Cyclin dependent kinase degraders and methods of use thereof

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for degrading CDK2 and / or CCNE (CCNE1 and / or CCNE2) with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) with the compounds and compositions of the disclosure.

Description

CYCLIN DEPENDENT KINASE DEGRADERS AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US provisional application no. 63 / 683,577, filed August 15, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for the modulation of cyclin dependent kinase 2 (CDK2) and / or cyclin E (CCNE1 and / or CCNE2) via ubiquitination and / or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[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 G1 / S transition and S phase progression. In complex with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), leading to de-repression of E2F transcription factors, expression of G1 / 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 ov erexpression of CCNE1 and mutationsthat 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., et al., Clin Cancer Res, 2017.23(7): 1862-1874; Rosen, D. G., et al., Cancer, 2006.106(9): 1925-32). Amplification and / or overexpression of CCNE1 also 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] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0007] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399- 434) titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.”

[0008] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a targetprotein 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 (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).

[0009] An ongoing need exists in the art for effective treatments for disease, especially cancers. As such, small molecule therapeutic agents that leverage UPP mediated protein degradation to target cancer-associated proteins such as cyclin-dependent kinase 2 ("CDK2"), cyclin E (“CCNE1” and / or “CCNE2”) or CDK2 and CCNE(CCNE1 and / or CCNE2) protein hold promise as therapeutic agents. Accordingly, there remains a need to find compounds that are CDK2 degraders, CCNE (CCNE1 and / or CCNE2) degraders or dual CDK2 and CCNE (CCNE1 and / or CCNE2) degraders useful as therapeutic agents. SUMMARY OF THE INVENTION

[0010] In one aspect of the invention, provided are compounds of Formula A:or pharmaceutically acceptable salts thereof, wherein Ring A iswhereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; Y is C(H) or N;LBM is selected from the group consisting of,Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and at least one of Q, J or W is N; X is C(H) or N; Z is -CH2- or C=O; R1is, independently, for each occurrence, –H or –D; R2is, independently, for each occurrence, –H or –Me; each instance of R3is independently selected from –D, halo, –OH,–C1-6alkyl, –O- C1-6alkyl, and –N(Ra)2; each instance of R4is independently selected from –D, halo, –OH, and –C1-6alkyl; each instance of Rais independently selected from –H and –C1-6alkyl.r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4

[0011] In one aspect of the invention, provided are compounds of Formula I:or pharmaceutically acceptable salts thereof, wherein A iswhereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; X is C(F) or N; Y is C(H) or N; R1is, independently, for each occurrence, H or D; and R2is, independently, for each occurrence, H or methyl.

[0012] In some embodiments, provided are compounds of Formula I-A:or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0013] In some embodiments, provided are compounds of Formula I-B:or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0014] In an embodiment, provided are pharmaceutical compositions comprising a compound as described herein (e.g., a compound of Formula A, Formula I, Formula I-A, or Formula I-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0015] In an embodiment, provided is a method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0016] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with the compound or composition.

[0017] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0018] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with the compound or composition.

[0019] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in manufacturing of a medicament for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivoor in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with the compound or composition.

[0020] In an embodiment, provided is a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0021] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0022] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro.

[0023] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0024] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro.

[0025] In an embodiment, provided is a method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0026] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0027] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g. , in vivo or in vitro.

[0028] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0029] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0030] In an embodiment, provided is a method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0031] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0032] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0033] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0034] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0035] In an embodiment, provided is a method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprisingadministering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0036] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0037] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.

[0038] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0039] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.

[0040] In an embodiment, provided is a method of treating a CDK2 -mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0041] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of treating a CDK2- mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0042] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for treating a CDK2 -mediated disorder in a patient in need thereof.

[0043] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of treating a CDK2 -mediateddisorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0044] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for treating a CDK2 -mediated disorder in a patient in need thereof.

[0045] In an embodiment, provided is a method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0046] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0047] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.

[0048] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0049] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.

[0050] In an embodiment, provided is a method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0051] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in a method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof,comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0052] In an embodiment, provided is a use of a compound or pharmaceutically acceptable salt thereof or composition as described herein in the manufacturing of a medicament for treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.

