at varying concentrations.

[0039] FIG. 11B is a graph depicting NanoBRET target engagement profiles of various CDK complexes after being treated with a compound according to some embodiments herein at varying concentrations.

[0040] FIG. 12A are a set of graphs illustrating the selective growth suppression of Cyclin E1 amplified cancer cell lines after being treated with a compound according to some embodiments herein.

[0041] FIG. 12B is an image of colony formation assays illustrating the dose-response effects of Cyclin E1 amplified and non-amplified cell lines after being treated with a compound according to some embodiments herein.

[0042] FIG. 12C is a graph illustrates the dose-response curves of Cyclin E1 amplified and nonamplified cell lines after being treated with a compound according to some embodiments herein at varying concentrations.WSGR Attorney Docket No. 64600-710.601

[0043] FIG. 12D is a graph illustrates the dose-response curves of Cyclin E1 amplified and nonamplified cell lines after being treated with a compound at varying concentrations.

[0044] FIG. 13 is a graph depicting OVCAR-3 tumor size over time for mice treated with a compound according to some embodiments herein.

[0045] FIG. 14A is a graph depicting MKN 1 gastric tumor size over time for mice treated with a compound according to some embodiments herein.

[0046] FIG. 14B are a set of graphs showing the free plasma concentration of a compound according to some embodiments herein when administered at three dosing regimens in relation to target protein inhibition levels.

[0047] FIG. 15A is a graph showing the free plasma concentration of a compound according to some embodiments herein when administered in rat models at different dosing regimens.

[0048] FIG. 15B is a graph showing the free plasma concentration of a compound according to some embodiments herein when administered in dog models at different dosing regimens.DETAILED DESCRIPTIONTerms and Definitions

[0049] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0050] The articles “a” and “an” are used in this disclosure to refer to one or more than one ( / .<., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, in certain contexts, “an element” means one element and / or in certain contexts more than one element. By way of another example, in certain contexts “a compound” means one compound and / or in certain contexts more than one compound (e.g., a mixture of two or more compounds).

[0051] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0052] It should be understood that the expression “at least one of ’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0053] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should beWSGR Attorney Docket No. 64600-710.601understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0054] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0055] At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22,23, 24,25, 26,27, 28,29, 30,31, 32,33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0056] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non -claimed element as essential to the practice of the present invention.Chemical Definitions

[0057] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0058] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.WSGR Attorney Docket No. 64600-710.601

[0059] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. 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 preparedby asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 332125 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). Additionally encompassed are compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0060] The “enantiomeric excess” (“e.e.”) or “% enantiomeric excess” (“%e.e.”) of a composition as used herein refers to an excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition can contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.e.e. = (90-10) / 100 = 80%

[0061] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0062] The “diastereomeric excess” (“d.e.”) or “% diastereomeric excess” (“%d.e.”) of a composition as used herein refers to an excess of one diastereomer relative to one or more different diastereomers present in the composition. For example, a composition can contain 90% of one diastereomer, and 10% of one or more different diastereomers.d.e. = (90-10) / 100 = 80%

[0063] Thus, a composition containing 90% of one diastereomers and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.

[0064] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, atWSGR Attorney Docket No. 64600-710.601least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0065] In a formula, — is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified.

[0066] When a range of values is listed, it is intended to encompass each value and sub -range within the range. For example, “Ci_6alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci_6, Cl_5, Ci^, Ci-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4_6, C45, and C5-6 alkyl.

[0067] It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0068] The term “unsaturated bond” refers to a double or triple bond.

[0069] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0070] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0071] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynyleneis the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0072] The term “azido” refers to the radical -N3.

[0073] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0074] “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,WSGR Attorney Docket No. 64600-710.601cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0075] “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.

[0076] “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.

[0077] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group havingfrom 1 to 20 carbon atoms (“Ci_20alkyl”). In an embodiment, an alkyl group has 1 to 12 carbon atoms (“Ci-i2alkyl”). In an embodiment, an alkyl group has 1 to 10 carbon atoms (“Ci-io alkyl”). In an embodiment, an alkyl group has 1 to 9 carbon atoms (“Ci-9 alkyl”). In an embodiment, an alkyl group has 1 to 8 carbon atoms (“Ci~8alkyl”). In an embodiment, an alkyl group has 1 to 7 carbon atoms (“Ci_7alkyl”). In an embodiment, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”, also referred to herein as “lower alkyl”). In an embodiment, an alkyl group has 1 to 5 carbon atoms (“Ci_5alkyl”). In an embodiment, an alkyl group has 1 to 4 carbon atoms (“Ci^ alkyl”). In an embodiment, an alkyl group has 1 to 3 carbon atoms (“Ci_3alkyl”). In an embodiment, an alkyl group has 1 to 2 carbon atoms (“Ci_2alkyl”). In an embodiment, an alkyl group has 1 carbon atom (“Ci alkyl”). In an embodiment, an alkyl group has 2 to 6 carbon atoms (“C2_6 alkyl”). Examples of Ci_6alkyl groups include methyl (Ci), 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 (Ce). 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, ie., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one ormore substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted CMO alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted CMO alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), Tr (-CH(CH3)2), " Pr (-CH2CH2CH3), " Bu (-CH2CH2CH2CH3), or 'Bu (-CH2CH(CH3)2).

[0078] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or un substituted. Unsubstituted alkylene groupsWSGR Attorney Docket No. 64600-710.601include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0079] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carboncarbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In an embodiment, an alkenyl group has 2 to 10 carbon atoms (“C2_i0alkenyl”). In an embodiment, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In an embodiment, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In an embodiment, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In an embodiment, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In an embodiment, an alkenyl group has 2 to 5 carbon atoms (“C2_s alkenyl”). In an embodiment, an alkenyl group has 2 to 4 carbon atoms (“C2 4alkenyl”). In an embodiment, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In an embodiment, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples ofC26 alkenyl groups include the aforementioned C24 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), 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, z.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2_i0alkenyl. In certain embodiments, the alkenyl group is substituted C2_io alkenyl.WSGR Attorney Docket No. 64600-710.601

[0080] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carboncarbon 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”). In certain embodiments, alkynyl does not contain any double bonds. In an embodiment, an alkynyl group has 2 to 10 carbon atoms (“C2-io alkynyl”). In an embodiment, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In an embodiment, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In an embodiment, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In an embodiment, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In an embodiment, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In an embodiment, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In an embodiment, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In an embodiment, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2 4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i. e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0081] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC, |0alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-9 alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi_8alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC, 7 alkyl”). In anWSGR Attorney Docket No. 64600-710.601embodiment, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroCi-6 alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroCi-s alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC, 4 alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). 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, the heteroalkyl group is an unsubstituted heteroC, 10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC,,0alkyl. Exemplary heteroalkyl groups include: -CH2OH, -CH2OCH3, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2.

[0082] “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 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In an embodiment, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In an embodiment, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g, naphthyl such as 1 -naphthyl and 2-naphthyl). In an embodiment, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is substituted Ce-i4 aryl.

[0083] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, Ci-C8alkyl, Ci-C8haloalkyl, cyano, hydroxy, Ci-C8alkoxy, and amino.

[0084] Examples of representative substituted aryls include the followingWSGR Attorney Docket No. 64600-710.601

[0085] wherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-C8alkyl, Ci-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR58COR59, -NR58SOR59NR58SO2R59, -COOalkyl, -COOaryl, -CONR58R59, -CONR58OR59, -NR58R59, - SO2NR58R59, -S-alkyl, -SOalkyl, -SO2alkyl, -Saryl, -SOaryl, -SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. R60and R61are independently hydrogen, -Ci-C8alkyl, -C1-C4 haloalkyl, -C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cioaryl, substituted Ce-Cw aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0086] “Fused aryl” refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0087] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 107t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, In such instances, unless otherwise specified, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).WSGR Attorney Docket No. 64600-710.601

[0088] In an embodiment, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In an embodiment, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In an embodiment, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1 -4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In an embodiment, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In an embodiment, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In an embodiment, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, ie., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. In an embodiment, a heteroaryl group is a bicyclic 8-12 membered aromatic ring system having ring carbon atoms and 1 -6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“8-12 membered bicyclic heteroaryl”). In an embodiment, a heteroaryl group is an 8-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“8-10 membered bicyclic heteroaryl”). In an embodiment, a heteroaryl group is a 9-10 membered bicyclic aromatic ring system having ring carbon atoms and 1 -6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“9- 10 membered bicyclic heteroaryl”). Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.WSGR Attorney Docket No. 64600-710.601

[0089] 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, andthiadiazolyl. 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, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, 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.

[0090] Examples of representative heteroaryls include the following:

[0091] wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, -Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Ci0aryl, and 5-10 membered heteroaryl.WSGR Attorney Docket No. 64600-710.601

[0092] In the structures described herein, a substituent attached to a polycyclic (e.g., bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl or heteroaryl with a bond that spans two or more rings is understood to mean that the substituent can be attached at any position in each of the rings.

[0093] “Heteroaralkyl” or “heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0094] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic monocyclic, bicyclic, or tricyclic or polycyclic hydrocarbon ring system having from 3 to 14 ring carbon atoms (“C3.14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyls), and partially saturated ring systems. In an embodiment, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3.10 carbocyclyl”). In an embodiment, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3.8carbocyclyl”). In an embodiment, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3.7 carbocyclyl”). In an embodiment, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In an embodiment, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4.6carbocyclyl”). In an embodiment, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5.6carbocyclyl”). In an embodiment, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5.10 carbocyclyl”). Exemplary C3.6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3.8carbocyclyl groups include, without limitation, the aforementioned C3.6 carbocyclyl groups as well as 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 C3.10 carbocyclyl groups include, without limitation, the aforementioned C3.8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0095] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) andean be saturated or can contain one or more carbon -carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the numberWSGR Attorney Docket No. 64600-710.601of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carb ocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3.14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3.14 carbocyclyl.

[0096] The term “cycloalkyl” as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 14 carbons containing the indicated number of rings and carbon atoms (for example a C3-C14 monocyclic, C4-C14 bicyclic, C5-C14 tricyclic, or C6-Ci4polycyclic cycloalkyl). In an embodiment “cycloalkyl” is a monocyclic cycloalkyl. In an embodiment, a monocyclic cycloalkyl has 3-14 ring carbon atoms. (“C3.14 monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms (“C3.10 monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 3 to 6 ring carbon atoms (“C3.6monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms (“C4.6monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms (“C5.6monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5.10 monocyclic cycloalkyl”). Examples of monocyclic C5.6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3.8cycloalkyl groups include the aforementioned C3.6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).

[0097] In an embodiment “cycloalkyl” is a bicyclic cycloalkyl. In an embodiment, a bicyclic cycloalkyl has 4-14 ring carbon atoms. (“C4-14 bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms (“C4.12 bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms (“C4-10 bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms (“C6-io bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 8 to 10 ring carbon atoms (“Cs-io bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms (“C7-9 bicyclic cycloalkyl”). Examples of bicyclic cycloalkyls include bicyclofl.1.0]butane (C4), bicyclofl. l.l]pentane (C5), spiro[2.2] pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (Ci), bicyclo[3.1.0]hexane (Ci), spiro[2.3]WSGR Attorney Docket No. 64600-710.601hexane (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- IH-in dene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), bicyclo[3.3.2]decane (C10), bicyclo[4.3.1]decane (C10), spiro[4.5]decane (Cw), bicyclo[3.3.3]undecane (Cn), decahydronaphthalene (C10), bicyclo[4.3.2]undecane (Cn), spiro[5.5]undecane (Cn) and bicyclo[4.3.3]dodecane (C12).

[0098] In an embodiment “cycloalkyl” is a tricyclic cycloalkyl. In an embodiment, a tricyclic cycloalkyl has 6-14 ring carbon atoms. (“C6-i4 tricyclic cycloalkyl”). In an embodiment, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms (“C8-i2 tricyclic cycloalkyl”). In an embodiment, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms (“C 10-12 tricyclic cycloalkyl. Examples of tricyclic cycloalkyls include adamantine (Ci2).

[0099] Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3.14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3.14 cycloalkyl.

[0100] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3 - to 10-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), andean be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue 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.,WSGR Attorney Docket No. 64600-710.601unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0101] In an embodiment, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In an embodiment, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In an embodiment, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In an embodiment, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In an embodiment, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In an embodiment, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0102] Exemplary 3 -membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, 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, andthiadiazolinyl. 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, 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, withoutWSGR Attorney Docket No. 64600-710.601limitation, azocanyl, oxecanyl andthiocanyl. Exemplary 5 -membered heterocyclyl groups fused to a Ce 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-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 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-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-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-l,6-naphthyridinyl, and the like. Exemplary 6 -membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6 -bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0103] “Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, 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-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0104] “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 by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0105] “Acyl” refers to a radical -C(=O)R20, where R20is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or un substituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. “Alkanoyl” is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are notWSGR Attorney Docket No. 64600-710.601limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), — C(=O)-Ci-C8alkyl, -C(=O)-(CH2)t(C6-Cio aryl), -C(=O)-(CH2)t(5-10 membered heteroaryl), -C(=0)-(CH2)t(C3-Cio cycloalkyl), and -C(=O)-(CH2)t(4- 10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21is Ci-C8alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, 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.

[0106] The term aminoalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -NH2group.

[0107] The term hydroxyalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -OH group.

[0108] The terms “alkylamino” and “dialkylamino” refer to -NH(alkyl) and~N(alkyl)2radicals respectively. In an embodiment the alkylamino is a -NH(CI-C4alkyl). In an embodiment the alkylamino is methylamino, ethylamino, propylamino, isopropylamino, w-butylamino, iso-butylamino, ec-butylamino or tert-butylamino. In an embodimentthe dialkylamino is -N(Ci-Ce alkyl)2. In an embodimentthe dialkylamino is a dimethylamino, a methylethylamino, a diethylamino, a methylpropylamino, a methylisopropylamino, a methylbutylamino, a methylisobutylamino or a methyltertbutylamino.

[0109] The term “aryloxy” refers to an -O-aryl radical. In an embodiment the aryloxy group is phenoxy.

[0110] The term “haloalkoxy” refers to alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the term “fluoroalkoxy” includes haloalkoxy groups, in which the halo is fluorine. In an embodiment haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0111] “Alkoxy” refers to the group -OR29where R29is substituted or unsubstituted alkyl, substituted or unsub stitued alkenyl, substituted or unsub stitued alkynyl, substituted or unsub stitued carbocyclyl, substituted or un substituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsub stitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, ec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.WSGR Attorney Docket No. 64600-710.601

[0112] In certain embodiments, R29is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, Ce-Cio aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, -0-(CH2)t(C6-Cio aryl), -O-(CH2)t(5-10 membered heteroaryl), -0-(CH2)t(C3-Cio cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves 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. Particular exemplary ‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2N(CH3)2.

[0113] “ Amino” refers to the radical -NH2.

[0114] “ Oxo group” refers to -C(=O)-.

[0115] “ Substituted amino” refers to an amino group of the formula -N(R38)2wherein R38is hydrogen, substituted or un substituted alkyl, substituted or unsub stitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsub stitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38is not a hydrogen. In certain embodiments, each R38is independently selected from hydrogen, -Ci-C8alkyl, -C3-C8alkenyl, -C3-C8alkynyl, C6-Ci0aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or Ci-C8alkyl, substituted with halo or hydroxy; C3-C8alkenyl, substituted with halo or hydroxy; C3-C8alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-Cio cycloalkyl), or -(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or un substituted C1-C4 haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0116] Exemplary “substituted amino” groups include, but are not limited to, -NR39-CI-C8alkyl, -NR39-(CH2)t(C6-Cio aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39-(CH2)t(C3-C10 cycloalkyl), and-NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or Ci-C8alkyl; and any alkylWSGR Attorney Docket No. 64600-710.601groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, un substituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0117] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -OR33, -N(RCC)2, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)0R33, -C(=NRcc)N(Rcc)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -S0R33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -CMO alkyl (e.g., aralkyl, heteroaralkyl), -C2-io alkenyl, -C2-io alkynyl, heteroCi-io alkyl, heteroC2.i0alkenyl, heteroC2.i0alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein R33, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0118] each instance of Raais, independently, selected from -CHO alkyl, -Cuo perhaloalkyl, -C2.io alkenyl, -C2.io alkynyl, heteroCi-io alkyl, heteroC2.i0alkenyl, heteroC2.i0alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two R33groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0119] each instance of Rbbis, independently, selected from hydrogen, -OH, -OR33, -N(RCC)2, -CN, -C(=0)R33, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRcc)0R33, -C(=NRcc)N(Rcc)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -S0R33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(R33)2, -P(=O)(OR“)2, -P(=O)(N(R“)2)2, -CMO alkyl, -CMO perhaloalkyl, -C2.io alkenyl, -C2.io alkynyl, heteroCMo alkyl, heteroC2.i0alkenyl, heteroC2.i0alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two RbbWSGR Attorney Docket No. 64600-710.601groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion.