[0053] In an embodiment, provided is compound or pharmaceutically acceptable salt thereof or composition as described herein for use in a method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound or pharmaceutically acceptable salt thereof or composition as described herein.

[0054] In an embodiment, provided is a compound or pharmaceutically acceptable salt thereof or composition as described herein for use in the manufacturing of a medicament for treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof.DETAILED DESCRIPTIONDefinitions

[0055] As used in the present disclosure, the following words and phrases are generally intended to have the meanings as set forth belowunless expressly indicated otherwise or the context in which they are used indicates otherwise.

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0057] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0058] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0059] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0060] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., 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).

[0061] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0062] 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.

[0063] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood 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.

[0064] 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.

[0065] 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.

[0066] 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

[0067] 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.

[0068] 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.

[0069] 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 prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (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.

[0070] 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%.

[0071] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0072] 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%.

[0073] 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%.

[0074] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (Tor 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%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0075] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified.

[0076] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0077] 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.

[0078] The term “unsaturated bond” refers to a double or triple bond.

[0079] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0080] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0081] 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, heteroalkynylene is 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.

[0082] The term “azido” refers to the radical –N3.

[0083] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0084] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0085] “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.

[0086] “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.

[0087] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In an embodiment, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In an embodiment, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In an embodiment, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In an embodiment, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In an embodiment, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In an embodiment, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”, also referred to herein as “lower alkyl”). In an embodiment, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In an embodiment, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In an embodiment, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In an embodiment, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In an embodiment, an alkyl group has 1 carbon atom (“C1alkyl”). In an embodiment, an alkyl group has 2 to 6 carbon atoms (“C2–6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certainembodiments, the alkyl group is unsubstituted C1–10alkyl (e.g., –CH3). In certain embodiments, the alkyl group is substituted C1–10alkyl. Common alkyl abbreviations include Me (–CH3), Et (–CH2CH3),iPr (–CH(CH3)2),nPr (–CH2CH2CH3),nBu (–CH2CH2CH2CH3), oriBu (–CH2CH(CH3)2).

[0088] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, 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.

[0089] “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 carbon–carbon 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 (“C2–10alkenyl”). 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 (“C2–6alkenyl”). In an embodiment, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). 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 of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups aswell as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (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 C2–10alkenyl. In certain embodiments, the alkenyl group is substituted C2–10alkenyl.

[0090] “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 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In an embodiment, an alkynyl group has 2 to 10 carbon atoms (“C2–10alkynyl”). In an embodiment, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In an embodiment, an alkynyl group has 2 to 8 carbon atoms (“C2–8alkynyl”). In an embodiment, an alkynyl group has 2 to 7 carbon atoms (“C2–7alkynyl”). In an embodiment, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In an embodiment, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In an embodiment, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In an embodiment, an alkynyl group has 2 to 3 carbon atoms (“C2–3alkynyl”). In an embodiment, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon–carbon 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 C2–6alkenyl 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 C2–10alkynyl. In certain embodiments, the alkynyl group is substituted C2–10alkynyl.

[0091] 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 moreheteroatoms 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 (“heteroC1–10alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–9alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–8alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–7alkyl”). In an embodiment, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1–6alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1–5alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC1–4alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1–3alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1–2alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In an embodiment, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2–6alkyl”). 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 heteroC1–10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–10alkyl. Exemplary heteroalkyl groups include: –CH2OH, –CH2OCH3, –CH2NH2, –CH2NH(CH3), –CH2N(CH3)2, – CH2CH2OH, –CH2CH2OCH3, –CH2CH2NH2, –CH2CH2NH(CH3), –CH2CH2N(CH3)2.

[0092] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In an embodiment, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In an embodiment, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In an embodiment, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groupswherein 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 C6–14aryl. In certain embodiments, the aryl group is substituted C6–14aryl.

[0093] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, C1–C8alkyl, C1–C8haloalkyl, cyano, hydroxy, C1–C8alkoxy, and amino.

[0094] Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1–C8alkyl, C1–C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1–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, –C1–C8alkyl, –C1–C4haloalkyl, –C3– C10cycloalkyl, 4-10 membered heterocyclyl, C6–C10aryl, substituted C6–C10aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0095] “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.

[0096] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π 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 carbocyclylor 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).

[0097] In an embodiment, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, 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, i.e., unsubstituted (an “un substituted 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 inthe 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.

[0098] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, 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.

[0099] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, –C1–C8alkyl, C3–C10cycloalkyl, 4-10 membered heterocyclyl, C6– C10aryl, and 5-10 membered heteroaryl.

[0100] 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.

[0101] “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.

[0102] 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 (“C3-14carbocyclyl”) 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 (“C3-10carbocyclyl”). 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 (“C3-7carbocyclyl”). In an embodiment, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). 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 (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4),cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl 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 C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0103] 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”)) and can 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 number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0104] 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–C14monocyclic, C4–C14bicyclic, C5– C14tricyclic, or C6–C14polycyclic cycloalkyl). In an embodiment “cycloalkyl” is a monocyclic cycloalkyl. In an embodiment, a monocyclic cycloalkyl has 3-14 ring carbon atoms. (“C3-14monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10monocyclic cycloalkyl”). In an embodiment, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8monocyclic 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, amonocyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10monocyclic cycloalkyl”). Examples of monocyclic C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl 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).

[0105] In an embodiment “cycloalkyl” is a bicyclic cycloalkyl. In an embodiment, a bicyclic cycloalkyl has 4-14 ring carbon atoms. (“C4-14bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms (“C4-12bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms (“C4-10bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms (“C6-10bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 8 to 10 ring carbon atoms (“C8-10bicyclic cycloalkyl”). In an embodiment, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms (“C7-9bicyclic cycloalkyl”). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[1.1.1]pentane (C5), spiro[2.2] pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (C6), bicyclo[3.1.0]hexane (C6), spiro[2.3] hexane (C6), bicyclo[2.2.1]heptane (norbornane) (C7), bicyclo[3.2.0]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[4.1.0]heptane (C7), spiro[2.4] heptane (C7), spiro [3.3] heptane (C7), bicyclo[2.2.2]octane (C8), bicyclo[4.1.1]octane (C8)octahydropentalene (C8), bicyclo[3.2.1]octane (C8), bicyclo[4.2.0]octane (C8), spiro[2.5]octane (C8), spiro[3.4]octane (C8), bicyclo[3.3.1]nonane (C9), octahydro-1H-indene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), bicyclo[3.3.2]decane (C10), bicyclo[4.3.1]decane (C10), spiro[4.5]decane (C10), bicyclo[3.3.3]undecane (C11), decahydronaphthalene (C10), bicyclo[4.3.2]undecane (C11), spiro[5.5]undecane (C11) and bicyclo[4.3.3]dodecane (C12).

[0106] In an embodiment “cycloalkyl” is a tricyclic cycloalkyl. In an embodiment, a tricyclic cycloalkyl has 6-14 ring carbon atoms. (“C6-14tricyclic cycloalkyl”). In an embodiment, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms (“C8-12tricyclic cycloalkyl”). In an embodiment, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms (“C10-12tricyclic cycloalkyl. Examples of tricyclic cycloalkyls include adamantine (C12).

[0107] Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) withone or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0108] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic 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”), and can 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., unsubstituted (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.

[0109] 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 ringheteroatoms selected from nitrogen, oxygen, and sulfur. In an embodiment, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0110] 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, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]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-1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6-naphthyridinyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0111] “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.

[0112] “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.

[0113] “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 unsubstituted 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 not limited to, formyl (–CHO), acetyl (–C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (–C(=O)Ph), benzylcarbonyl (–C(=O)CH2Ph), ––C(=O)– C1–C8alkyl, –C(=O)-(CH2)t(C6–C10aryl), –C(=O)-(CH2)t(5-10 membered heteroaryl), – C(=O)-(CH2)t(C3–C10cycloalkyl), and –C(=O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21is C1–C8alkyl, substituted with halo or hydroxy; or C3–C10cycloalkyl, 4-10 membered heterocyclyl, C6–C10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1– C4alkyl, halo, unsubstituted C1–C4alkoxy, unsubstituted C1–C4haloalkyl, unsubstituted C1– C4hydroxyalkyl, or unsubstituted C1–C4haloalkoxy or hydroxy.

[0114] The term aminoalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an –NH2group.

[0115] The term hydroxyalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an –OH group.