[0120] each instance of Rccis, independently, selected from hydrogen, -CMO alkyl, -CMO perhaloalkyl, -C2-io alkenyl, -C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0121] each instance of Rddis, independently, selected from halogen, -CN, -NO2, ~N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rfi)2, -N(Rfi)2, N(Rir)3X, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rfi)2, -OC(=O)N(Rfi)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRirC(=O)N(Rir)2, -C(=NRir)ORX -OC(=NRir)R^ -OC(=NRfi)ORee, -C(=NRfi)N(Rfi)2, -OC(=NRfi)N(Rfi)2, -NRffC(=NRfi)N(Rfi)2, -NRffSO2Ree, -SO2N(Rfi)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rfi)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, -Ci-6 alkyl, -Ci-6 perhaloalkyl, -C2.6 alkenyl, -C2-6 alkynyl, heteroCi-ealkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, C3.io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X is a counterion;

[0122] each instance of Reeis, independently, selected from -Ci.6alkyl, -Ci.6perhaloalkyl, -C2.6alkenyl, -C2.6 alkynyl, heteroCi-6 alkyl, heteroC2.6alkenyl, heteroC2.6 alkynyl, C3.io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;

[0123] each instance of Rffis, independently, selected from hydrogen, -Ci-6 alkyl, -Ci-6 perhaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroCi-ealkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, C3.io carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring,WSGR Attorney Docket No. 64600-710.601wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.gggroups; and

[0124] each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi.6alkyl, -ON(CI.6alkyl)2, -N(CI.6alkyl)2, -N(CI.6alkyl)3+X-, -NH(CI.6alkyl)2+X-, -NH2(CI-6alkyl) X, -NH3+X-, -N(OCI.6alkyl)(Ci.6alkyl), -N(OH)(CI.6alkyl), -NH(OH), -SH, -SCi-6 alkyl, -SS(Ci.6alkyl), -C(=O)(Ci.6alkyl), -CO2H, -CO2(Ci.6alkyl), -OC(=O)(Ci.6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI.6alkyl)2, -OC(=O)NH(CI.6alkyl), -NHC(=O)(CI-6alkyl), -N(CI.6alkyl)C(=O)(Ci.6alkyl), -NHCO2(CI.6alkyl), -NHC(=O)N(CI.6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=0)NH2, -C(=NH)O(CI.6alkyl), -OC(=NH)(CI.6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI.6alkyl)2, -C(=NH)NH(CI.6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(CI.6alkyl), -0C(NH)NH2, -NHC(NH)N(CI.6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6 alkyl), -SO2N(CI.6alkyl)2, -SO2NH(CI.6alkyl), -SO2NH2, -SO2Ci-6 alkyl, -SO2OCi.6alkyl, -OSO2Ci.6alkyl, -SOCi.6alkyl, -Si(Ci_6alkyl)3, -OSi(Ci.6alkyl)3-C(=S)N(CI-6alkyl)2, -C(=S)NH(CI.6alkyl), -C(=S)NH2, -C(=O)S(Ci.6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi.6alkyl, -P(=O)(OCi.6alkyl)2, -P(=O)(Ci.6alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi.6alkyl)2, -Ci.6alkyl, -Ci.6perhaloalkyl, -C2.6alkenyl, -C2.6 alkynyl, heteroCi.6alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, C3.io carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5 -10 membered heteroaryl; ortwo geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0125] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarb oxamide, N-benzoylphenylalanyl derivative, benzamide, p -phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3 -(p-hydroxyphenyl)propanamide, 3 -(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acety Im ethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0126] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di- / -butyl-[9-WSGR Attorney Docket No. 64600-710.601(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2 -trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1 -(l-adamantyl)-l-methylethyl carbamate (Adpoc), 1,1 -dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB- / -BOC), 1, 1 -dimethyl-2, 2, 2-trichloroethyl carbamate (TCBOC), 1-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3,5 -di- / -butylphenyl)-l -methylethyl carbamate (Z-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC orBoc), 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, alkyldithio carbamate, benzyl carbamate (Cbz), p -methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p -chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9 -anthrylmethyl carbamate, diphenylmethyl carbamate, 2 -methylthioethyl carbamate, 2 -methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4 -dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5 -dimethoxy benzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)m ethyl carbamate, / -amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2 -dimeth oxyacylvinyl carbamate, o-(N, N-dimethylcarboxamido)benzyl carbamate, 1,1 -dimethyl-3-(N, N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobomyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3,5-dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri- / -butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.WSGR Attorney Docket No. 64600-710.601

[0127] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzen esulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0128] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl -( 10)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’ -phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide(Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3, 5-dinitro-4-pyridone, N-m ethylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3 -acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenyhn ethylamino (Fem), N-2 -picolylamino N’-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’, N’-dimethylaminomethylene)amine, N, N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,WSGR Attorney Docket No. 64600-710.601pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0129] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -R33, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si R^, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein R33, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0130] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), Z-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxy methyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), Z-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2 -methoxy ethoxymethyl (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), l,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 -ethoxy ethyl, 1 -(2-chloroethoxy)ethyl, 1 -methyl- 1 -meth oxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy -2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, / -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-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri (p -meth oxy phenyl)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-l-yl)bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S-WSGR Attorney Docket No. 64600-710.601dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), Z-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), Z-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, meth oxy acetate, triphenylmethoxy acetate, phenoxy acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4 -methoxy crotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2, 2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimeth oxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2 -iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (m ethoxy acyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4 -dinitrophenylsulf enate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0131] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(R“)3+X, -P(OR“)2, -P(OR“)3+X, -P(=O)(Raa)2, -P(=O)(OR“)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0132] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile.WSGR Attorney Docket No. 64600-710.601Examples of suitable leaving groups include, but are not limited to, halogen (such as F, -Cl, -Br, or I (iodine)), alkoxy carbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, pixyl, and haloformates. In certain embodiments, the leaving group is halogen, alkane sulfonyloxy, arenesulfonyloxy, diazonium, alkyl diazenes, aryl diazenes, alkyl triazenes, aryl triazenes, nitro, alkyl nitrate, aryl nitrate, alkyl phosphate, aryl phosphate, alkyl carbonyl oxy, aryl carbonyl oxy, alkoxcarbonyl oxy, aryoxcarbonyl oxy ammonia, alkyl amines, aryl amines, hydroxyl group, alkyloxy group, or aryloxy. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), / ?-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as / ?-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In an embodiment, the leaving group is a sulfonate -containing group. In an embodiment, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu 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.

[0133] “Carboxy” refers to the radical -C(=O)OH.

[0134] “Cyano” refers to the radical -CN.

[0135] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0136] “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 (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CH2F), chloromethyl (-CH2C1), dichloromethyl (-CHC12), tribromomethyl (-CH2Br), and the like.

[0137] “Hydroxy” refers to the radical -OH.

[0138] “Nitro” refers to the radical -NO2.

[0139] “ Thioketo” refers to the group =S.

[0140] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “un substituted” heterocyclyl, “substituted” orWSGR Attorney Docket No. 64600-710.601“unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. Any and all such combinations are contemplated in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0141] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR”, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3+X, -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO^33, -0C(=0)R33, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=0)R33, -NRbbCO2R33, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SOjR”, -S020R33, -OSO2R, -S(=0)R33, -S(=0)(=NRbb)R33, -0S(=0)R33, -SiCR^, -OSi R^ -C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SR33, -SC(=S)SR33, -SC(=0)SR33, -0C(=0)SR33, -SC(=O)ORaa, -SC(=0)R33, -P(=0)2R33, -OP(=O)2Raa, -P(=O)(Raa)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, -OP(=O)(NRbb)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(NRbb)2, -P(RCC)2, -P(RCC)3, -OP(RCC)2, -OP(RCC)3, -BQU3)^ -B(ORCC)2, -BRaa(ORcc), -Ci-io alkyl, -Ci-io haloalkyl, -C2_i0alkenyl, -C2_i0alkynyl, C3_i0carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=O)2R33, =NRbb, or =NORCC;

[0142] each instance of Raais, independently, selected from Ci-io alkyl, -Ci-io haloalkyl, -C2_i0alkenyl, -C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14WSGR Attorney Docket No. 64600-710.601membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0143] each instance of Rbbis, independently, selected from hydrogen, -OH, -OR”, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO^, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P ^R”, -P(=O)(Raa)2, -P(=O)2N(RCC)2, -P(=O)(NRCC)2, -Ci-io alkyl, -CUD haloalkyl, -C2_i0alkenyl, -C2_io alkynyl, C3_i0carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0144] each instance of Rccis, independently, selected from hydrogen, -Ci-io alkyl, -CUD haloalkyl, -C2_io alkenyl, -C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0145] each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rfi)2, -N(R®)2, -N(Rir)3X, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rfi)2, -OC(=O)N(Rfi)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRirC(=O)N(Rir)2, -C(=NRir)ORag -OC(=NRir)Rag -OC(=NRfi)ORee, -C(=NRfi)N(Rfi)2, -OC(=NRfi)N(Rfi)2, -NRffC(=NRfi)N(Rff)2,-NRffSO2Ree, -SO2N(R®)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rfi)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, -Ci-6 alkyl, -Ci_6haloalkyl, -C2-6alkenyl, -C2-6alkynyl, C3_i0carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rddsubstituents can be joined to form =0 or =S;

[0146] each instance of Reeis, independently, selected from Ci_6alkyl, -Ci_6haloalkyl, -C2-6alkenyl, -C26 alkynyl, C3_io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rss groups;WSGR Attorney Docket No. 64600-710.601

[0147] each instance of Rffis, independently, selected from hydrogen, -Ci_6alkyl, -Ci_6haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and

[0148] each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi_6alkyl, -ON(Ci6alkyl)2, -N(CI_6alkyl)2, -N(C6alkyl)3+X- -NH(Ci6alkyl)2+X, -NH2(CI-6alkyl)+X, -NH3+X, -N(OCi6alkyl)(Ci_6alkyl), -N(OH)(Ci6alkyl), -NH(OH), -SH, -SC.6alkyl, -SS(Ci_6alkyl), -C(=O)(Ci6alkyl), -CO2H, -CO2(Ci6alkyl), -OC(=O)(Ci6alkyl), -OCO2(Ci_6alkyl), -C(=O)NH2, -C(=O)N(Ci6alkyl)2, -OC(=O)NH(Ci6alkyl), -NHC(=O)(Ci^ alkyl), -N(CI_6alkyl)C(=O)(Ci^ alkyl), -NHCO2(CI6alkyl), -NHC(=O)N(Ci6alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=0)NH2, -C(=NH)O(Ci6alkyl),-OC(=NH)(Ci^ alkyl), -OC(=NH)OCI_6alkyl, -C(=NH)N(Ci6alky 1)2, -C(=NH)NH(Ci6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(Ci^ alkyl), -0C(NH)NH2, -NHC(NH)N(Ci6alkyl)2, -NHC(=NH)NH2, -NHSO^C]6alkyl), -SO2N(CI_6alkyl)2, -SO2NH(CI^ alkyl), -SO2NH2,-SO2C!6alkyl, -SO2OCi6alkyl, -OSO2Ci^ alkyl, -SOC]6alkyl, -Si(Ci_6alkyl)3, -OSi(Ci^ alkyl)3-C(=S)N(CI_6 alkyl)2, -C(=S)NH(Ci6alkyl), -C(=S)NH2, -C(=O)S(Ci6alkyl), -C(=S)SCi_6alkyl, -SC(=S)SC6alkyl, -P(=O)2(Ci6alkyl), -P(=O)(Ci6alkyl)2, -OP(=O)(Ci6alkyl)2, -OP(=O)(OCi-6alkyl)2, -Ci_6alkyl, -Ci-6 haloalkyl, -C2 6alkenyl, -C2-6alkynyl, C3-10 carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0149] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F, Cl", Br, I ), NO3, C1O4, OH", H2PO4, HSO4, SO4'2sulfonate ions (e.g., methansulf onate, trifluoromethanesulfonate, p -toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, nap hthalene-2-sulf onate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulf onate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0150] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -OR”, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -WSGR Attorney Docket No. 64600-710.601SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR.aa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(RCC)2, -P(=O)(NRCC)2, -CI-10 alkyl, -CHO haloalkyl, -C2-10alkenyl, -C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0151] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0152] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refer to the combination of a therapeutically active agent with a pharmaceutically acceptable excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0153] “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or human, as appropriate; or means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0154] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of Formula I, Formula II-A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B), which salt is compatible with pharmaceutical administration.

[0155] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may beWSGR Attorney Docket No. 64600-710.601employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0156] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is Cl -4 alkyl, and the like.

[0157] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulf onate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a Ci.4alkyl group), and the like.

[0158] For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0159] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non -limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavors, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinyl pyrrolidine, and colors, and the like. For examples of excipients, see Gennaro, Remington’s Pharmaceutical Sciences, 18th Ed., MackPubl. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9th Ed. Pharmaceutical Press, London, UK (2020).

[0160] Examples of diluents or fillers include, but are not limited to, a sugar (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, poly dextrose, and combinations thereof), an inorganic material (e.g., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate,WSGR Attorney Docket No. 64600-710.601magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, a starch (e.g., a pregelatinized starch), a microcrystalline cellulose, a silicified microcrystalline cellulose, a polysaccharide, a cellulose (e.g., a hydroxypropylcellulose, a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropylmethylcellulose, ahydroxy ethylcellulose), a dextrin, a maltodextrin, an alginate, a collagen, a polyvinylpyrrolidone, a polyvinylacrylate, polyethylene oxide, and polyethylene glycol. Sugar is defined herein to include sugar alcohols.

[0161] Examples of disintegrants include, but are not limited to, alginic acid, an alginate, primogel, a cellulose (e.g., hydroxypropylcellulose), polacrillin potassium, sodium starch glycolate, sodium croscarmellose, apolyplasdone(e.g.,acrospovidone), and a starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0162] Examples of binders include, but are not limited to, a hydroxypropylcellulose, hydroxy ethylcellulose, a hydroxypropylmethy cellulose (e.g., a low viscosity hydroxypropylmethycellulose), a sugar, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl acetate, a polydextrose, a chitosan, a carrageenan, carbophil, a microcrystalline cellulose, gum tragacanth, guar gum, gellan gum, gelatin, and a starch (e.g., corn starch).

[0163] Examples of wetting agents include, but are not limited to, a poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), a poly dimethylsiloxane, a polysorbate (e.g., polyoxyethylene 20 sorbitan mono-oleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholate, polyethoxylated castor oil, cetyl trimethylammonium bromide, nonoxynol, a -tocopherol polyethylene glycol 1000 succinate, and docusate sodium.

[0164] Examples of lubricants and glidants include, but are not limited to, a wax, a glyceride, a light mineral oil, a polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oil (e.g., hydrogenated vegetable oil), an alkyl sulfate, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0165] Examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0166] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.

[0167] Examples of coatings include but are not limited to, a film forming polymer (e.g., a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropylmethylWSGR Attorney Docket No. 64600-710.601cellulose, a hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvinyl alcohol, a Eudragit / acrylate) and a plasticizer (e.g., triacetin, polyethylene glycol, propylene glycol).

[0168] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of the compound of Formula I, Formula II-A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B described herein) can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.

[0169] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a nonhuman animal, e.g.,a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0170] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, minitabs, sachets, stickpacks, reconstitutable powders, dry powder inhalers, lozenges, and chewables.

[0171] As used herein, “administering” means oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow -release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or). Parenteral administration includes, e.g., intramuscular and subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of Formula I, Formula II-A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B can be administered alone or can be co-administered to the patient. Co-administration is meant to includeWSGR Attorney Docket No. 64600-710.601simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0172] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0173] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”). In an embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subjectbegins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0174] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g., to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors 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 (ie., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).

[0175] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition. The termWSGR Attorney Docket No. 64600-710.601“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0176] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the 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.

[0177] As used herein, the term "selective" refers to a compound that is at least about 3 -fold more potent (e.g., 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000 fold) against one target compared to other targets. For example, a CDK2 degrader that is selective over CCNE (CCNE1 and / or CCNE2) is at least 3 -fold more potent (e.g., 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000 fold) more potent against CDK2 than against CCNE (CCNE1 and / or CCNE2). For example, a CCNE (CCNE1 and / or CCNE2) degrader that is selective over CDK2 is at least 3 -fold potent (e.g., 3 -fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000 fold) more potent against CCNE (CCNE1 and / or CCNE2) than against CDK2. The difference in potency can be determined, for example, by comparing the DC50values against different targets.Ubiquitination Pathway

[0178] Ubiquitination of proteins in vivo is normally carried out by three enzymes: El, E2 and a ubiquitin ligase, often referred to in the art as an E3 ligase. The process occurs in three stages. Firs, activation of ubiquitin is undertaken by the ubiquitin activating enzyme El. A ubiquitin -adenylate is produced from ubiquitin and ATP, and is transferred to the active site of El, where AMP is released. The second step involves the transfer of ubiquitin from the active site of El to the active site of E2, a ubiquitin conjugating enzyme, via a trans(thio)esterification reaction. The final step of ubiquitination produces an isopeptide bond between a lysine residue of the target protein and the ubiquitin. This is achieved by an E3 ligase which recognizes the target protein, forms interactions with both the ubiquitin bound E2 enzyme and the target protein, and finally forms the isopeptide bond between the lysine and the ubiquitin. Further ubiquitins are then addedWSGR Attorney Docket No. 64600-710.601by the same mechanism to a lysine residue present on the ubiquitin attached to the target protein, and the process is repeated in order to form a chain of poly -ubiquitin (poly-Ub).

[0179] Ubiquitin is a highly conserved regulatory protein that is present in all eukaryotic cells.

[0180] The ubiquitin used in the methods of the invention may comprise any known variant of ubiquitin including naturally occurring alleles or modified variants.

[0181] It will be appreciated that poly-Ub comprises at least two ubiquitin monomers covalently attached to one another. Poly-Ub of the present invention is a polymer formed from ubiquitin as described above. Poly-Ub comprises two or more labelled ubiquitins covalently attached to one another (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or more). Poly-Ub may be free poly-Ub chains, poly-Ub bound to a substrate protein, or poly-Ub bound to the ubiquitin ligase.

[0182] Ubiquitin-activating enzymes, also known as El enzymes, catalyze the first step in the ubiquitination cascade. Ubiquitin-activating enzyme (El) starts the ubiquitination process. The El enzyme along with ATP binds to the ubiquitin protein. The El enzyme then passes the ubiquitin protein to the ubiquitin carrier or conjugation protein (E2).