[0116] The terms “alkylamino” and “dialkylamino” refer to −NH(alkyl) and−N(alkyl)2radicals respectively. In an embodiment the alkylamino is a −NH(C1−C4alkyl). In an embodiment the alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n- butylamino, iso-butylamino, sec-butylamino or tert-butylamino. In an embodiment the dialkylamino is −N(C1−C6alkyl)2. In an embodiment the dialkylamino is a dimethylamino, a methylethylamino, a diethylamino, a methylpropylamino, a methylisopropylamino, a methylbutylamino, a methylisobutylamino or a methyltertbutylamino.

[0117] The term “aryloxy” refers to an –O–aryl radical. In an embodiment the aryloxy group is phenoxy.

[0118] 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.

[0119] “Alkoxy” refers to the group –OR29where R29is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0120] 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, C6–C10aryl, aryloxy, carboxyl, cyano, C3–C10cycloalkyl, 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, –O–(CH2)t(C6–C10aryl), –O–(CH2)t(5-10 membered heteroaryl), –O–(CH2)t(C3–C10cycloalkyl), 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–C4alkyl, halo, unsubstituted C1–C4alkoxy, unsubstituted C1– C4haloalkyl, unsubstituted C1–C4hydroxyalkyl, or unsubstituted C1–C4haloalkoxy orhydroxy. Particular exemplary ‘substituted alkoxy’ groups are –OCF3, –OCH2CF3, – OCH2Ph, –OCH2-cyclopropyl, –OCH2CH2OH, and –OCH2CH2N(CH3)2.

[0121] “Amino” refers to the radical –NH2.

[0122] “Oxo group” refers to –C(=O)–.

[0123] “Substituted amino” refers to an amino group of the formula –N(R38)2wherein R38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued 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, –C1–C8alkyl, –C3– C8alkenyl, –C3–C8alkynyl, C6–C10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3–C10cycloalkyl; or C1–C8alkyl, substituted with halo or hydroxy; C3–C8alkenyl, substituted with halo or hydroxy; C3–C8alkynyl, substituted with halo or hydroxy, or –(CH2)t(C6–C10aryl), –(CH2)t(5-10 membered heteroaryl), –(CH2)t(C3–C10cycloalkyl), or – (CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1–C4alkyl, halo, unsubstituted C1–C4alkoxy, unsubstituted C1–C4haloalkyl, unsubstituted C1–C4hydroxyalkyl, or unsubstituted C1–C4haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0124] Exemplary “substituted amino” groups include, but are not limited to, –NR39–C1– C8alkyl, –NR39-(CH2)t(C6–C10aryl), –NR39-(CH2)t(5-10 membered heteroaryl), –NR39- (CH2)t(C3–C10cycloalkyl), 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 C1–C8alkyl; and any alkyl groups 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–C4alkyl, halo, unsubstituted C1– C4alkoxy, unsubstituted C1–C4haloalkyl, unsubstituted C1–C4hydroxyalkyl, or unsubstituted C1–C4haloalkoxy or hydroxy. For the avoidance of doubt the 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.

[0125] 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 protectinggroups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −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, −C1-10alkyl (e.g., aralkyl, heteroaralkyl), −C2-10alkenyl, −C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 Raa, 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. each instance of Raais, independently, selected from −C1-10alkyl, −C1-10perhaloalkyl, −C2-10alkenyl, −C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups 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; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −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(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, −C1-10alkyl, −C1-10perhaloalkyl, −C2-10alkenyl, −C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, 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. each instance of Rccis, independently, selected from hydrogen, −C1-10alkyl, −C1-10perhaloalkyl, −C2-10alkenyl, −C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)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, −C1-6alkyl, −C1-6perhaloalkyl, −C2-6alkenyl, −C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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 =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from −C1-6alkyl, −C1-6perhaloalkyl, −C2-6alkenyl, −C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 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; each instance of Rffis, independently, selected from hydrogen, −C1-6alkyl, −C1-6perhaloalkyl, −C2-6alkenyl, −C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 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 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6alkyl, −ON(C1-6alkyl)2, −N(C1-6alkyl)2, −N(C1-6alkyl)3+X−, −NH(C1-6alkyl)2+X−, −NH2(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1-6alkyl), −NHC(=O)(C1-6alkyl), −N(C1-6alkyl)C(=O)(C1-6alkyl), −NHCO2(C1-6alkyl), −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(NH)NH(C1-6alkyl), −OC(NH)NH2, −NHC(NH)N(C1-6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6alkyl), −SO2N(C1-6alkyl)2, −SO2NH(C1-6alkyl), −SO2NH2, −SO2C1-6alkyl, −SO2OC1-6alkyl, −OSO2C1-6alkyl, −SOC1-6alkyl, −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, −C(=S)NH(C1-6alkyl), −C(=S)NH2, −C(=O)S(C1-6alkyl), −C(=S)SC1-6alkyl, −SC(=S)SC1-6alkyl, −P(=O)(OC1-6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, −C1-6alkyl, −C1-6perhaloalkyl, −C2-6alkenyl, −C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0126] 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- pyridylcarboxamide, 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-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0127] 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-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2’– and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, 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-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl 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, isobornyl 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, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0128] 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-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0129] 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 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-nitro-2-oxo-3-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-ferrocenylmethylamino (Fcm), 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-1-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, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0130] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygenprotecting groups include, but are not limited to, −Raa, −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(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 Raa, 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.

[0131] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-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- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0132] 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, −Raa, −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(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 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.

[0133] 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. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, –Cl, –Br, or I (iodine)), alkoxycarbonyloxy, 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, alkanesulfonyloxy, 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), p-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 p- 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.

[0134] “Carboxy” refers to the radical –C(=O)OH.

[0135] “Cyano” refers to the radical –CN.

[0136] “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.

[0137] “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 (– CH2Cl), dichloromethyl (–CHCl2), tribromomethyl (–CH2Br), and the like.

[0138] “Hydroxy” refers to the radical –OH.

[0139] “Nitro” refers to the radical –NO2.

[0140] “Thioketo” refers to the group =S.

[0141] 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 “unsubstituted” heterocyclyl, “substituted” or “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.

[0142] Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –ON(Rbb)2, –N(Rbb)2, –N(Rbb)3+X–, –N(ORcc)Rbb, – SH, –SRaa, –SSRcc, –C(=O)Raa, –CO2H, –CHO, –C(ORcc)2, –CO2Raa, –OC(=O)Raa, – OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, – 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, –SO2Raa, –SO2ORaa, –OSO2Raa, –S(=O)Raa, –S(=O)(=NRbb)Raa, – OS(=O)Raa, –Si(Raa)3, –OSi(Raa)3–C(=S)N(Rbb)2, –C(=O)SRaa, –C(=S)SRaa, –SC(=S)SRaa, – SC(=O)SRaa, –OC(=O)SRaa, –SC(=O)ORaa, –SC(=O)Raa, –P(=O)2Raa, –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, –B(Raa)2, –B(ORcc)2, –BRaa(ORcc), –C1–10alkyl, –C1–10haloalkyl, –C2–10alkenyl, –C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, 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 =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1–10alkyl, –C1–10haloalkyl, – C2–10alkenyl, –C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered 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; each instance of Rbbis, independently, selected from hydrogen, –OH, –ORaa, – N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –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(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, –C1–10alkyl, –C1–10haloalkyl, –C2–10alkenyl, –C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, 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; each instance of Rccis, independently, selected from hydrogen, –C1–10alkyl, –C1–10haloalkyl, –C2–10alkenyl, –C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, 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; each instance of Rddis, independently, selected from halogen, –CN, –NO2, –N3, – SO2H, –SO3H, –OH, –ORee, –ON(Rff)2, –N(Rff)2, –N(Rff)3+X–, –N(ORee)Rff, –SH, –SRee, – SSRee, –C(=O)Ree, –CO2H, –CO2Ree, –OC(=O)Ree, –OCO2Ree, –C(=O)N(Rff)2, – OC(=O)N(Rff)2, –NRffC(=O)Ree, –NRffCO2Ree, –NRffC(=O)N(Rff)2, –C(=NRff)ORee, – OC(=NRff)Ree, –OC(=NRff)ORee, –C(=NRff)N(Rff)2, –OC(=NRff)N(Rff)2, – NRffC(=NRff)N(Rff)2,–NRffSO2Ree, –SO2N(Rff)2, –SO2Ree, –SO2ORee, –OSO2Ree, –S(=O)Ree, –Si(Ree)3, –OSi(Ree)3, –C(=S)N(Rff)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, –C1–6alkyl, –C1–6haloalkyl, –C2–6alkenyl, – C2–6alkynyl, C3–10carbocyclyl, 3–10 membered heterocyclyl, C6–10aryl, 5–10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, 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 =O or =S; each instance of Reeis, independently, selected from C1–6alkyl, –C1–6haloalkyl, –C2–6alkenyl, –C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 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 Rgggroups; each instance of Rffis, independently, selected from hydrogen, –C1–6alkyl, –C1–6haloalkyl, –C2–6alkenyl, –C2–6alkynyl, C3–10carbocyclyl, 3–10 membered heterocyclyl, C6–10aryl 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 each instance of