[0183] The skilled person will appreciate that the methods of the invention are suitable for use with any known El enzyme.

[0184] While the nomenclature for E2, also known as ubiquitin -conjugating enzyme is not standardized across species, investigators in the field have addressed this issue and the skilled person can readily identify various E2 proteins, as well as species homologues (See Haas and Siepmann, FASEB J. 11:1257-1268 (1997)). These enzymes catalyse the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome.

[0185] Once activated by El, the activated ubiquitin is then transferred to an E2 cysteine. Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligases or E3s via a structurally conserved binding region.

[0186] The skilled person will appreciate that the methods of the invention are suitable for use with any known E2 enzyme.

[0187] Some E3 ubiquitin ligases are known to have a single subunit responsible for the ligase activity. Such E3 ligases that have been characterized include the HECT (homologous to E6 -AP carboxy terminus) domain proteins, represented by the mammalian E6AP-E6 complex which functions as a ubiquitin ligase for the tumor suppressor p53 and which is activated by papillomavirus in cervical cancer (See Huang et al., Science 286: 1321-26 (1999)).

[0188] Single subunit ubiquitin ligases having a RING domain include Mdm2, which has also been shown to act as a ubiquitin ligase for p53, as well as Mdm2 itself. Other RING domain,WSGR Attorney Docket No. 64600-710.601single subunit E3 ligases include: TRAF6, involved in IKK activation; Cbl, which targets insulin and EGF; Sina / Siah, which targets DCC; Itchy, which is involved in haematopoesis (B, T and mast cells); and IAP, involved with inhibitors of apoptosis.

[0189] The best characterized E3 ligase is the APC (anaphase promoting complex), which is a multi-subunit complex that is required for both entry into anaphase as well as exit from mitosis (See King et al., Science 274:1652-9 (1996)). The APC plays a crucial role in regulating the passage of cells through anaphase by promoting ubiquitin -dependent proteolysis of many proteins. In addition to degrading the mitotic B-type cyclin for inactivation of CDC2 kinase activity, the APC is also required for degradation of other proteins for sister chromatid separation and spindle disassambly. Most proteins known to be degraded by the APC contain a conserved nine amino acid motif known as the “destruction box” that targets them for ubiquitination and subsequent degradation. However, proteins that are degraded during Gl, including G1 cyclins, CDK inhibitors, transcription factors and signaling intermediates, do not contain this conserved amino acid motif. Instead substrate phosphorylation appears to play an important role in targeting their interaction with an E3 ligase for ubiquitination (see Hershko et al., Ann. Rev. Biochem.6TA29-15 (1998)).

[0190] In eukaryotes, a family of complexes with E3 ligase activity play an important role in regulating Gl progression. These complexes, called SCF’s, consist of atleast three subunits, SKP 1, Cullins (having at least seven family members) and an F-box protein (of which hundreds of species are known) whichbind directly to and recruit the substrate to the E3 complex. Because the E3 complex is the major determinant of selection for protein degradation by the ubiquitin -dependent proteolytic process, modulators of E3 ligase activity may be used to upregulate or downregulate specific molecules involved in cellular signal transduction.

[0191] The skilled person will appreciate that the methods of the invention are suitable for use with any known E3 ligase, which in turn can comprise any E3 ligase component.

[0192] In some embodiments, the present disclosure is directed to methods for ubiquitinating one or more select lysine residues. In some embodiments, the methods include identifying one or more ubiquitin-competent lysine residues on a target protein and ubiquitinating the one or more select lysine residues of the target protein. In general, the method involves forming a non-native ternary complex comprising a protein complex and a ligase. As disclosed herein, a “protein complex” is a collection of proteins that interact with each other at the same time and location, and which has essential roles in regulatory processes, cellular functions, and / or signaling cascades. In some embodiments, the protein complex comprises at least one target protein. InWSGR Attorney Docket No. 64600-710.601some embodiments, the protein complex comprises two or more target proteins. In some embodiments, the protein complex may be a specific arrangement of two or more proteins that form a stable or transient association. In certain embodiments, the protein complex described herein may serve structural, enzymatic, transport, or regulatory functions and may involve cellular processes such as gene expression regulation, signal transduction, metabolic control, protein trafficking, or immune responses.

[0193] In some embodiments, the non-native ternary complex comprises a protein complex, a ligase, and a molecule. In some embodiments, the molecule induces proximity between the protein complex and the ligase thereby causing ubiquitinating of at least one lysine residue. Embodiments of the present disclosure further involve binding ubiquitin to a lysine residue of a target protein in a ternary complex. Therefore, as used herein, “a non-native ternary complex” or “ternary complex” means a protein complex to which a ligase is bound, and “ubiquitination” and grammatical equivalents thereof means the binding of ubiquitin to a lysine residue of a target protein. As described herein, in certain embodiments, the ternary complex induces lysine ubiquitination.

[0194] In some embodiments, no specific target protein is used. By “target protein” herein is meant a protein other than ubiquitin to which ubiquitin is ligated by ubiquitination enzymes. In certain embodiments, ubiquitinating comprises trans -ubiquitination. In some embodiments, the target protein comprises one or more lysine residues.

[0195] As used herein, “ligase” is meant a ubiquitination enzyme capable of catalyzing the covalent binding of a ubiquitin to another protein. In some embodiments, the present disclosure involves combining ubiquitin and ubiquitination enzymes, including ubiquitin ligase, under conditions in which ubiquitination may take place. In a certain embodiment, the ligase is an E3 ubiquitin ligase.

[0196] The addition of other elements or factors may be sequential or in a predetermined order or grouping, as long as the conditions amenable to ubiquitination are obtained.Lysine Residues

[0197] As described herein, a lysine residue comprises an amino acid unit within a protein molecule. According to the present invention, specific lysine residues (e.g., lysine residues on a target protein) may be solvent-accessible. In some embodiments, a target protein comprises the lysine residue. In some embodiments, the protein complex comprises the lysine residue. In some embodiments, the lysine residue may be solvent-accessible after formation of the proteinWSGR Attorney Docket No. 64600-710.601complex. In some embodiments, lysine residue may be accessible upon the formation of the protein complex.

[0198] Compared with the prior art, the present disclosure has remarkable technical progress. According to the application of select lysine residues, the present disclosure provides a highly selective inhibition and / or degradation method of a protein in a protein complex through ubiquitination of at least one of the selected lysine residues.

[0199] According to the present invention, specific lysine residues (e.g., lysine residues on a target protein) can be regioselectively modified. Such regioselectivity is 50% or more, preferably 60% or more, more preferably 70% or more, even more preferably 80% or more, particularly preferably 90% or more, 95% or more, 96% or more, It may be 97% or more, 98% or more, 99% or more, 99.5% or more, or 100%.Cyclin-Dependent Kinase 2 (CDK2) and Cyclin El

[0200] CDK2 is a human gene which encodes a protein which is a member of the cyclin-dependent kinase family of Ser / Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae Cdc28, and S. pombe cdc2. Two alternatively spliced variants and multiple transcription initiation sites of this gene have been reported.

[0201] Cyclin-El is a protein that in humans is encoded by the CCNE1 gene. Cyclin El belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK2, whose activity is required for cell cycle Gl / S transition.

[0202] This protein accumulates at the Gl-S phase boundary and is degraded as cells progress through S phase. Overexpression of this gene has been observed in many tumors, which results in chromosome instability, and thus may contribute to tumorigenesis. Two alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been described.

[0203] The methods of the present disclosure are directed to selectively degrading a target protein in a protein complex. In some embodiments, the methods described herein are generally useful for the degradation and / or inhibition of a target protein.

[0204] In some embodiments, no specific target protein is used. In other embodiments, the target protein exhibits kinase activity. In some embodiments, the methods involve the degradation and / or inhibition of a protein with kinase activity. In some embodiments, the target protein is anWSGR Attorney Docket No. 64600-710.601enzyme. In some embodiments, the methods described herein are generally useful for the degradation and / or inhibition of kinase activity of one or more enzymes.

[0205] In some embodiments, the target protein comprises CDK2. In some embodiments, the target protein comprises Cyclin El. In some embodiments, the target protein comprises Cyclin E2. In some embodiments, the target protein comprises CDK2, Cyclin El, and Cyclin E2. In some embodiments, the target protein comprises CDK2, Cyclin El, or Cyclin E2, or a combination thereof. In some embodiments, the protein complex comprises CDK2. In some embodiments, the protein complex comprises Cyclin El. In some embodiments, the protein complex comprises Cyclin E2. In some embodiments, the protein complex comprises CDK2, Cyclin El, and Cyclin E2. In some embodiments, the protein complex comprises CDK2, Cyclin El, or Cyclin E2, or a combination thereof.

[0206] In some embodiments, the target protein comprises a lysine residue. In some embodiments, the lysine residue comprises CDK2 K250, CDK2 K291, CCNE1 KI 45, or CCNE1 KI 10. In some embodiments, the lysine residue comprises CDK2 K250, CDK2 K291, or CCNE1 K145. In some embodiments, the lysine residue comprises CDK2 K250, CDK2 K291, CCNE1 KI 45, or CCNE1 KI 10, or a combination thereof.

[0207] As used herein, the terms “CDK1 -mediated,” “CDK2 -mediated,” “CDK4-mediated,” “CDK6- mediated,” “CDK7-mediated,” “CDK8-mediated,” and / or “CDK9-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8, CDK9 or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8, and / or CDK9 or a mutant thereof, are known to play a role. In some embodiments, the term “CDK2 -mediated” also includes treating or lessening the severity of one or more diseases in which CCNE (e.g., CCNE1) or a mutant thereof, are known to play a role.

[0208] The methods of the present disclosure can degrade CDK2 or CDK2 and CCNE1 and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by CDK2. Such diseases include cancer and other diseases with proliferation disorder. In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a provided compound or a pharmaceutically acceptable salt thereof such that growth of cancerous tumors is inhibited. A provided compound or a pharmaceutically acceptable salt thereof can be used to inhibit the growth of cancerous tumors with aberrations that activateWSGR Attorney Docket No. 64600-710.601CDK2 activity. These include, but not limited to, disease (e.g., cancers) that are characterized by amplification or overexpression of CCNE1 such as ovarian cancer, uterine carcinosarcoma and breast cancer and p27 inactivation such as breast cancer and melanomas. Accordingly, in some embodiments of the methods, the patient has been previously determined to have an amplification of the CCNE1 gene and / or an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. Alternatively, a provided compound or a pharmaceutically acceptable salt thereof can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with CCNE1 amplification and overexpression in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, provided herein is a method of degrading and / or inhibiting one or more proteins in a protein complex, comprising contacting the protein complex with a molecule to form a non-native ternary complex. In some embodiments, provided herein is a method of degrading and / or inhibiting one or more proteins in a protein complex, comprising contacting the protein complex with a provided compound or a pharmaceutically acceptable salt thereof to form a non-native ternary complex.

[0210] In some embodiments, provided herein is a method of degrading one or more proteins in a protein complex, comprising contacting the protein complex with a molecule to form a non-native ternary complex. In some embodiments, provided herein is a method of degrading one or more proteins in a protein complex, comprising contacting the protein complex with a provided compoundor a pharmaceutically acceptable salt thereof to form a non-native ternary complex.

[0211] In some embodiments, provided herein is a method of inhibiting one or more proteins in a protein complex, comprising contacting the protein complex with a molecule to form a non-native ternary complex. In some embodiments, provided herein is a method of inhibiting one or more proteins in a protein complex, comprising contacting the protein complex with a provided compoundor a pharmaceutically acceptable salt thereof to form a non-native ternary complex.

[0212] In some embodiments, provided herein is a method of inhibiting CDK2, comprising contacting the CDK2 with a provided compound or a pharmaceutically acceptable salt thereof. InWSGR Attorney Docket No. 64600-710.601some embodiments, provided herein is a method of inhibiting CDK2 in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1, comprising contacting the CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1 in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, provided herein is a method of degrading CDK2, comprising contacting the CDK2 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1, comprising contacting the CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1 in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, provided herein is a method of degrading CDK2 and CCNE1, comprising contacting the CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method of degrading CDK2 and CCNE1 in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient (in need thereof), a therapeutically effective amount of a provided compound or a pharmaceutically acceptable saltthereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

[0218] In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with an amplification of the CCNE1 gene and / or overexpression of CCNE1.WSGR Attorney Docket No. 64600-710.601

[0219] In some embodiments, the disease or disorder may be resistantto CDK2 inhibition alone. In some embodiments, the disease or disorder may be unresponsive, or partially unresponsive, to CDK2 inhibition alone. In some embodiments, the disease or disorder may be unresponsive to CDK2 inhibition alone. In some embodiments, the disease or disorder may be partially unresponsive to CDK2 inhibition alone.

[0220] In some embodiments, the disease or disorder may be characterized by cyclin E amplification or overexpression. In some embodiments, the disease or disorder may be characterized by cyclin E amplification. In some embodiments, the disease or disorder may be characterized by cyclin E overexpression. In some embodiments, the disease or disorder may be characterized by CCNE1 orCCNE2 amplification or overexpression. In some embodiments, the disease or disorder may be characterized by CCNE1 amplification or overexpression. In some embodiments, the disease or disorder may be characterized by CCNE2 amplification or overexpression.

[0221] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar et al., Proc. Natl. Acad. Set. USA, 2009, 106(31): 12968-12973), K-Ras mutant lung cancers (see Hu, S., etal., A7o / . Cancer Ther., 2015, 14(11):2576-85), and cancers with FBW7 mutation and CCNE1 overexpression (see Takada et al., Cancer Res., 2017, 77(18):4881-4893).

[0222] In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0223] In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

[0224] In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0225] In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer. In some embodiments, the disease or disorder associated with CDK2 is a cancer.WSGR Attorney Docket No. 64600-710.601

[0226] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

[0227] In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0228] Examples of cancers that are treatable using the methods of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

[0229] In some embodiments, cancers treatable with the methods of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition -resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non -small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high micro satellite instability (MSIhi8h). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.WSGR Attorney Docket No. 64600-710.601

[0230] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0231] In some embodiments, cancers that are treatable using the methods of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer. In some embodiments, the compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0232] In some embodiments, diseases and indications that are treatable using the methods of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0233] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PML), polycythemia vera (PV), andWSGR Attorney Docket No. 64600-710.601essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).

[0234] Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0235] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0236] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0237] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm’s tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0238] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0239] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

[0240] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma,WSGR Attorney Docket No. 64600-710.601retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0241] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0242] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple -negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0243] It is believed that a provided compound or a pharmaceutically acceptable salt thereof may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

[0244] In some embodiments, the methods of the present disclosure are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.Exemplary Immune Checkpoint Inhibitors

[0245] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0246] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronicWSGR Attorney Docket No. 64600-710.601exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.

[0247] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain -3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0248] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti -tumor immune response.

[0249] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL- 15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0250] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on allNK, gd, and memory CD8+(ab) T cells), CD160 (also referredWSGR Attorney Docket No. 64600-710.601to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD- L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[0251] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti -PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech). In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.

[0252] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti- PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for nonsmall cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladderWSGR Attorney Docket No. 64600-710.601cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[0253] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).

[0254] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0255] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene- 3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S. A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0256] Checkpoint inhibitors that can be used in the present invention include 0X40 agonists.0X40 agonists that are being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), anWSGR Attorney Docket No. 64600-710.601agonistic anti- 0X40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti -0X40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCTO 1862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[0257] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4- IBB) agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol- Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti- CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0258] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0259] Checkpoint inhibitors that can be used in the present invention include glucocorticoid -induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti -GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 andNCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165).WSGR Attorney Docket No. 64600-710.601

[0260] Checkpoint inhibitors that can be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[0261] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102 / BMS- 986015, Innate Pharma / Bristol -Myers Squibb), an anti -KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), andlymphoma (NCTO 1592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 andNCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0262] Checkpoint inhibitorsthat can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa -mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[0263] Checkpoint inhibitorsthat can be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); andBMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0264] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-WSGR Attorney Docket No. 64600-710.601SI 00 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

[0265] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0266] Checkpoint inhibitorsthat can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0267] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.Bifunctional Molecule

[0268] Bifunctional molecules composed of a target protein binding ligand and an E3 ubiquitin ligase ligand induce proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins.

[0269] Provided herein are bifunctional molecules of the present disclosure. Provided herein are compounds of Formula I, Formula II- A, Formula II-B, Formula II-C, Formula III- A, Formula III-B, Formula IV-A, and Formula IV-B, as well as the compounds of Table 1, Table 2, Table 3, and Table 4. In an embodiment, provided are compounds of Formula I, Formula II- A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B or pharmaceutically acceptable salts thereof. In an embodiment, the compounds of Formula I,WSGR Attorney Docket No. 64600-710.601Formula II-A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B are provided as pharmaceutically acceptable salts. In an embodiment, the compounds Formula I, Formula II-A, Formula II-B, Formula II-C, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B are provided as the corresponding free base (i.e., are not salts).

[0270] Included herein, when chemically relevant, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.Compounds of Formula I

[0271] In an embodiment, provided herein is a compound of Formula I:N N NH 1 XA ^X,,B)Por a pharmaceutically acceptable salt thereof, wherein:L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C i.5Ohydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O-, wherein:each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiroWSGR Attorney Docket No. 64600-710.601heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc;LBM is selected fromeach instance of RA, RB, Rc, R4and R5is independently selected from deuterium, halogen, -OH, and -Ci.6alkyl;;each instance of R is independently selected from hydrogen and -Ci.6alkyl;n is 0, 1, 2, 3, or 4;r is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, or 4; ands is 0, 1, 2, 3, or 4.