Rggis, independently, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, – OH, –OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(C1–6alkyl)3+X–, –NH(C1–6alkyl)2+X–, –NH2(C1–6alkyl)+X–, –NH3+X–, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –SS(C1–6alkyl), –C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), –OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), –C(=O)NH2, –C(=O)N(C1–6alkyl)2, – OC(=O)NH(C1–6alkyl), –NHC(=O)(C1–6alkyl), –N(C1–6alkyl)C(=O)(C1–6alkyl), – NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, – C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), –OC(=NH)OC1–6alkyl, –C(=NH)N(C1–6alkyl)2, –C(=NH)NH(C1–6alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6alkyl)2, –OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, –NHSO2(C1–6alkyl), – SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2,–SO2C1–6alkyl, –SO2OC1–6alkyl, – OSO2C1–6alkyl, –SOC1–6alkyl, –Si(C1–6alkyl)3, –OSi(C1–6alkyl)3–C(=S)N(C1–6alkyl)2, – C(=S)NH(C1–6alkyl), –C(=S)NH2, –C(=O)S(C1–6alkyl), –C(=S)SC1–6alkyl, –SC(=S)SC1–6alkyl, –P(=O)2(C1–6alkyl), –P(=O)(C1–6alkyl)2, –OP(=O)(C1–6alkyl)2, –OP(=O)(OC1–6alkyl)2, –C1–6alkyl, –C1–6haloalkyl, –C2–6alkenyl, –C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion.

[0143] 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–, ClO4–, OH–, H2PO4–, HSO4–,SO4-2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0144] 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, –ORaa, –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, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –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, –C1–10alkyl, –C1–10haloalkyl, –C2–10alkenyl, –C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, 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.

[0145] 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

[0146] 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.

[0147] “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.

[0148] 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 A, Formula I, Formula I-A, or Formula I-B), which salt is compatible with pharmaceutical administration.

[0149] 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 be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0150] 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 C1-4 alkyl, and the like.

[0151] 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-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, 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 C1-4 alkyl group), and the like.

[0152] 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.

[0153] 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 acceptableexcipients 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).

[0154] 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, polydextrose, and combinations thereof), an inorganic material (e.g., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium 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, a hydroxyethylcellulose), 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.

[0155] 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, a polyplasdone (e.g., a crospovidone), and a starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0156] Examples of binders include, but are not limited to, a hydroxypropylcellulose, hydroxy ethylcellulose, a hydroxypropylmethycellulose (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., com starch).

[0157] 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,polyethylene glycol 1000 succinate, and docusate sodium.

[0158] 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.

[0159] Examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0160] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.

[0161] 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 hydroxypropylmethyl cellulose, 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).

[0162] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of the compound of Formula A, Formula I, Formula I-A, or Formula I-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.

[0163] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male orfemale 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 non-human 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.

[0164] 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.

[0165] 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 A, Formula I, Formula I-A, or Formula I-B can be administered alone or can be co- administered to the patient. Co-administration is meant to include simultaneous 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).

[0166] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0167] 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 subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorderor condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0168] 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 (i.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).

[0169] 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 term “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.

[0170] 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.