[0272] In an embodiment, provided is a compound of Formula I:WSGR Attorney Docket No. 64600-710.601or a pharmaceutically acceptable salt thereof, wherein RA, RB, n, p, L, LBM and n are as defined in any of the embodiments described herein:

[0273] As generally defined herein, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1.50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O-, wherein each -Cy- and -R are as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601In an embodiment, -L-C(=O)- is. In an embodiment, -L-C(=O)- is. In an embodiment, -L-C(=O)- isembodiment, -L-C(=O)- is. In an embodiment, -L-C(=O)- is

[0274] As generally defined herein, each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5- 11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independentlyWSGR Attorney Docket No. 64600-710.601selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.

[0275] In an embodiment, each -Cy- is independently a bivalent ring selected from phenylene, a 4-7 membered monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each phenylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.

[0276] In an embodiment, each -Cy- is independently a phenylene substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy-is independently a 4-7 membered monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy- is a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy- is a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy-is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.

[0277] In an embodiment, Cy is selected from:WSGR Attorney Docket No. 64600-710.601any of the embodiments described herein.In an embodiment, -Cy- is unsubstituted. In an embodiment, -Cy- is substituted with 0 or 1 instances of Rc. In an embodiment, -Cy- is substituted with 0, 1 or 2 instances of Rc. In an embodiment, -Cy- is substituted with 0, 1, 2 or 3 instances of Rc. In an embodiment, -Cy- is substituted with 1 instance of Rc. In an embodiment, -Cy- is substituted with 2 instances of Rc. In an embodiment, -Cy- is substituted with 3 instances of Rc. In an embodiment, -Cy- is substituted with 4 instances of Rc.

[0278] As generally defined herein, LBM is selected fromany of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601(R5)s(R5)S

[0279] In an embodiment, the moiety represented by:5)sembodiment, the moiety represented by

[0280] In an embodiment, LBM is is as defined in any of the embodiments described herein. In an embodiment, LBM is, wherein each R4, R5, r and s is as defined in any of theembodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an (R5(R4). Oembodiment,LBM is, wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment, LBM is(R4)r, wherein each R4, R5, r and s is as defined in any of theWSGR Attorney Docket No. 64600-710.601embodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an (R4)r(R5)sembodiment,LBM is, wherein each R4, R5, r and s is as defined in any of (R4)r(R5)Sthe embodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment,LBM is, wherein each R4, R5, r and s is as defined in any of the (R4)rembodiments described herein. In an embodiment,LBM is O wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment, LBMis (R)r, wherein each R4, R5, r and s is as defined in any of the embodimentsdescribed herein. In an embodiment, LBM is (R)rwherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment, LBM isWSGR Attorney Docket No. 64600-710.601(R4)r, wherein each R4, R5, r and s is as defined in any of the embodimentss is as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601

[0282] In an embodiment, LBM isembodiment, LBM isWSGR Attorney Docket No. 64600-710.601embodiment, LBM is

[0284] As generally defined herein, each instance of RAis independently selected from deuterium, halogen, -OH, and -Ci.6alkyl.

[0285] In an embodiment, each instance of RAis independently selected from deuterium, -F, -Cl, -Me, and -OH. In an embodiment, each instance of RAis independently selected from deuterium, -F, -Me, and -OH. In an embodiment, each instance of RAis deuterium. In an embodiment, each instance of RAis -F. In an embodiment, each instance of RAis -Cl. In an embodiment, each instance of RAis -Me. In an embodiment, each instance of RAis -OH.

[0286] As generally defined herein, each instance of RBis independently selected from deuterium, halogen, -OH, and -Ci.6alkyl.

[0287] In an embodiment, each instance of RBis independently selected from deuterium, -F, -Cl, -Me, and -OH. In an embodiment, each RBis independently selected from deuterium, halogen, OH and -Me. In an embodiment, each instance of RBis independently selected from deuterium, -F, -Me, and -OH. In an embodiment, each instance of RBis deuterium. In an embodiment, each instance of RBis -F. In an embodiment, each instance of RBis -Cl. In an embodiment, each instance of RBis -Me. In an embodiment, each instance of RBis -OH.

[0288] As generally defined herein, each instance of Rcis independently selected from deuterium, halogen, -OH, and -Ci.6alkyl.WSGR Attorney Docket No. 64600-710.601

[0289] In an embodiment, each instance of Rcis independently selected from deuterium, -F, -Cl, -Me, and -OH. In an embodiment, each instance of Rcis independently selected from deuterium, -F, -Me, and -OH. In an embodiment, each instance of Rcis deuterium. In an embodiment, each instance of Rcis -F. In an embodiment, each instance of Rcis -Cl. In an embodiment, each instance of Rcis -Me. In an embodiment, each instance of Rcis -OH.

[0290] As generally defined herein, each instance of R4is independently selected from deuterium, halogen, -OH, and -Ci-6 alkyl.

[0291] In an embodiment, each R4is independently selected from -D, -Me, -Et, -F, -Cl and -OH. In an embodiment, each instance of R4is independently selected from deuterium, -F, -Cl, -Me, and -OH. In an embodiment, each instance of R4is independently selected from deuterium, -F, -Me, and -OH. In an embodiment, each R4is independently selected from -Me and -F. In an embodiment, each instance of R4is deuterium. In an embodiment, each instance of R4is -F. In an embodiment, each instance of R4is -Cl. In an embodiment, each instance of R4is -Me. In an embodiment, each instance of R4is -OH.

[0292] As generally defined herein, each instance of R5is independently selected from deuterium, halogen, -OH, and -Ci.6alkyl.

[0293] In an embodiment, each R5is independently selected from -Me, -Et, -F, -Cl and -OH. In an embodiment, each instance of R5is independently selected from deuterium, -F, -Cl, -Me, and -OH. In an embodiment, each instance of R5is independently selected from deuterium, -F, -Me, and -OH. In an embodiment, each instance of R5is deuterium. In an embodiment, each instance of R5is -F. In an embodiment, each instance of R5is -Cl. In an embodiment, each instance of R5is -Me. In an embodiment, each instance of R5is -OH.

[0294] As generally defined herein, each instance of Ris independently hydrogen and -Ci.6alkyl. In an embodiment, R is H. In an embodiment R is -Ci-6 alkyl. In an embodiment, R is selected from H and -Me. In an embodiment, R is -Me.

[0295] As generally defined herein, n is 0, 1, 2, 3, or 4. In an embodiment, n is 0, 1, 2 or 3. In an embodiment, n is 0, 1 or 2. In an embodiment, n is 0 or 1. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0296] As generally defined herein, ris 0, 1, 2, 3, or4. In an embodiment, r is 0, 1, 2 or 3. In an embodiment, r is 0, 1 or 2. In an embodiment, r is 0 or 1. In an embodiment, r is 0. In an embodiment, r is 1. In an embodiment, r is 2. In an embodiment, r is 3. In an embodiment, r is 4.WSGR Attorney Docket No. 64600-710.601

[0297] As generally defined herein, s is 0, 1, 2, 3, or 4. In an embodiment, s is 0, 1, 2 or 3. In an embodiment, s is 0, 1 or 2. In an embodiment, s is 0 or 1. In an embodiment, s is 0. In an embodiment, s is 1. In an embodiment, s is 2. In an embodiment, s is 3. In an embodiment, s is 4.

[0298] As generally defined herein, p is 0, 1, 2, 3, or 4. In an embodiment, p is 0, 1, 2 or 3. In an embodiment, p is 0, 1 or 2. In an embodiment, p is 0 or 1. In an embodiment, p is 0. In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, p is 3. In an embodiment, p is 4.

[0299] In an embodiment of a compound of Formula I, the compound is selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof, or elsewhere in the specification and figures. In an embodiment, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. In an embodiment, provided herein is a composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0300] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds marked with (or) or (rel) in Table 1 and the Examples section are single enantiomers wherein the absolute stereochemistry was arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section). Compounds marked with and) or (rac) are mixtures of enantiomers wherein the relative stereochemistry is as shown. Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted and that have no designation in the stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds that have a stereogenic center where the configuration is indicated in the structure as depicted and have no designation in the stereochemistry column of Table 1 or that are marked with (abs) are single enantiomers wherein the absolute stereochemistry is as indicated.

[0301] A person of skill in the art would be able to separate racemic compounds into the respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization and the like. References to compounds that are racemic mixtures are meant to also include the individual enantiomers contained in the mixture.WSGR Attorney Docket No. 64600-710.601Table 1. Exemplary CompoundsCDK2CDK2 HiBiT CCNEl Protein HiBiT Protein CCNElHiBiT Protein HiBiT Protein Structure No. Quantificatio Quantificatio Quantificatio Quantificatio n DCso (nM) n Maximum n DCso (nM) n Maximum (%) (%) 0z^NHC>o°< X H or \-N / / 1 NA 10.7 NA 36.7( / N*\^xH6- oANHN^OO=ZvA H2 NA 32 NA 34.3 N^\\ _ 7 N=\ ^H NA J) / cKVUr i uhn^A A o ' — <CT NH^O \ _, \ / ? n3 NA 40.3 1760 54HN—(\2 —M— / 0WSGR Attorney Docket No. 64600-710.601CDK2 CCNEl CDK2 HiBiT HiBiT Protein CCNEl HiBiT Protein Protein Quantificatio HiBiT Protein Structure No. Quantificatio Quantificatio n Maximum Quantificatio n Maximum n DCso (nM) n DCso (nM)(%) (%)4 107.2 67.6 657 54.7■?. rr°( / V-% o\— / 0NH 4^HN Vo y / l _ z5 55 80.8 160.5 78.3 \ \ ^0N^,QHN^ FAv N-\ 7 —Ny.c4”0 / =\ 0VT'HNfl i Lt:*' HN6 27.2 71.6 210 51.6XV__ Y_^°N — \Q N-xHN-(\ / Ax N"\ / N— \c5~ °WSGR Attorney Docket No. 64600-710.601CDK2 CCNEl CDK2 HiBiT HiBiT Protein CCNEl HiBiT Protein Protein Quantificatio HiBiT Protein Structure No. Quantificatio Quantificatio n Maximum Quantificatio n Maximum n DCso (nM) n DCso (nM)> (%) (%)o\— / oHN— \O_ ^07 45.8 81.5 745 55.9 N^QHN^\N\ N^< 7 —°8 80.1 88.5 314 73.3VQ$» ° S^$9 36.4 91.3 126 74.9 °^°M°QHN—(\N\ / — KeVWSGR Attorney Docket No. 64600-710.601Compounds of Formula II-A, Formula II-B, and Formula II-C

[0302] In an embodiment, provided herein is a compound of Formula II-A:II-Aor a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 3-14 membered cycloalkyl or 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S;R1is selected from -Ci.6alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -Ci.6haloalkyl, -Ci.6heteroalkyl, -C3-14 cycloalkyl, 6-14 membered aryl, 4-14 membered heterocyclyl, 5-14 membered heteroaryl, -C1.4 alkyl-C3.i4 cycloalkyl, -C1.4 alkyl-(6-14 membered aryl), -C1.4 alkyl- (4-14 membered heterocyclyl), and -C1.4 alkyl (5-14 membered heteroaryl), wherein each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of R6;each R2and R3is independently selected from -Ci-6 alkyl, -Ci-6 haloalkyl, -Ci-6 heteroalkyl, -C2.6 alkenyl, -C2.6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3WSGR Attorney Docket No. 64600-710.601heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of RB;or R2and R3, together with the carbon atom to which they are attached, form Ring B, wherein Ring B is a 3-7 membered cycloalkyl ring or a 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S, wherein Ring B is substituted with 0, 1, 2, 3, or 4 instances of RB;L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1.50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O-, wherein:each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc;WSGR Attorney Docket No. 64600-710.601each instance of RA, RB, Rc, R4, R5and R6is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S;each instance of R is independently hydrogen, -Ci.6alkyl, -Ci.6haloalkyl, -Ci.6heteroalkyl, -C2.6alkenyl, -C2.6alkynyl, -C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form an optionally substituted 4-7 heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S;n is 0, 1, 2, 3, or 4;r is 0, 1, 2, 3, or 4; ands is 0, 1, 2, 3, or 4.

[0303] In an embodiment, provided is a compound of Formula II-B or Formula II-C:WSGR Attorney Docket No. 64600-710.601II-Cor a pharmaceutically acceptable salt thereof, wherein R1, RA, L, LBM, m and n are as defined in any of the embodiments described herein.

[0304] In an embodiment, the compound is of Formula II-B.

[0305] In an embodiment, the compound is of Formula II-C.

[0306] As generally defined herein, Ring B is a 3-7 membered cycloalkyl ring or a 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S, wherein Ring B is substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is un substituted.

[0307] In an embodiment, RingB is a 3-7 membered cycloalkyl ring substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is an unsubstituted 3-7 membered cycloalkyl ring. In an embodiment, Ring B is a 3-7 membered monocyclic cycloalkyl ring substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, Ring B is an unsubstituted 3-7 membered monocyclic cycloalkyl ring.

[0308] In an embodiment, Ring B is selected from cyclopropyl and cyclobutyl.

[0309] In an embodiment, Ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, Ring B is selected from cyclopropyl and cyclobutyl substituted with 0, 1, 2, 3, or 4 instances ofRB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In an embodiment, Ring B is selected from unsubstituted cyclopropyl and cyclobutyl. In an embodiment, Ring B is cyclopropyl substitutedWSGR Attorney Docket No. 64600-710.601with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is cyclopropyl substituted with 0, 1 or 2 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is unsubstituted cyclopropyl.

[0310] In an embodiment, RingB is cyclobutyl substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, Ring B is unsubstituted cyclobutyl. In an embodiment, Ring B is cyclopentyl substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, Ring B is unsubstituted cyclopentyl. In an embodiment, Ring B is cyclohexyl substituted with 0, 1, 2, 3, or 4 instances of RB, wherein RBis as defined in any of the embodiments described herein. In an embodiment, RingB is unsubstituted cyclohexyl.

[0311] In an embodiment, Ring B is a 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S (e.g., azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl), wherein Ring B is substituted with 0, 1, 2, 3, or 4 instances of RB. In an embodiment, RingB is an unsubstituted 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S (e.g., azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl).

[0312] As generally defined herein, Ring A is phenyl, 3-14 membered cycloalkyl or 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S.

[0313] In an embodiment, Ring Ais 3-14 membered cycloalkyl or 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S.

[0314] In an embodiment, Ring A is a monocyclic 3 -7 membered cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane). In an embodiment, Ring A is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

[0315] In an embodiment, Ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S (including S(O) and S(O)2). In an embodiment, Ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O. In an embodiment, Ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 nitrogen atoms. In an embodiment, Ring A is a monocyclic 4-7 membered heterocyclyl containing 1 nitrogen atom. In an embodiment, Ring A is a monocyclic 4-7 membered heterocyclyl containing 2 nitrogen atoms.WSGR Attorney Docket No. 64600-710.601

[0316] In an embodiment, Ring A is selected from azetidine, pyrrolidine, piperidine, azepane, oxetane, tetrahydrofuran, tetrahydropyran, piperazine, morpholine and diazepane.

[0317] In an embodiment, Ring A is selected from azetidine, pyrrolidine, piperidine, and azepane.

[0318] In an embodiment, Ring A is azetidine. In an embodiment, Ring A is pyrrolidine. In an embodiment, Ring A is piperidine. In an embodiment, Ring A is azepane. In an embodiment,Ring A is piperidin-4-yl. In an embodiment, Ring A is l \ ' — ' H, wherein the nitrogen atom is attached to the S(=O)2group and the 4-position carbon is attached to the NH of the compound of Formula I.

[0319] In an embodiment, Ring A is phenyl. In an embodiment, Ring A is\= /

[0320] As generally defined herein, R1is selected from-Ci.6alkyl, -C2-6 alkenyl, -C2.6alkynyl, -Ci-6 haloalkyl, -Ci.6heteroalkyl, -C3-14 cycloalkyl, 6-14 membered aryl, 4-14 membered heterocyclyl, 5-14 membered heteroaryl, -C1.4 alkyl-Cs-14 cycloalkyl, -C1.4 alkyl-(6-14 membered aryl), -C1.4 alkyl-(4-14 membered heterocyclyl), and -C1.4 alkyl (5-14 membered heteroaryl), wherein each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each R6is as defined herein.

[0321] In an embodiment, R1is selected from -Ci.6haloalkyl, -C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl (e.g., heterocyclyl containing 1 or 2 atoms independently selected from N, O and S, including S(O) and S(O)2), and 5-6 membered heteroaryl (e.g., heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S), each of which is substituted with O, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0322] In an embodiment, R1is selected from Ci.6haloalkyl, C3.7 cycloalkyl, and phenyl, each of which is substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0323] In an embodiment, R1is selected from -C3.7 cycloalkyl, phenyl and -C1.4 alkyl-C3.i4 cycloalkyl, each of which is substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601

[0324] In an embodiment, R1is cyclopentyl, cyclohexyl, phenyl or -CH(CH3)-cyclopropyl, each substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0325] In an embodiment, R1is cyclopentyl, cyclohexyl, phenyl or -CH(CH3)-cyclopropyl, each substituted with 0, 1 or 2 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0326] In an embodiment, R1is cyclopentyl or cyclohexyl, each substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0327] In an embodiment, R1is C3.7cycloalkyl substituted with 0, 1, 2, 3 or 4 instances of R6wherein each instance of R6is as defined in any of the embodiments described herein.

[0328] In an embodiment, R1is monocyclic C3.7cycloalkyl substituted with 0, 1, 2, 3 or 4 instances of R6wherein each instance of R6is as defined in any of the embodiments described herein.

[0329] In an embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl substituted with 0, 1, 2, 3 or 4 instances of R6wherein each instance of R6is as defined in any of the embodiments described herein.

[0330] In an embodiment, R1is cyclopentyl substituted with 0, 1, 2, 3 or 4 instances of R6wherein each instance of R6is as defined in any of the embodiments described herein.

[0331] In an embodiment, R1is cyclohexyl substituted with 0, 1, 2, 3 or 4 instances of R6wherein each instance of R6is as defined in any of the embodiments described herein.

[0332] In an embodiment, R1is selected from l,l-difluorobutan-2-yl, cyclopentyl, 2-methylcyclopentyl, 3 -hydroxy cyclohexyl, 2-hydroxy-2-methylcyclopentyl, 2- methylphenyl, 2-chloro-5 -fluorophenyl l,5-dimethyl-lH-pyrazol-4-yl, 7-chloro- l,2,3,4-tetrahydroisoquinolin-6-yl, and 1 -cyclopropylethyl.

[0333] In an embodiment, R1is selected from cyclopentyl, 2-methylcyclopentyl, 3-hydroxy cyclohexyl, 2 -methylphenyl, and l,l-difluorobutan-2-yl.

[0334] In an embodiment, R1is selected from cyclopentyl, 2-methylcyclopentyl, 2-methylphenyl, and l,l-difluorobutan-2-yl. In an embodiment, R1is selected from 2-methylcyclopentyl and 3 -hydroxy cyclohexyl.WSGR Attorney Docket No. 64600-710.601

[0335] In an embodiment, R1is selected from

[0336] In an embodiment, R1is selected from:

[0337] In an embodiment, R1is selected from:

[0338] In an embodiment, R1is selected from:

[0339] In an embodiment, R1is selected from:

[0340] In an embodiment, R1is 2-methylcyclopentyl. In an embodiment, R1is selected fromembodiment, R1is. In an embodiment, R1isWSGR Attorney Docket No. 64600-710.601

[0341] In an embodiment, R1is 3 -hydroxy cyclohexyl. In an embodiment, R1is selected from

[0342] In an embodiment, R1isembodiment, R1is

[0343] In an embodiment, R1is -Ci.6haloalkyl (e.g., -CH2CF3, CH2CHF2, CH2CH2F).

[0344] In an embodiment, R1is phenyl, substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0345] In an embodiment, R1is 4-7 membered heterocyclyl containing 1 or 2 atoms independently selected from N, O and S, including S(O) and S(O)2(e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, piperazinyl, azepanyl), each of which is substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0346] In an embodiment, R1is 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S e.g., furanyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, diazinyl, triazinyl), each of which is substituted with 0, 1, 2, 3 or 4 instances of R6, wherein each instance of R6is as defined in any of the embodiments described herein.

[0347] As generally defined herein, each R2and R3is independently selected from -Ci-6 alkyl, -Ci-6 haloalkyl, -Ci-6 heteroalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of RB, wherein each RBis as defined herein.WSGR Attorney Docket No. 64600-710.601

[0348] In an embodiment, each R2and R3is independently -Ci.6alkyl. In an embodiment, each R2and R3is independently selected from -Me, -Et-, -Pr, -!Pr andfBu. In an embodiment, each R2and R3is -Me.

[0349] In an embodiment, R2and R3, together with the carbon atom to which they are attached, form Ring B.

[0350] As generally defined herein, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1.50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O-, wherein each -Cy- and -R are as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601independently as defined in any of the embodiments described herein;wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM;L1and L2are each independently selected from a bond and -N(R’), wherein R’ is selected from H and Ci-6alkyl; andq is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.WSGR Attorney Docket No. 64600-710.601WSGR Attorney Docket No. 64600-710.601wherein the left side attachment point connects to the — S(0)2— group and the right side attachment point connects to LBM;L1and L2are each independently selected from a bond and -N(R’), wherein R’ is selected from H and Ci-6alkyl; andWSGR Attorney Docket No. 64600-710.601q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM and L1, L2, -Cy- and q are as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM and L1, L2, -Cy- and q are as defined in any of the embodiments described herein.

[0355] In an embodiment, L is selected from:side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM.

[0356] In an embodiment, L is selected from:, each substituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM.

[0357] In an embodiment, L issubstituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toWSGR Attorney Docket No. 64600-710.601LBM. In an embodiment, L issubstituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment, L issubstituted 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment, L issubstituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment, L issubstituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment,L is substituted with 0, 1, 2 or 3 instances of R7, wherein R7is as defined in any of the embodiments described herein; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment,L is; wherein the left side attachment point connects to the — S(O)2— group and the right side attachment point connects to LBM. In an embodiment, Lis; wherein the left side attachment point connects to the -S(O)2- groupWSGR Attorney Docket No. 64600-710.601and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group andthe right side attachment point connects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group and the right side attachment pointconnects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment,L is; wherein the left side attachment point connects to the — S(O)2— group and the right side attachment point connects to LBM. In an embodiment, L isWSGR Attorney Docket No. 64600-710.601; wherein the left side attachment point connects to the -S(O)2-group and the right side attachment point connects to LBM. In an embodiment, L isJ; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. The compound of any one of claims 1 -115, or apharmaceutically acceptable salt thereof, wherein Lis wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connectsto LBM. In an embodiment, L is; wherein the left side attachment pointWSGR Attorney Docket No. 64600-710.601connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment, L is; wherein the left side attachment point connects to the - S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group andthe right side attachment point connects to LBM. In an embodiment,L is wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment,L is wherein the left side attachment point connects to the -S(O)2- group and the right side attachment pointconnects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment,L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment,L is; wherein the left side attachment point connects to the - S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group andWSGR Attorney Docket No. 64600-710.601the right side attachment point connects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment,L is wherein the left side attachment point connects to the -S(O)2- group and the right side attachment pointconnects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment, Lis; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment, L is; wherein the left side attachment point connects to the - S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group andthe right side attachment point connects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right side attachment pointWSGR Attorney Docket No. 64600-710.601connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment,L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment, L is; wherein the left side attachment point connects to the — S(O)2— group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isN; wherein the left side attachment point connects to the -S(O)2- group andthe right side attachment point connects to LBM. In an embodiment, Lis£wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment,L is; wherein theWSGR Attorney Docket No. 64600-710.601left side attachment point connects to the -S(O)2- group and the right side attachment pointconnects to LBM. In an embodiment, Lis; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toLBM. In an embodiment,L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment, L is; wherein the left side attachment point connects to the - S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isN; wherein the left side attachment point connects to the -S(O)2- group andthe right side attachment point connects to LBM. In an embodiment, Lis wherein the left side attachment point connects to the -S(O)2- group and the right sideattachment point connects to LBM. In an embodiment,L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment pointconnects to LBM. In an embodiment, Lis =; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects toWSGR Attorney Docket No. 64600-710.601LBM. In an embodiment,L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In anembodiment,L is; wherein the left side attachment point connects to the — S(O)2— group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is=; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isN; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is£; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isWSGR Attorney Docket No. 64600-710.601' wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isN N IL wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isNNwherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is.0wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L isNwherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2-group and the right side attachment point connects to LBM. In an embodiment, L iswherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM. In an embodiment, L is,0I)wherein the left side attachment point connects to the -S(O)2-group and the right side attachment point connects to LBM. In an embodiment, L isWSGR Attorney Docket No. 64600-710.601wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM.

[0358] In an embodiment, L is: wherein L1, -Cy-, L2and q are as defined in any of the embodiments described herein and wherein the left side attachment point connects to the — S(O)2— group and the right side attachment point connects to LBM.wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.|— L1— Cy— L2— |

[0360] In an embodiment, is selected fromWSGR Attorney Docket No. 64600-710.601wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.M|-L’-Cy-L!-|is

[0361] In an embodiment, / wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment,|-L'-Cy-L*-|,sN-A / wherein the left attachment point connects to -S(O)2- and the|— L1— Cy— L2-| right attachment point connects to LBM. In an embodiment,iswherein the left attachment point connects to -S(O)2- and the right attachment point connects to|-L'-Cy-L*-|LBM. In an embodiment,iswherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment,|-L'-Cy-I?-|.swherein the left attachment point connects to -S(O)2- and the|-L’-Cy-I?-|. right attachment point connects to LBM. In an embodiment,swherein the left attachment point connects to -S(O)2- and the right attachment point connects toLBM. In an embodiment,wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment,|-L'-Cy-L*-|.swherein the left attachment point connects to -S(O)2- and the|-L’-Cy-I?-|,sb right attachment point connects to LBM. In an embodiment,WSGR Attorney Docket No. 64600-710.601wherein the left attachment point connects to -S(O)2- and the right attachment point connects to|-L'-Cy-L*-|LBM. In an embodiment,jswherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, |_L1_Cy-L2-|,s|-N^N-|wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment,wherein the left attachment point connects to -S(O)2- and the right attachment point connects toLBM. In an embodiment,wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment,|— L’— Cy— L2-],sFNA 1wherein the left attachment point connects to -S(O)2- andhL’-Cy-l?-|the right attachment point connects to LBM. In an embodiment,iswherein the left attachment point connects to -S(O)2- and the right attachmentpoint connects to LBM. In an embodiment,wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In anembodiment,wherein the left attachment point connects to - L1— Cy— L2— |.sS(O)2- and the right attachment point connects to LBM. In an embodiment,wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.WSGR Attorney Docket No. 64600-710.601and, wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.WSGR Attorney Docket No. 64600-710.601defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.WSGR Attorney Docket No. 64600-710.601and, wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.

[0365] In an embodiment, L is selected fromWSGR Attorney Docket No. 64600-710.601, wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.

[0366] In an embodiment, Lis wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, Lis as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects toLBM. In an embodiment,L is7qwherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, L is N^\ O7q^wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects toWSGR Attorney Docket No. 64600-710.601LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, Lis as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects toLBM. In an embodiment,L is wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, L isas defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects toLBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, L is HOO / q| wherein qWSGR Attorney Docket No. 64600-710.601is as defined in any of the embodiments described herein. In an embodiment, L isK'q ’wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects toembodiments described herein and wherein the left attachment point connects to -S(O)2- and theright attachment point connects to LBM. In an embodiment, L iswherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM. In an embodiment, L isN N, wherein q is as defined in any of the embodiments described herein and wherein the left attachment point connects to -S(O)2- and the right attachment point connects to LBM.

[0367] As generally defined herein, each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601

[0368] In an embodiment, each -Cy- is independently a bivalent ring selected from phenylene, a 4-7 membered monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each phenylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.

[0369] In an embodiment, each -Cy- is independently a phenylene substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy-is independently a 4-7 membered monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy- is a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy- is a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein. In an embodiment, each -Cy-is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein.

[0370] In an embodiment, Cy is selected from:WSGR Attorney Docket No. 64600-710.601 / -i / , each substituted with 0, 1, 2, 3, or 4 instances of Rc, wherein Rcis as defined in any of the embodiments described herein and wherein the left side attachment point connects to L1group and the right side attachment point connects to L2.

[0371] In an embodiment, Cy is selected from:instances of Rc, wherein Rcis as defined in any of the embodiments described herein and wherein the left side attachment point connects to L1group and the right side attachment point connects to L2.

[0372] In an embodiment, -Cy- is unsubstituted. In an embodiment, -Cy- is substituted with 0 or 1 instances of Rc. In an embodiment, -Cy- is substituted with 0, 1 or 2 instances of Rc. In an embodiment, -Cy- is substituted with 0, 1, 2 or 3 instances of Rc. In an embodiment, -Cy- is substituted with 1 instance of Rc. In an embodiment, -Cy- is substituted with 2 instances of Rc. In an embodiment, -Cy- is substituted with 3 instances of Rc. In an embodiment, -Cy- is substituted with 4 instances of Rc.

[0373] In an embodiment, Cy is selected from:WSGR Attorney Docket No. 64600-710.601each not further substituted wherein the left side attachment point connects to L1group and the right side attachment point connects to L2.

[0374] In an embodiment, Cy is selected from:and, each not further substituted wherein the left side attachment point connects to L1group and the right side attachment point connects to L2.

[0375] In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right sideattachment point connects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In anembodiment, Cy iswherein the left side attachment point connects to L1group andthe right side attachment point connects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment point connects to L2.In an embodiment, Cy is | *— N NZ> — wherein the left side attachment point connects to L1group I — N jf ' N — | and the right side attachment point connects to L2. In an embodiment, Cy is’ wherein the left side attachment point connects to L1group and the right side attachment pointWSGR Attorney Docket No. 64600-710.601connects to L2. In an embodiment, Cy is wherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In an embodiment, Cy is|_NpN' wherein the left side attachment point connects to L1group and the right sideattachment point connects to L2. In an embodiment, Cy is wherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In an j — N N — |embodiment, Cy is\ / wherein the left side attachment point connects to L1group andthe right side attachment point connects to L2. In an embodiment, Cy isthe left side attachment point connects to L1group and the right side attachment point connects to I — N — IL2. In an embodiment, Cy is5vv’wherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In an embodiment, Cy isHwherein the left side attachment point connects to L1group and the right sideattachment point connects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment point connects to L2. In anembodiment, Cy iswherein the left side attachment point connects to L1group N-j F~N, and the right side attachment point connects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment pointconnects to L2. In an embodiment, Cy iswherein the left side attachment point connects to L1group and the right side attachment point connects to L2.I l lWSGR Attorney Docket No. 64600-710.601

[0376] As generally defined herein, LBM is selected fromany of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601R5, r and s is as defined in any of the embodiments described herein.

[0378] In an embodiment, LBM is is as defined in any of the embodiments described herein. In an embodiment, LBM is(R4)r, wherein each R4, R5, r and s is as defined in any of theembodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In anembodiment,LBM is, wherein each R4, R5, r and s is as definedWSGR Attorney Docket No. 64600-710.601in any of the embodiments described herein. In an embodiment, LBM is, wherein each R4, R5, r and s is as defined in any of theembodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an (R4)r(R5):embodiment,LBM is, wherein each R4, R5, r and s is as defined in any of (R4)r(R5):the embodiments described herein. In an embodiment, LBM is wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment,(R5kLBM is, wherein each R4, R5, r and s is as defined in any of the (R4)rembodiments described herein. In an embodiment, LBM is O, wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment,LBM is (R4)r, wherein each R4, R5, r and s is as defined in any of theWSGR Attorney Docket No. 64600-710.601embodiments described herein. In an embodiment,LBM is (R4)r wherein each R4, R5, r and s is as defined in any of the embodiments described herein. In an embodiment, LBMis (R4)r, wherein each R4, R5, r and s is as defined in any of the embodiments described herein.WSGR Attorney Docket No. 64600-710.601WSGR Attorney Docket No. 64600-710.601WSGR Attorney Docket No. 64600-710.601o

[0386] In an embodiment, LBM is selected from0WSGR Attorney Docket No. 64600-710.601 o, N

[0387] In an embodiment, LBM is. In an embodiment, LBM isembodiment, LBM isWSGR Attorney Docket No. 64600-710.601

[0388] As generally defined herein, each instance of RAis independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0389] In an embodiment, each instance of RAis independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -OR, -SR, - NR2,- C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein each R is as defined in any of the embodiments described herein.

[0390] In an embodiment, each instance of RAis independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkynyl, -CN, -OR, -NR2,-C3-7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0391] In an embodiment, each instance of RAis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6haloalkyl, -OR, -C3.7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0392] In an embodiment, each instance of RAis independently selected from oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, -Tr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.WSGR Attorney Docket No. 64600-710.601

[0393] In an embodiment, each instance of RAis independently selected from oxo, deuterium, -F, and -Me.

[0394] In an embodiment, each instance of RAis independently selected from halogen and -Ci-6 alkyl.

[0395] In an embodiment, each instance of RAis independently selected from -F and -Me.

[0396] In an embodiment, RAis -F.

[0397] In an embodiment, the moiety represented by or by

[0398] In an embodiment, the moiety represented byH. In an embodiment, the moietyWSGR Attorney Docket No. 64600-710.601

[0399] In an embodiment, the -NH- and F- are in a cis configuration.

[0400] In an embodiment, the -NH- and F- are in a trans configuration.(RA)nAA 9. ( A )— s - L — LBM / \ / 11o

[0401] In an embodiment, the moiety represented byHor by

[0402] In an embodiment, the -NH- and Me- are in a cis configuration.

[0403] In an embodiment, the -NH- and Me- are in a trans configuration.LBM

[0404] In an embodiment, the moiety represented by or by (RA).O,^LBM, sLoNH is selected from:WSGR Attorney Docket No. 64600-710.601is selected from:LBM

[0407] In an embodiment, the moiety represented by or by. In an embodiment, the moietyWSGR Attorney Docket No. 64600-710.601represented by

[0408] As generally defined herein, each instance of RBis independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0409] In an embodiment, each instance of RBis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkenyl, -C2.6alkynyl, -CN, -OR, -SR, - NR2,- C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein each R is as defined in any of the embodiments described herein.

[0410] In an embodiment, each instance of RBis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkynyl, -CN, -OR, -NR2,-C3.7cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0411] In an embodiment, each instance of RBis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6haloalkyl, -OR, -C3.7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0412] In an embodiment, each instance of RBis independently selected from deuterium, -F, -Cl, -Me, -Et, -Pr, -Tr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.WSGR Attorney Docket No. 64600-710.601

[0413] In an embodiment, each instance of RBis independently selected from deuterium, -F, and -Me.

[0414] As generally defined herein, each instance of Rcis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0415] In an embodiment, each instance of Rcis independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2.6 alkenyl, -C2.6 alkynyl, -CN, -OR, -SR, - NR2,- C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein each R is as defined in any of the embodiments described herein.