[0171] 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 / orCCNE2) 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. Compounds

[0172] Provided herein are compounds of Formula A, Formula I, Formula I-A, or Formula I-B. Unless the context requires otherwise, reference throughout this specification to “a compound of Formula A, Formula I, Formula I-A, or Formula I-B” or “compounds of Formula A, Formula I, Formula I-A, or Formula I-B” refers to all embodiments of Formula A, Formula I, Formula I-A, or Formula I-B including, for example, compounds of Table 1. In an embodiment, provided are compounds of Formula A, Formula I, Formula I-A, or Formula I-B or pharmaceutically acceptable salts thereof. In an embodiment, the compounds of Formula A, Formula I, Formula I-A, or Formula I-B are provided as pharmaceutically acceptable salts. In an embodiment, the compounds of Formula A, Formula I, Formula I-A, or Formula I-B are provided as the corresponding free base (i.e., are not salts).

[0173] 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.

[0174] In one aspect, provided is a compound of Formula A,or a pharmaceutically acceptable salt thereof, whereinRing A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; Y is C(H) or N; LBM is selected from the group consisting of,Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and at least one of Q, J, and W is N; X is C(H) or N; Z is -CH2- or C=O; R1is, independently, for each occurrence, –H or –D; R2is, independently, for each occurrence, –H or –Me;each instance of R3is independently selected from –D, halo, –OH,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2; each instance of R4is independently selected from –D, halo, –OH, and –C1-6alkyl; each instance of Rais independently selected from –H and –C1-6alkyl. r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4.

[0175] In some embodiments, Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

[0176] In some embodiments, Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

[0177] In some embodiments, Y is C(H).

[0178] In some embodiments, Y is N.

[0179] In some embodiments, each R1is independently –H.

[0180] In some embodiments, each R1is independently –D.

[0181] In some embodiments, both instances of R1are –D. In some embodiments, one instance of R1is –H and one instance of R1is –D.

[0182] In some embodiments, each R2is independently –H.

[0183] In some embodiments, each R2is independently –Me.

[0184] In some embodiments, both instances of R2are –Me. In some embodiments, one instance of R2is –H and one instance of R2is –Me.

[0185] In some embodiments, Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and at least two of Q, J, or W is N.

[0186] In some embodiments, Q is N and J and W are C(H). In some embodiments, J is N and Q and W are C(H). In some embodiments, W is N and J and Q are C(H). In some embodiments, Q and J are N and W is C(H). In some embodiments, Q and W are N and J is C(H). In some embodiments, J and W are N and Q is C(H).

[0187] In some embodiments, X is C(H).

[0188] In some embodiments, X is N.

[0189] In some embodiments, Z is -CH2-.

[0190] In some embodiments, Z is C=O.

[0191] In some embodiments, each instance of R3is independently selected from halo,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2.

[0192] In some embodiments, each instance of R3is independently selected from –F, –Cl,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2.

[0193] In some embodiments, each instance of R3is independently selected from –F, –Cl, –Me, –Et, –iPr, –O-CH3, –NH2, –NH(CH3), or –N(CH3)2.

[0194] In some embodiments, each instance of R3is independently –F.

[0195] In some embodiments, each R4is independently selected from –Me, –Et, –F, – Cl and–OH.

[0196] In some embodiments, each R4is independently–Me.

[0197] In some embodiments, r is 0, 1, or 2.

[0198] In some embodiments, r is 0.

[0199] In some embodiments, r is 1.

[0200] In some embodiments, r is 2.

[0201] In some embodiments, s is 0, 1, or 2.

[0202] In some embodiments, s is 0.

[0203] In some embodiments, s is 1.

[0204] In some embodiments, s is 2.

[0205] In some embodiments, LBM isIn some

[0206] In some embodiments, LBM is selected from the group consisting of:.

[0207] In some embodiments, LBM isIn some.

[0208] In some embodiments, LBM is selected from the group consisting of:

[0209] In some embodiments, LBM isIn some embodiments, LBM is

[0210] In one aspect, provided is a compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein Ring A iswhereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; T is C(F) or N; Y is C(H) or N; R1is, independently, for each occurrence, –H or –D; and R2is, independently, for each occurrence, –H or –Me.

[0211] In some embodiments, Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

[0212] In some embodiments, Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

[0213] In some embodiments, T is C(F).

[0214] In some embodiments, T is N.

[0215] In some embodiments, Y is C(H).

[0216] In some embodiments, Y is N.

[0217] In some embodiments, each R1is independently –H.