[0416] In an embodiment, each instance of Rcis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkynyl, -CN, -OR, -NR2,-C3.7cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0417] In an embodiment, each instance of Rcis independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6haloalkyl, -OR, -C3.7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0418] In an embodiment, each instance of Rcis independently selected from oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, -!Pr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.

[0419] In an embodiment, each instance of Rcis independently selected from oxo, deuterium, -F, and -Me.

[0420] As generally defined herein, each instance of R4is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkenyl, -C2.6alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -WSGR Attorney Docket No. 64600-710.601S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0421] In an embodiment, each instance of R4is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkenyl, -C2.6alkynyl, -CN, -OR, -SR, - NR2,- C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein each R is as defined in any of the embodiments described herein.

[0422] In an embodiment, each R4is independently selected from deuterium, halogen, -Ci.6alkyl, -Ci.6 haloalkyl, -CN, -OR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)NR2, -C(O)N(R)OR, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2NR2and -N(R)S(O)2R, wherein R is H or Cj.6alkyl.

[0423] In an embodiment, each instance of R4is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkynyl, -CN, -OR, -NR2,-C3.7cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0424] In an embodiment, each instance of R4is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6haloalkyl, -OR, -C3.7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0425] In an embodiment, each R4is independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe and -NMe2.

[0426] In an embodiment, each instance of R4is independently selected from deuterium, -F, -Cl, -Me, -Et, -Pr, -Tr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.

[0427] In an embodiment, each instance of R4is independently selected from deuterium, -F, and -Me. In an embodiment, each R4is independently selected from -Me and -F.

[0428] As generally defined herein, each instance of R5is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkenyl, -C2.6alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -WSGR Attorney Docket No. 64600-710.601S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0429] In an embodiment, each instance of R5is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2.6alkynyl, -CN, -OR, -NR2,-C3.7cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0430] In an embodiment, each instance of R5is independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 haloalkyl, -OR, -C3-7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0431] In an embodiment, each R5is independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe and -NMe2.

[0432] In an embodiment, each instance of R5is independently selected from deuterium, -F, -Cl, -Me, -Et, -Pr, -!Pr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.

[0433] In an embodiment, each instance of R5is independently selected from deuterium, -F, and -Me.

[0434] In an embodiment, each instance of R5is independently selected from -F, and -Me.

[0435] As generally defined herein, each instance of R6is independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein eachR is as defined in any of the embodiments described herein.

[0436] In an embodiment, each instance of R6is independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2.6 alkenyl, -C2.6 alkynyl, -CN, -OR,WSGR Attorney Docket No. 64600-710.601-SR, - NR2,- C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1 -3 heteroatoms independently selected from N, O and S, wherein each R is as defined in any of the embodiments described herein.

[0437] In an embodiment, each instance of R6is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6heteroalkyl, -Ci.6haloalkyl, -C2-6 alkynyl, -CN, -OR, -NR2,-C3.7cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0438] In an embodiment, each instance of R6is independently selected from oxo, deuterium, halogen, -Ci.6alkyl, -Ci.6haloalkyl, -OR, -C3.7 cycloalkyl and 4-7 membered heterocyclyl, wherein said each heterocyclyl and heteroaryl contains 1 or 2 heteroatoms independently selected from N and O, wherein each R is as defined in any of the embodiments described herein.

[0439] In an embodiment, R6is selected from halo, -OH and -Ci-6 alkyl.

[0440] In an embodiment, each instance of R6is independently selected from oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, -!Pr, -fBu, -CF3, -OH, -OMe, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl.

[0441] In an embodiment, R6is selected from -F, -Cl, -OH, -Me, -Et-, -!Pr.

[0442] In an embodiment, each instance of R6is independently selected from oxo, deuterium, -F, and -Me. In an embodiment, each instance of R6is independently selected from -OH, -F and -Me.

[0443] In an embodiment, R6is selected from-F and -Me. In an embodiment, each instance of R6is independently selected from -OH and -Me.

[0444] In an embodiment, R6is -Me.

[0445] In an embodiment, R6is -OH.

[0446] As generally defined herein, eachR7is independently selected from -C1.4 alkyl and halo. In an embodiment, eachR7is independently selected from -Me, -'Prand -F. In an embodiment, each R7is independently selected from -Me and -F. In an embodiment, R7is -Me. In an embodiment, R7is -F.

[0447] As generally defined herein, each instance of Ris independently hydrogen, -Ci.6alkyl, -Ci-6 haloalkyl, -Ci-6 heteroalkyl, -C2-6 alkenyl, -C2.6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they areWSGR Attorney Docket No. 64600-710.601attached to form an optionally substituted 4-7 heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S.

[0448] In an embodiment, each instance of R is independently hydrogen, -Ci-6 alkyl, -Ci-6 haloalkyl, -Ci.6heteroalkyl, -C3.7 cycloalkyl and 4-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form a 4-7-membered heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S, substituted with 0, 1, 2 or 3 substituents independently selected from -F, -Me, oxo, -OH- or -OMe.

[0449] In an embodiment, each instance of R is independently hydrogen, -Ci.6alkyl, -Ci.6haloalkyl, -Ci.6heteroalkyl or -C3.7 cycloalkyl or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form a 4 -7 -membered heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S, substituted with 0, 1, 2 or 3 substituents independently selected from -F, -Me, oxo, -OH- or -OMe.

[0450] In an embodiment, two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form an azetidine, pyrrolidine, piperidine, piperazine, morpholine or azepane, each substituted with 0, 1, 2 or 3 substituents independently selected from -F, -Me, oxo, -OH- or -OMe.

[0451] In an embodiment, each instance of Ris independently selected from hydrogen and -Ci-6 alkyl. In an embodiment, R is H. In an embodiment R is -Ci-6 alkyl. In an embodiment, R is selected from H and -Me. In an embodiment, R is -Me.

[0452] As generally defined herein, eachL1is independently selected from a bond and -N(R’), wherein R’ is as defined in any of the embodiments described herein. In an embodiment, L1is a bond. In an embodiment, L1is -N(R’), wherein R’ is as defined in any of the embodiments described herein. In an embodiment, L1is selected from a bond, -NH- and -NMe-. In an embodiment, L1is selected from a bond and -NH-. In an embodiment, L1is selected from a bond -NMe-. In an embodiment, L1is -NH-. In an embodiment, L1is -NMe-.

[0453] As generally defined herein, each L2independently selected from a bond and -N(R’), wherein R’ is as defined in any of the embodiments described herein.

[0454] In an embodiment, L2is a bond. In an embodiment, L2is -N(R’), wherein R’ is as defined in any of the embodiments described herein. In an embodiment, L2is selected from a bond, -NH- and -NMe-. In an embodiment, L2is selected from a bond and -NH-. In an embodiment,WSGR Attorney Docket No. 64600-710.601L2is selected from a bond -NMe-. In an embodiment, L2is -NH-. In an embodiment, L2is -NMe-.

[0455] In an embodiment, L1is a bond and L2is a bond or N(R’)-. In an embodiment, L1is a bond and L2is a bond or NMe-.

[0456] In an embodiment, L1is a bond and L2is a bond or -NH-.

[0457] As generally defined herein, each R’ is independently selected from H and Ci-6 alkyl.

[0458] As generally defined herein, n is 0, 1, 2, 3, or 4. In an embodiment, n is 0, 1, 2 or 3. In an embodiment, n is 0, 1 or 2. In an embodiment, n is 0 or 1. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0459] As generally defined herein, ris 0, 1, 2, 3, or4. In an embodiment, r is 0, 1, 2 or 3. In an embodiment, r is 0, 1 or 2. In an embodiment, r is 0 or 1. In an embodiment, r is 0. In an embodiment, r is 1. In an embodiment, r is 2. In an embodiment, r is 3. In an embodiment, r is 4.

[0460] As generally defined herein, s is 0, 1, 2, 3, or 4. In an embodiment, s is 0, 1, 2 or 3. In an embodiment, s is 0, 1 or 2. In an embodiment, s is 0 or 1. In an embodiment, s is 0. In an embodiment, s is 1. In an embodiment, s is 2. In an embodiment, s is 3. In an embodiment, s is 4.

[0461] As generally defined herein, m is 0, 1, 2, 3, or 4. In an embodiment, m is 0, 1, 2 or 3. In an embodiment, m is 0, 1 or 2. In an embodiment, m is 0 or 1. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4.

[0462] As generally defined herein, p is 0, 1, 2, 3, or 4. In an embodiment, p is 0, 1, 2 or 3. In an embodiment, p is 0, 1 or 2. In an embodiment, p is 0 or 1. In an embodiment, p is 0. In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, p is 3. In an embodiment, p is 4.

[0463] As generally defined herein, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In an embodiment, q is 1, 2, 3, 4, 5, 7 or 9. In an embodiment, q is 0. In an embodiment, q is 1. In an embodiment, q is 2. In an embodiment, q is 3. In an embodiment, q is 4. In an embodiment, q is 5. In an embodiment, q is 6. In an embodiment, q is 7. In an embodiment, q is 8. In an embodiment, q is 9. In an embodiment, q is 10.

[0464] In an embodiment of a compound of Formula II-A, Formula II-B, or Formula II-C, the compound is selected from the compounds disclosed in Table 2, or a pharmaceutically acceptable salt thereof, or elsewhere in the specification and figures. In an embodiment, the compound is a compound identified in Table 2 below or a pharmaceutically acceptable salt thereof. In anWSGR Attorney Docket No. 64600-710.601embodiment, provided herein is a composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0465] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds marked with (or) or (rel) in Table 2 and the Examples section are single enantiomers wherein the absolute stereochemistry was arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section). Compounds marked with and) or (rac) are mixtures of enantiomers wherein the relative stereochemistry is as shown. Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted and that have no designation in the stereochemistry column of Table 2 are mixtures of enantiomers at that center. Compounds that have a stereogenic center where the configuration is indicated in the structure as depicted and have no designation in the stereochemistry column of Table 2 or that are marked with (abs) are single enantiomers wherein the absolute stereochemistry is as indicated.

[0466] A person of skill in the art would be able to separate racemic compounds into the respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization and the like. References to compounds that are racemic mixtures are meant to also include the individual enantiomers contained in the mixture.Table 2. Exemplary CompoundsCDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)11 16 70.2 NA 30.9 NA NAy yA J0I VHWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) ZV12 NA 45.7 NA 41.1 NA NA O CP HN-Aex13 NA 34.6 NA 19.4 NA NA £JN°D-N-MM14 6.7 56.5 NA 21.2 NA NA Z-*N0WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT A A Protein Protein Protein Protein Protein Protein ^ 9 zz^z / Z-z.^ Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif IZ ication ication cation cation cation ication f I p zO, _ DCso Maxim DCso Maximu DCso Maxim 0' 0' CO°z '"0_ O ^X,z-'-— r. (nM) um (%) (nM) m (%) (nM) um (%) | | z V— _I / TZXX>°\ / O—A °^\ / Z-_015 NA 24.9 NA 21.9 NA NA 0AH / N~X^16 14.6 66.2 NA 30 NA NA rNosLy_ X5AN0 '°o=vA17 NA 37.9 NA 21.2 NA NAWSGR Attorney Docket No. 64600-710.601 [ oX CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT AA CT\ Protein Protein Protein Protein Protein Protein XV o i Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif \ " z ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) O^. N^.0S / o 7 TAz,— N 7 A^z o / A o0 hr 18 8.8 59.2 NA 24.7 NA NA OiC.^ 0NHA A / / 00ANHC^Ao_ N Q>0 / ~~N 19 NA 48.4 NA NA NA NA Ox,,N / — N0A 7-A Z A~NV A~N^H°^A^-20 NA 38.9 NA NA NA NAWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) a.0oKA \ J— N T2<0N21 NA 49.5 NA 23.6 NA NA oxXO / ^NH\ )A, XZ < 22 NA 34.6 NA 16.9 NA NA, n x °> z—J > L / o- o=z x— / x— '0HNAoVO^N / ? 23 17.3 79 17.6 52.8 NA NA °»? SS-OpAprWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)24 4.56 57.4 NA 37.7 NA NA / z25 27 15 -3 / \ o>1Vi\r "" % ft / / \ V 25 V—^ °skbJ O <?T rxNAJor^7<9 26 49 17 3.67 57 pWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)Yo=s=o27 17 54 26 26 0, N., NHcYY0XKA.o=pCE >°J \28 12 63 20 5 N1o=s=o0N NHYWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) ^7y29 19 26 25\I ' 30 46 29 86.3 71y / 31 41 54 28 28 QuWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) / 32 44 57 18 35 Y80^5C \ J rJr8 N\°xJ \8 33 98 64 20 49 YZSXX^N° 8088j~CyI 834 41 21 -1 <7 Xt>WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT °\ Protein Protein Protein Protein Protein Protein / \*T \zStructure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif £r~~ °~ / \ ication ication cation cation cation ication II / \ hrt -1 M — DCso Maxim DCso Maximu DCso Maximz / / / —v\ o / \ _ (nM) um (%) (nM) m (%) (nM) um (%) < A7 / L~T^ N < N -L / N\ 1 II 1 J ° f —r-JH _ / 0C^~ £ 35 29 25 15N'^O£ o<7 °\\ ^NCJ^N^'st J\ JL 1 1 J ° 1r£_hU 36 42 8 9N*"\s^X—-NH037 19 57 27 49WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein / \ \TZ< \ 1 y^ 2 _ Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication \ o / DCso Maxim DCso Maximu DCso Maxim '2'~~~ (nM) um (%) (nM) m (%) (nM) um (%) iY2oyo rY38 42 8 8 / Z= o^UsE Y ° e^ \YYY / — °^ o V / 39 35 76 47 95.8 57 I \ p*- V AZ z^ xZz^ / TYWSGR Attorney Docket No. 64600-710.601 T> O. CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 o HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT f\Z\ (J zf \z^ Protein Protein Protein Protein Protein Protein X\ \ ( Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif O45~<y V \ / o \, ication ication cation cation cation ication ° — \11SA\ / Z _ \< / ,, \ oz _ DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) '''! Gr| / f> L°\ °^\w o40 11 72 37 17.6 75I< A ° / \ o>oz t>g< Af^ °z'41 17 62 14 1542 86 59 22 41WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 o. HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein \ 1^ z _ Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif \o= ication ication cation cation cation ication O§'s0 / ~r«~ DCso Maxim DCso Maximu DCso MaximZ' °v (nM) um (%) (nM) m (%) (nM) um (%)1AZOx / - _<o P) ¥yYV^^Z Q0 XA°X° o 43 42 9 4 XN^NHA / yN / ~N / ° u44 6 72 44 13.6 6145 34 21 17WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 01 NH / X)°.46 46 515 59 49 \ \ _l " yN\ \V ZN~S~N'^'7 >0o \ — 7— N<7 °XVNOQo=ofi [ °H1\ 1 47 40 30 0 M XjW- A / ^0NH0A \ \ OV / / / / y g _ \ / z \ O-z'\ \ / _ O VZ~"v^= / \z^ X^ / 48 4 71 46 23 57WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein A L Z — © \ Structure No. Quantif Quantif Quantifi Quantifi Quantifi QuantifzX \ ' ' II —xication ication cation cation cation ication \ / o DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 1A _r O^ / = o\49 7 54 9 60Crvr z=oJ \o. / 50 5 69 29 44 sN°Z°N 9 ' / V \^NZ~ N.° u0NH-^osss\^_ / rf!=5?X--'NkX >=oT \51 11 65 15 33 o^ A-7.r. Q> NH ~WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 52 7 70 23 17 oy2y, °u / U A o°O / \1 „ oA 1 \U vy A 53 16 60 62 32WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) QA54 39 44 5 XNoU55 8 59 18 41WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HNX C J X \56 5 74 35 44o 0=s=oN 0 NHA0HN'^ x.C JX \57 44 18 10o=s=oN Q NHo V7N / / \WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif Z?z / °— / / x. ication ication cation cation cation ication \ rvr? V-A DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) °A58 35 42 15 / / \ _ Z _co \ / w o \ — r -—w S.f S0^59 34 62 8 6.53 66WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) \ NHYj60 37 16 17 No=s=oQ, NHJJY~No0HN^y0=\ 2L IT >=o\ \61 53 56 40 41 NO=s=oQ, NH^XYYN / °WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)2 56 19 2910 62 46 36WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT A q \ZZ>j\j Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif AA° / ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)oHN A° ^z° N / >\^°zo°64 14 4 Jr°^oA / ^NHN^°n nAo, As^ 65 25 13 8 Z AAA r- y PJ >=N66 41 19 15WSGR Attorney Docket No. 64600-710.601 o. CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT \ \ Protein Protein Protein Protein Protein Protein Quantif Quantif Quantifi Quantifi Quantifi Quantif k \ / ~ — o \- Structure No.11SA * / \ \ _ > >p _7ication ication cation cation cation ication o DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0A?N^OfCTp “ oO^,N67 53 22 15Aoj — \ y~ NHZ^N68 12 10 9 <y zxiQ °z\ zz^69 46 24 17WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein \ \z / \ i _ Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif \ / ~ — o \ / / 2 ication ication cation cation cation icationV / / ' / - \ DCso Maxim DCso Maximu DCso Maxim O - ' \ - / (nM) um (%) (nM) m (%) (nM) um (%) ° § QxQ y° i r^> zxAZ / 70 18 17 28o\ / ° / A - ° 71 3 60 29 23 \ \ o1 \V >< / WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)H 8N )O^ N^°Ck J. N72 40 23 -6 8 N<8=0y'^y^NH / \A^NJ— N / 0800ii V / -N HKN^\8 y° no° r> \73 15 2 14 <N~A r~NHN~ / < 0 O8 "08 / 'r^^.\ 1 N if 1 r N J \\0 / — / H _ / / XN8\ 8 74 29 18 17 °8N0= / \HN^ / OWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Z\ \i \ i _ Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication \ / o^z DCso Maxim DCso Maximu DCso Maxim / Q(nM) um (%) (nM) m (%) (nM) um (%) PlO. s..No \ _ _z-N ° >—M °J PN / = / 75 30 4 9NP “^ > N H 'VVl odr"0° H °76 39 14 80N^°0 i - '<N77 26 21 16 s<.A y~ N 0HJ >=NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Of Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication OfZ) DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) Sr~N78 38 9 6Yfj79 13 8 8 r-w80 -3 6 15WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ^-2 ication ication cation cation cation icationzDCso Maxim DCso Maximu DCso Maxim \ o _ (nM) um (%) (nM) m (%) (nM) um (%)p VP "o81 51 18 150AoVfxr°x0 82 25 8 42 oAoYT"NHz / ~N / u7^ N^Z Af IlI H J V AO0 H^N^ X)A N 83 3 52 19 41 o=s 1=o_N. 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NHWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)84 19 29 8°xxs' J.o r ovAJ V XNANz ~N > / O H r o85 40 51 29 x)\ - / "''" N Q °\ _ ox\ / z— NHnx z OZ0X^NIIV / ^ \Z EC. 0°'0ZXi) / = \zXX 186 29 20 9 <7 RxN < N X'0X 0 IL 1 J0^5 ”WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DCso Maxim DCso Maximu DCso Maxim ^ (nM) um (%) (nM) m (%) (nM) um (%)^87 46 25 40)\rf88 29 17 230yWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) / A > O89 6 16 21 AXAM° r90 24 29 8 Z~-N' 0HA^ / j91 8 50 15 14\ )HWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)92 26 43 11oHN ZA >M / 0(V- Ao Z°. r\ o — ' 93 29 13 16t_ z o—) ) zZ < «J- / \ \ s II / Q No^LS*o4Zx0^J^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0M0u94 21 53 47 30 / — N'0 / \ / — NHZ^N0HN—) / JI N / =oJ \cX 95 17 41 14 O=s'=o9fNY^nVA XA— NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)JL96 16 65 37 34 r9 / V"X97 44 11 13 X9Xr333WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) X HN >A / Fj°x J98 7 55 21 24 9 NNy QNKu7 \ M H 1 W3A Z—>—\ o z — \ \ s.i i \ / ° °1 >v >yn zz99 50 25 35WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)100 5 67 34 45^5QA°101 6 64 25 37WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)102 39 7 26oo o\k\-)- °o=—\ o JL=1 zi Vz^ / O•' • 103 13 13 -3 \ / Z / p n7HO\n r owO~A'v / °< AN> 104 16 63 39 2 51 °xyXN^ / YJ5^Nrf°°cyZ§WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)105 11 65 15 7A5AH106 46 46 26<^ AN<^NHZXAX^N2~NO°K 7107 41 14 46 O=QLuWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein X Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication * 17 o DCso Maxim DCso Maximu DCso Maxim I n X / - (nM) um (%) (nM) m (%) (nM) um (%) B "c-uX s »O^z'§108 31 150AfT >°1X109 31 1 11 No=s=o9, NHXTAWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)HO0 \ )— N ><Yj)°^ J110 6 62 31 34 0— X NHJ / =NO^ N< A NHASor NJ 1Q. A111 38 47 23 °+°^W<y^NH / — N0WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)0N^°112 25 25 20 A0P XTJ l / 1 NAkOp 113 31 7 0 °XoP ZSky^NJ—N z° u" U,»U114 25 6 11 JT"Ny^\ iO^°° U ”oWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)115 40 15 36 yoVN'NA>VNJX-N116 32 3 12 " O H V^r- Xfj117 28 25 22 yXWSGR Attorney Docket No. 64600-710.601vx o. CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9HiBiT HiBiT HiBiT HiBiT HiBiT HiBiTZV\ \Z< \ 17^, Protein Protein Protein Protein Protein Protein z _° / A Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif a \ o ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) / z zKo118 42 16 4j y Y Y0 / UH°x J$ N°=s=o 119 4 57 22 47 N Q1£ZSXXs^NJ^N / ° YWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication ® 1 I oI U DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) D 0Yj °AoAN>14 120 20 5 14 OA s^oA ^NHAN0121 13 9 257 ^ N^Z Af II Jl z Vz ^N z^O0 HO. J122 22 14 28 o=s=o9N NHkA'AN / oz / \WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)123 21 28 6A.y<2UV ob > A §vJ °o \ \ 4 o~ / / < Zi A / 'o _ / vi? Oz124 37 18 1 sbKl o \A’WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 JY O HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication YYI s / / / \ DCso Maxim DCso Maximu DCso Maxim V o _ (nM) um (%) (nM) m (%) (nM) um (%) Oo H^ KN >oY / X FiJ,cX 125 23 7 °=S=OJ— N° '^3^126 14 86 23.2 75 74.9 81WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication HJ P / 7 / / DCso Maxim DCso Maximu DCso Maxim \ o _ (nM) um (%) (nM) m (%) (nM) um (%) 712 —127 10 78 7.43 64 21.8 650HN^oYZ^N■QA / =\N^ / CR / 128 7 76 44 140r. p^V-\ y- NH / / =NT ^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 o> o.\ « / HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein U A 11^ zV / o A Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif §JL / ^ \ z^ ' > ‘1 \ — ication ication cation cation cation ication \ / o==^fQ- DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) o AA ^XZzA VVzAS- o^^= O5§xob129 3 70 22 25130 23 62 23 25WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT I Protein Protein Protein Protein Protein Protein Quantif Quantif Quantifi Quantifi Quantifi Quantif 11 Structure No. / ~~~ O\ ication ication cation cation cation ication " STA~ / \- 2v' > \ II DCso Maxim DCso Maximu DCso Maxim \Z o^ (nM) um (%) (nM) m (%) (nM) um (%)oi / y^^z^A °zS o131 47 79 44 12n\ NH00J132 7 79 25 22 o=XoZSXX^NJ— N° HO 0WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) oOQryXry133 92 52 47 8 0T^NHNp134 6 61 48 73.6 57WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)135 4 54 2.35 81 13§ oc j / o <°<?0\ / = O ^ \ > rI I^E \E - 1 y^< v X X1 X* 136 6 66 29.6 71 33.4 84 \ 1 ® — °T°. •?'J— N’ HO 0WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) ~ \ d NH9Lj 137 6 69 46 49 °x0AHO OVHNY o°o 1 1— N *10-0N138 32 32 34 °A °A^\^NH / XNANHO 9WSGR Attorney Docket No. 64600-710.601 JX o CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 A °zv\-. HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein X u - ^ Z^ o\~ Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif o ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) dC tr' " ° zV o139 42 51 0 18 17xo / rV^1 ozo ' °1 z—_% \z CT''Vo ^ 140 15.8 76 0 34 13 X V z XZ«v> / / z-■-- Ui □ °^ Xi nz^X YT"JpO < <b^141 21.9 83 19.9 63 69.2 56WSGR Attorney Docket No. 64600-710.601D °>\ CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication Mt) DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)142 48 47 7! rN / ^°rj143 9.23 61 26 149V YN.° C iWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 °\ HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT \ / \ / v Protein Protein Protein Protein Protein Proteinzz^Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif p ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) j voIZIo144 4.22 74 18 31cAA^>x zo^LX<'Z145 16.3 54 8 8 ^ / \ -w% 4iQ. xO)xO ' ' Q4, ^°A H °ZIZIQ °'1 U? A o 7o146 131 61 7 14147 3.25 52 38 8WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)\NZ0? '0OxN— ' 148 45 14 3 x / ^N "0 / =^N V )0^N^N YN H149 3.23 65 50 11 / Y < j° 'O AXo OoR6- 150 2.09 71 20 8VCY151 49 25 27 NO<ON^J°=XNZXNWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) X,. / =N Q 152 36.1 53 26 5153 11 1 -2Ny°AA0 AANnr5 °V°>\? Zz / ^ 154 1.97 75 39 49 XL / N°~<s: X?- ro155 4.08 79 25 14 4^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) / ^X N-h156 30 76 36.2 82 4 ^^157 11 64 13 2>Chi158 6 78 44 2WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication Xl DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) V °(159 13.9 69 11 17160 12.9 67 41 45 vva VHNV161 3.31 80 78.5 69 3 <v / NYvO^-N^N H^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Quantif Quantif Quantifi Quantifi Quantifi Quantif V Structure No.ication ication cation cation cation ication Z C DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) HAAx N162 4.22 88 23.6 53 2170 52AN^N^N H^^163 9.42 57 28 17HAS164 7.87 64 31 15AN^NN H^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)165 19 14 8HApi?166 1.66 81 44 9 4 / ^nAN' V'O^N^N HA^iHA CA" N167 18 14 12AN''O-<^N H^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT w Protein Protein Protein Protein Protein Proteinzr Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif z ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) n ° 0HA CAN VH M ( / N><oRON168 2.64 80 5.96 56 13 oxJR / '" N 0 / ^N \ _ / O J N VN HHO*^^0HA(AN / 7-V^NCy\ / =\169 2.83 68 5.99 54 49 osA~\s<. \04 V-“ 0rA NHZ~NCr NHO*^^170 25.2 75 34 38WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HAd / N=o<. r~^ 171 6.06 79 45 17,s<..^ N0 / — N 0 / — \K / >- HA Z~O^NNHO*^^0HA CAN^Cy\ / =\ N172 8.03 75 42 4 0.Sxx7 — A. / ~ N00\\ / ^ANHA ANO^NL^CIA fjF173 26 38 25.3 51WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Proteinzzy Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif Z _VN i. ication ication cation cation cation ication A DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)A1- 174 2.63 85 6.18 54 12175 10.1 78 44 130A CAN, — / ^N / =\ N176 21.3 64 44 18 Ox / N" SxO AN7 — \\ / ^NHO^N / ^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0AcAA—Aj / \ / =A N— ZCL 1 rA~^ 177 3.77 70 32 15 / — N ®d y-=" OA~NO NHO*^^0HA°^ LZ— Z^NCH / \ 178 2.91 71 40 26 Ck \xr^Sx / — N OzANZ — \\ / ^NHz ~NO^NHO*^^O HAcAA, — / ^NJA\F \ ) / =(179 5.85 84 47 10 o. vA'7s<O AN7 — \\ / ^NHO^NHO*^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein ProteinzY Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)\^' ZCANAn z v — ANF / =\1A 180 3.63 75 46 5 Ox / —Sx0N1 — \\ / ^~~NH / ~NO^N181 4.43 55 29 150HNnO^N— ANCy\ / =\ N— / l A 182 4.05 74 49 17 Ox. A~\z-NS" OFrA NHA~NO^ NHO*^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)183 3.58 82 470HAQ^\ / \ F / =\ ^ \,z 184 4.19 78 44 8 o. / —X / " N0, / )~N 0O 7-N H^ N O °Z'z Z^HO*^^0HAc / 'yF^0 — Z^^NNX / =\ 185 3.34 79 45 20 Ck / —Ax / “~N0<5^NHO^NNHO*^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)186 6.51 81 41 14A CAN^, — / ^N / =\ N 187 1.8 75 38 23 o. r~^Sxxr~ N0zA / -» O7^\ Z~~NH 6 A'O^Nzz^aoH0:. >z / N^ON / =\ NV / )~^O.'S. 188 7.82 78 20 15 / — N0d 7- O7 — \\ Z~~NHO^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT w Protein Protein Protein Protein Protein Protein V Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif Z - A1l ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HA< AA>>\ / " F / =\ N—CLS189 7.18 85 48 34 s> / — N 0rA NHO A^, N AHO*^^HA0,,NAn A / =\ N— / Ch l / ^7'SA / ~N0190 6.02 77 38 114 y=N(j7 — \\ / ANHO^N ANHO*^^191 4.8 82 8.09 52 46WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein A Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif Z.. ication ication cation cation cation ication DCso Maxim DCso Maximu DCso Maxim Au, (nM) um (%) (nM) m (%) (nM) um (%)A>192 2.84 67 43 240A(AANo193 5.47 90 43 22 (X / s<_ANzxAO^N AN0HAO^N / 7— A^NCA\194 6.77 84 36 5 (X'Sx / — N 0z\ y-" OO^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HAcA'Jd / / \ N-Z0* N-A 195 2.82 62 43 27,s<. / — N ® / A NHAO^N ANO HA(ANz — ANAA / =\ c N—V f - / M 196 4.32 91 45 11 O. / ~^xS<sA~N O=F'"( )z / N \ _ / 7 — \\ ZANHA ANO^N0HA(AN-AC / vAd 197 1.92 85 45 24 Ox A^xs.OF" ( \z4 / — N \ _ / 7 — Z^NHA ANO^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)198 2.62 88 470HA / 7—CZ / Q5 0IAUlioK / =\ N— (199 13.6 70 27Ck / —x / s<. / “— N 0F" \ ) / \ / =N \ _ / 1TA / )-NH 6ZU z NO^N:. > 0HA0<^ LCA\200 21.9 90 48 9 o. ''s* / “~N 0F'’ \ ) / A / =N \ _ / TA / )-NHO^NWSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%)201 4.67 92 45 160HAz —<^2 / N\N ULA - 202 10.3 85 48Ox ''Sxxz^N 0F<- ( \x\ / =N \ _ / 7 — \\ / ^ANHA ANO^NA °0HN^A, / N, / NCAA 203 3.86 94 42AF" ( ). / =N ) — / < V4 / ^NHz~NO^NHO*^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HAO^NZ^\ N— Z204 5.54 92 41 21 Ox / \'Sx / ~~N 0F“ ( \ / =N \ _ / 7 — \\ / XNH / ^NO^N0HA0<^Nk, — Z^NCZ / N\N / =\ N205 12 93 36 14 Ox r~^Sx0F" \ )ZN7 — \\ / ^NHz^NO^NHO^^AO^Zz — Z^NN / =\ N206 10.5 91 33 8 Ox V / —zX *Sx0F" \ )Z\ / ^N7 — \\ / ^NHz^N0^ NHoZ"^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HA CAN— Z^NCy\ / =\ NA207 2.48 80 40 2 X4^NHA ANO^N0HA CAN, — ANrpxLH 208 3.79 88 9.5 53 15 SxO / ^NHANO^N0HAcA*1F\ ) / =( N— / AJH 209 3.81 89 9.88 61 13 Sxx0F“ / ) / A / ^N \ _ / / XNHO^N ANHO^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HAO^N(^A^ / A NAAH 210 5.66 88 47 23 Ox *Sx / ~N 0F'"( )zA / =N \ _ / AA\ / ^NHA ANO^N0HAO^N, — MNI M 211 10.9 88 37 20 Ox / ~^ *Sx0F-A \ / A / =N \ _ / 7 — \\ / XNHANO^NHO*^^0A°^Nkz — MNM / t A 212 10.2 85 34 18 Ox / —Sx0F" (zA z=N \ _ / 7 — ^ANHA ANO^NHO^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Structure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif ication ication cation cation cation ication DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0HAO^NfVN213 10.4 85 33 15 o.'Sx0F,’ \ ) / \ / =N \ _ / rA / ^NHO^N0HNA°^ LC / 1 / M 214 13.1 88 38 14 Ox 2 — *SxM 0F" ( ) / A / =N \ _ / 7 — (\,^NHO^N / ^NHO*^^O HA CAN / 7-A^NC / N / =\ N—7215 10.9 91 43 13 Ox VA\xSxO / =NF" A \ _ / )7 — 0 / ^NHz^NO^NHO*^^WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein Quantif Quantif Quantifi Quantifi Quantifi QuantifZZStructure No.^zzication ication cation cation cation ication CA DC₅₀ Maxim DC₅₀ Maximu DC₅₀ Maxim (nM) um (%) (nM) m (%) (nM) um (%) 0A CAN■■■•■..N / =\ N216 3.5 90 38 23 Ox r~^Sx0F'“\ )A / =N \ _ / 7^\ / ^NHA z ~NO^N0AO^N, — ANAAC^"VjK 217 4.62 91 45 14 oxxSxA~N 0FA )A / =N \ _ / 7 — \\ / XNHANO^NHO*^^218 12.7 91 43 16WSGR Attorney Docket No. 64600-710.601CDK2 CDK2 CCNE1 CCNE1 CDK9 CDK9 HiBiT HiBiT HiBiT HiBiT HiBiT HiBiT Protein Protein Protein Protein Protein Protein C bz Sztructure No. Quantif Quantif Quantifi Quantifi Quantifi Quantif cc° ication ication cation cation cation ication DCso Maxim DCso Maximu DCso Maxim X1’ ° (nM) um (%) (nM) m (%) (nM) um (%)0HCCo VJ7 O N—'Ox / 219 4.7 91 47OFSxZ=N O'" N\ \H _ / ) ON220 12.1 88 40Compounds of Formula III-A and Formula III-B

[0467] In one aspect, provided herein is a compound of Formula III-A:or a pharmaceutically acceptable salt thereof, wherein:= is a single or a double bond;WSGR Attorney Docket No. 64600-710.601Ring A is selected from the group consisting of a nitrogen -containing 4-10 member heterocyclyl, a Ce-io aryl and a 5-10-member heteroaryl, wherein the 4-10 member heterocyclyl, Ce-io aryl and 5 -10-member heteroaryl are attached to the -NH- through a carbon atom;V1is nitrogen and V2is carbon, and Ringor V2isnitrogen and V1is carbon, and RingT is CH or N;Q1and Q2are independently selected from N and CH;R1Ais independently selected from H, D, halo, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6haloalkyl, C3.10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C3.10 cycloalkyl-Ci.4alkyl-, 6-10 membered aryl-Ci.4alkyl-, 4-10 membered heterocyclyl-Ci.4alkyl-, 5-10 membered heteroaryl-Ci.4alkyl-, ORal, SRal, NH0Ral, C(O)Rbl, C(O)NRalRal, C(O)NRal(ORal), C(O)ORal, OC(O)Rbl, OC(O)NRalRal, NRalRal, NRalNRalRal, NRalC(O)Rbl, NRalC(O)ORal, NRalC(O)NRalRal, C(=NRal)Rbl, C(=NRal)NRalRal, NRalC(=NRal)NRalRal, NRalC(=NRal)Rbl, NRalS(O)NRalRal, NRalS(O)Rbl, NRalS(O)2Rbl, NRalS(O)(=NRal)Rbl, NRalS(O)2NRalRal, S(O)Rbl, S(O)NRalRal, S(O)2Rbl, S(O)2NRalRal, OS(O)(=NRal)Rbl, OS(O)2Rbl, S(O)(=NRal)Rbl, SF5, P(O)RalRbl, OP(O)(ORal)(ORal) and P(O)(ORal)(ORal), wherein said Ci.6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3.10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci.4alkyl-, 6-10 membered aryl-Ci.4alkyl-, 4-10 membered heterocyclyl-Ci.4alkyl-, and 5-10 membered heteroaryl-Ci.4alkyl- are each substituted with 0, 1, 2, 3, or 4 independently selected R2substituents;each R2is independently selected from H, D, halo, CN, NO2, Ci.6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C3.7 cycloalkyl-Ci.4alkyl-, phenyl-Ci.4alkyl-, 4-7 membered heterocyclyl-Ci.4alkyl-, 5-6 membered heteroaryl-Ci.4alkyl-, ORa2, SRa2, NH0Ra2, C(O)Rb2, C(O)NRa2Ra2, C(O)NRa2(ORa2), C(O)ORa2, OC(O)Rb2, OC(O)NRa2Ra2, NRa2Ra2, NRa2NRa2Ra2, NRa2C(O)Rb2, NRa2C(O)ORa2, NRa2C(O)NRa2Ra2, C(=NRa2)Rb2, C(=NRa2)NRa2Ra2, NRa2C(=NRa2)NRa2Ra2,WSGR Attorney Docket No. 64600-710.601NRa2C(=NRa2)Rb2, NRa2S(O)NRa2Ra2, NRa2S(O)Rb2, NRa2S(O)2Rb2, NRa2S(O)(=NRa2)Rb2, NRa2S(O)2NRa2Ra2, S(O)Rb2, S(O)NRa2Ra2, S(O)2Rb2, S(O)2NRa2Ra2, OS(O)(=NRa2)Rb2, OS(O)2Rb2, S(O)(=NRa2)Rb2, SF5, P(O)Ra2Ra2, OP(O)(ORa2)(ORa2) and P(O)(ORa2)(ORa2), wherein said Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, Ci.6haloalky 1, C3.7cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C3.7cycloalkyl-Ci.4alkyl-, phenyl-Ci.4alkyl-, 4-7 membered heterocyclyl-Ci.4alkyl-, and 5-6 membered heteroaryl-Ci.4alkyl- are each substituted with 0, 1, 2, 3, or 4 substituents independently selected from Ci.4alkyl, C3.7cycloalkyl, cyclopropyl, oxo, -C(O)Ci.4alkyl, -C(O)OCi.4alkyl, -C(O)NH2, -OH, -F, -Cl, -O-Ci.4alkyl and -CN;each instance of RAis independently selected from -D, halo, CN, Ci.4alkyl, Ci.4haloalkyl, C3.6cycloalkyl, 4-6 membered heterocyclyl, ORal, SRal, SF5, NRalRal, C3.6cycloalkyl-Ci.3alkyl-, and 4-6 membered heterocyclyl-Ci.3alkyl-, wherein said Ci.4alkyl, Ci.4haloalkyl-, C3-6 cycloalkyl, 4-6 membered heterocyclyl-, C3.6 cycloalkyl-Ci.3alkyl-, and 4-6 membered heterocyclyl-Ci.3alkyl are substituted with 0, 1, 2, 3, or 4 substituents independently selected from -D, halo, -OH, -Ci.4alkyl and -OCi.4alkyl;or, alternatively, two RAgroups on adjacent atoms of Ring A, together with the ring atoms to which they are attached, form RingD, wherein RingD is selected from C3.6cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from -D, halo, -OH, -Ci.4alkyl and -OCi.4alkyl;each Ralis independently selected from H, Ci.6alkyl, Ci.6haloalkyl, C2.6alkenyl, C2.6alkynyl, C3.i0cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C3.i0cycloalkyl-Ci.4alkyl-, 6-10 membered aryl-Ci.4alkyl-, 4-10 membered heterocyclyl-Ci.4alkyl-, and 5-10 membered heteroaryl-Ci.4alkyl-, wherein said Ci-6 alkyl, C2.6 alkenyl, C2.6alkynyl, Ci.6haloalkyl, C3.i0cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C3.io cycloalkyl-Ci.4alkyl, 6-10 membered aryl-Ci.4alkyl, 4-10 membered heterocyclyl-Ci.4alkyl, and 5-10 membered heteroaryl-Ci.4alkyl are each substituted with 0, 1, 2, 3, or 4 independently selected R2substituents; ortwo Ralgroups attached to the same nitrogen atom together with the nitrogen to which they are attached form a 4-7-membered heterocyclyl group substituted with 0, 1, 2, 3, or 4 substituents independently selected from -D, halo, -OH, -Ci.4alkyl and -OCi.4alkyl;eachRblis independently selected from Ci.6alkyl, Ci.6hydroxyalkyl, C3.9cycloalkyl and C2-6 heteroalkyl;WSGR Attorney Docket No. 64600-710.601each Ra2is independently selected from H, Ci.6alkyl, Ci.6hydroxyalkyl, C3.9 cycloalkyl and C2-6 heteroalkyl, or, when possible, two instances of Ra2and the atom to which they are attached are taken together to form a4-7 member heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from -D, halo, -OH, -C1.4 alkyl and -OC1.4 alkyl;each Rb2is independently selected from Ci.6alkyl, Ci.6hydroxyalkyl, C3.9 cycloalkyl and C2-6 heteroalkyl;X is X1when Ring A is heterocyclyl and is selected from X1and X2when Ring A is aryl or heteroaryl;XIis selected from -S(O)2- and -C(O)-;X2is selected from -O-, -NH-, -N(CH3)- and -CH2-;L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C i.5Ohydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O-, wherein:each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc;LBM is selected from:Yais CH or N;WSGR Attorney Docket No. 64600-710.601Zais a bond, -CH2-, -NH-, O, or -NHC(O)- where NH of -NHC(O)- is atached to Ya; RingB is phenylene, a 4-10-membered heterocyclylene, a 5-6-membered monocyclic heteroarylene or a 9-10-membered fused bicyclic heteroarylene, wherein each heteroarylene contains one to three nitrogen ring atoms.ring C together with the (R4)rsubstituents is selected from the group consisting of:each instance of Rcis independently selected from -D, halogen, -OH, and -Ci.6alkyl; each instance of R4is independently selected from -D, halogen, -OH, and -Ci-6 alkyl; each instance of R5is independently selected from -D, halogen, -OH, and -Ci.6alkyl; each instance of R is independently selected from hydrogen and -Ci.6alkyl;n is 0, 1, 2, 3, or 4;r is 0, 1, 2, 3, or 4; ands is 0, 1, 2, 3, or 4.

[0468] In an embodiment, provided is a compound of Formula III-B:or a pharmaceutically acceptable salt thereof, wherein Ring A, T, R1, RA, L, LBM and n are as defined in any of the embodiments described herein.w1-w2

[0469] As generally defined herein, Ring A is selected fromand W4=w3, wherein W1, W2, W3and W4are as defined in any of the embodiments described herein. In anWSGR Attorney Docket No. 64600-710.601embodiment, ring A is selected fromw1-w2Ring A isIn an embodiment, Ring Ais w4=w3, wherein W1, W2, W3and W4are as defined in any of the embodiments described herein. In an embodiment, ring A is

[0470] As generally defined herein, V1is nitrogen and V2is carbon, and Ringor V2is nitrogen and V1is carbon, and Ring. In oneembodiment, V1is nitrogen and V2is carbon, and Ringembodiment, V2is nitrogen and V1is carbon, and Ring

[0471] As generally defined herein, T is CH orN. In one embodiment, T is CH. In one embodiment, T is N.

[0472] As generally defined herein, Q1and Q2are independently selected from N and CH. In an embodiment, Q1and Q2are both CH. In an embodiment, Q1and Q2are both N. In an embodiment, Q1is N and Q2is CH. In an embodiment, Q2is N and Q1is CH.

[0473] As generally defined herein, X is X1when Ring A is heterocyclyl and is selected from X1and X2when Ring A is aryl or heteroaryl, wherein X1and X2are as defined in any of the embodiments described herein. In an embodiment, X is X1. In an embodiment, Ring A is aryl or heteroaryl and X is X2. In an embodiment, X is selected from -S(O)2- and -C(O)-. In an embodiment, Xis -S(O)2- In an embodiment, X is C(O)-. In an embodiment, X is -O-. In an embodiment, X is -NH-. In an embodiment, X is -N(CH3)-. In an embodiment, X is -CH2-WSGR Attorney Docket No. 64600-710.601

[0474] As generally defined herein, X1is selected from -S(O)2- and -C(O)-. In an embodiment, X1is — S(O)2—. In an embodiment, X1is C(O)-.

[0475] As generally defined herein, X2is selected from -O-, -NH-, -N(CH3)- and -CH2- In an embodiment, X2is -O-. In an embodiment, X2is -NH-. In an embodiment, X2is -N(CH3)-. In an embodiment, X2is -CH2-.

[0476] As generally defined herein, Yais CH or N. In an embodiment, Yais CH. In an embodiment, Yais N.

[0477] As generally defined herein, Zais a bond, -CH2-, -NH-, O, or -NHC(O)- where NH of -NHC(O)- is attached to Ya. In an embodiment, Zais selected from the group consisting of a bond, -NH-, -O- and -NHC(O)-. In an embodiment, Zais selected from the group consisting of a bond, -NH- and -NHC(O)-. In an embodiment, Zais selected from the group consisting of -NH-, and -NHC(O)-. In an embodiment, Zais a bond. In an embodiment, Zais -CH2-. In an embodiment, Zais -NH-. In an embodiment, Zais O. In an embodiment, Zais -NHC(O)- where NH of -NHC(O)-is attached to Ya.

[0478] As generally defined herein, RingB is phenylene, a 4-10-membered heterocyclylene, a 5-6-membered monocyclic heteroarylene or a 9-10-membered fused bicyclic heteroarylene, wherein each heteroarylene contains one to three nitrogen ring atoms. In an embodiment, Ring B is phenylene. In an embodiment, RingB is a 4-10 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof. In an embodiment, RingB is a 5-6-membered monocyclic heteroarylene containing 1, 2, 3 or 4 heteroatoms selected from O, N and S and oxidized forms thereof. In an embodiment, RingB is a 9-10-membered fused bicyclic heteroarylene containing 1, 2, 3 or 4 heteroatoms selected from O, N and S and oxidized forms thereof.

[0479] As generally defined herein, ring C together with the (R4)rsubstituents is selected from the group consisting of:WSGR Attorney Docket No. 64600-710.601

[0480] As generally defined herein, R1Ais independently selected from H, D, halo, CN, NO2, Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5 -10 membered heteroaryl, C3-10 cycloalkyl-Ci.4 alkyl, 6-10 membered aryl-Ci.4 alkyl, 4-10 membered heterocyclyl-Ci.4alkyl, 5-10 membered heteroaryl-Ci.4 alkyl, ORal, SRal, NH0Ral, C(O)Rbl, C(O)NRalRal, C(O)NRal(ORal), C(O)ORal, OC(O)Rbl, OC(O)NRalRal, NRalRal, NRalNRalRal, NRalC(O)Rbl, NRalC(O)ORal, NRalC(O)NRalRal, C(=NRal)Rbl, C(=NRal)NRalRal, NRalC(=NRal)NRalRal, NRalC(=NRal)Rbl, NRalS(O)NRalRal, NRalS(O)Rbl, NRalS(O)2Rbl, NRalS(O)(=NRal)Rbl, NRalS(O)2NRalRal, S(O)Rbl, S(O)NRalRal, S(O)2Rbl, S(O)2NRalRal, OS(O)(=NRal)Rbl, OS(O)2Rbl, S(O)(=NRal)Rbl, SF5, P(O)RalRbl, OP(O)(ORal)(ORal) and P(O)(ORal)(ORal), wherein said Ci.6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3.10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C3.10 cycloalkyl-Ci.4 alkyl, 6-10 membered ary 1-C 1.4 alkyl, 4-10 membered heterocyclyl-Ci.4 alkyl, and 5-10 membered heteroaryl-Ci.4 alkyl are each substituted with 0, 1, 2, 3, or 4 independently selected R2substituents, wherein each Ral, Rbland R2are as defined in any of the embodiments described herein.

[0481] In an embodiment, R1Ais independently selected from H, halo, CN, NO2, Ci.6alkyl, C2.6 alkenyl, C2-6 alkynyl, Ci.6haloalkyl, C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C3.7 cycloalkyl-Ci.4 alkyl-, phenyl-Ci_4alkyl-, 4-7 membered heterocyclyl-Ci.4 alkyl-, 5-6 membered heteroaryl-Ci.4 alkyl-, ORal, SRal, C(O)Rbl, C(O)NRalRal, C(O)ORal, OC(O)Rbl, OC(O)NRalRal, NRalRal, NRalC(O)Rbl, NRalC(O)ORal, NRalC(O)NRalRal, NRalS(O)2Rbl, NRalS(O)2NRalRal, S(O)2Rbl, and S(O)2NRalRal, wherein said Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, Ci.6haloalkyl, C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C3.7 cycloalkyl-Ci.4 alkyl-, phenyl-Ci_4alkyl-, 4-7 membered heterocyclyl-Ci.4 alkyl-, and 5-6 membered heteroaryl-Ci.4 alkyl- are each substituted with 0, 1, 2, 3, or 4 independently selected R2substituents, wherein each Ral, Rbland R2are as defined in any of the embodiments described herein.

[0482] In an embodiment, R1Ais independently selected from H, halo, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6haloalkyl, C3.7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C3.7 cycloalkyl-Ci.4 alkyl-, phenyl-Ci_4alkyl-, 4-7 membered heterocyclyl-Ci.4 alkyl-, 5-6 membered heteroaryl-Ci.4 alkyl-, ORal, C(O)Rbl, C(O)NRalRal, C(O)ORal, OC(O)Rbl, OC(O)NRalRal, NRalRal, NRalC(O)Rbl, NRalC(O)ORal, NRalC(O)NRalRal, NRalS(O)2Rbl, NRalS(O)2NRalRal, S(O)2Rbl, and S(O)2NRalRal, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 memberedWSGR Attorney Docket No. 64600-710.601heterocyclyl, 5-6 membered heteroaryl, C3.7 cy...

Claims

1. WSGR Attorney Docket No. 64600-710.601CLAIMS WHAT IS CLAIMED IS:

1. A method for selectively degrading a one or more proteins in a cell, comprising:a. selecting one or more lysine residues for ubiquitinating on at least one target protein of a protein complex;b. contacting the protein complex with a molecule to form a non -native ternary complex comprising the protein complex and a ligase, whereby the molecule induces proximity between the protein complex and the ligase thereby causing ubiquitinating of at least one of the selected lysine residues; and c. selectively degrading at least one protein in the protein complex containing the ubiquitinated selected lysine residues.

2. The method of claim 1, wherein ubiquitinating at least one of the selected lysine residues comprises trans-ubiquitination.

3. The method of claim 2, wherein trans-ubiquitination comprises an ubiquitin ligase specific to the target protein.

4. The method of claim 1, wherein the molecule comprises a bifunctional molecule.

5. The method of claim 1, wherein the one or more lysine residues comprise solvent- exposed lysine residues.

6. The method of claim 1, wherein the target protein is selected from CDK2, CCNE1, and CCNE2.

7. The method of claim 6, wherein the selected lysine residue comprises CDK2 K250, CDK2 K291, or CCNE1 KI 45.

8. The method of claim 1, wherein the method treats a disease or disorder that is resistant to CDK2 inhibition alone.

9. The method of claim 1, wherein the method treats a disease or disorder characterized by CCNE1 or CCNE2 amplification or overexpression.

10. The method of claim 1, wherein the method ablates the cyclin E upregulation resistance mechanism induced by kinase inhibitors.WSGR Attorney Docket No. 64600-710.60111. A method for ubiquitinating one or more select lysine residues, comprising:a. identifying one or more ubiquitin -competent lysine residues on a target protein of a protein complex;b. inducing a ubiquitin-competent ternary complex via a bifunctional molecule; and c. ubiquitinating the one or more select lysine residues of the target protein.

12. The method of claim 11, wherein identifying one or more ubiquitin-competent lysine residues comprises predicting selectivity for a CDK2 lysine residue over a homologous lysine residue.

13. The method of claim 11, wherein ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of CDK2 K250.

14. The method of claim 11, wherein ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of CDK2 K291.

15. The method of claim 11, wherein ubiquitinating the one or more select lysine residues comprises lysine ubiquitination of cyclin E.

16. The method of claim 11, wherein ubiquitinating the bifunctional molecule comprises a dual CDK2 and cyclin E affinity degrader.

17. The method of claim 11, wherein the one or more ubiquitinated lysine residues are subsequently degraded via a proteasome pathway.

18. A method fortreating a disease or disorder that is unresponsive, or partially unresponsive, to CDK2 inhibition alone, comprising the method of claim 11.

19. A method for treating a disease or disorder characterized by cyclin E amplification or overexpression, comprising the method of claim 11.

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