[0218] In some embodiments, each R1is independently –D.

[0219] In some embodiments, each R2is independently –H.

[0220] In some embodiments, each R2is independently –Me.

[0221] In some embodiments, the compound is a compound of Formula I-A:

[0222] In some embodiments, the compound is a compound of Formula I-B:

[0223] In some embodiments, the compound is selected from the group consisting of:

[0224] In an embodiment of a compound of Formula A, Formula I, Formula I-A, or Formula I-B, the compound is selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof, or elsewhere in the specification and figures.

[0225] In an embodiment, provided herein is a composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0226] In an embodiment, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.

[0227] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted in Table 1 are mixtures of enantiomers at that center.

[0228] 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 1. Exemplary compoundsAlternative Embodiments

[0229] 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%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. Pharmaceutical Compositions

[0230] In an embodiment, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-A, or Formula I-B or a compound of Table 1), or a pharmaceutically acceptable salt thereof.

[0231] The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound provided herewith,and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0232] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions provided herewith include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d–α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α–, β–, and γ- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2 and 3 hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0233] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0234] In an embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0235] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-A, or Formula I-B or a compound of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use as a pharmaceutical or a medicament (e.g., a medicament for the treatment of a CDK2 or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof). In an embodiment, the disease is a CDK2 mediated disease. In an embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In an embodiment, the disease is a CDK2 and a CCNE (CCNE1 and / or CCNE2)-mediated disease. In an embodiment, the disease or disorder is a proliferating disease or disorder. In a further embodiment, the disease or disorder is a cancer. In an embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer(e.g., endometrial cancer), and breast cancer (e.g., triple negative breast cancer (TNBC), hormone-receptor positive (HR+) breast cancer, HER2 positive (HER2+) positive breast cancer).

[0236] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-A, or Formula I-B or a compound of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use in the treatment of a CDK2 or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof. In an embodiment, the disease is a CDK2 mediated disease. In an embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In an embodiment, the disease is a CDK2 and a CCNE (CCNE1 and / or CCNE2)-mediated disease. In an embodiment, the disease or disorder is a proliferating disease or disorder. In a further embodiment, the disease or disorder is a cancer. In an embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g. , endometrial cancer), and breast cancer (e.g. , triple negative breast cancer (TNBC), hormone-receptor positive (HR+) breast cancer, HER2 positive (HER2+) positive breast cancer).

[0237] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-A, or Formula I-B or a compound of Table 1, or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use in the manufacturing of a medicament (e.g., a medicament for the treatment of a CDK2 or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof). In an embodiment, the disease or disorder is a proliferating disease or disorder. In an embodiment, the disease is a CDK2 mediated disease. In an embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In an embodiment, the disease is a CDK2 and a CCNE (CCNE1 and / or CCNE2)-mediated disease. In a further embodiment, the disease or disorder is a cancer. In an embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple negative breast cancer (TNBC), hormone-receptor positive (HR+) breast cancer, HER2 positive (HER2+) positive breast cancer).

[0238] Generally, the compounds provided herein are administered in an effective amount (e.g., a therapeutically effective amount). The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0239] The pharmaceutical compositions provided herewith may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions provided herewith may contain any conventional nontoxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0240] The compositions for oral administration 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 prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0241] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0242] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the activecompound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their poly oxy ethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0243] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0244] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0245] The pharmaceutical compositions provided herewith may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound provided herewith with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0246] The pharmaceutical compositions provided herewith maybe administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0247] The above-described components for orally administrable, injectable or topically administrable, rectally administrable and nasally administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0248] The compounds described herein can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington ’s Pharmaceutical Sciences.

[0249] When the compositions provided herewith comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds provided herewith. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds provided herewith in a single composition.

[0250] Also provided is the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., compound of Formula A, Formula I, Formula I-A, or Formula I-B or a compound of Table 1).

[0251] The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0252] The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmuco sally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight, alternatively dosages between 1 mg and lOOO mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions provided herewith will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0253] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0254] Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination provided herewith may be administered, if necessary.Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long term basis upon any recurrence of disease symptoms.Methods of treatment

[0255] Compounds of the present disclosure can inhibit CDK2 and / or CCNE (CCNE1 and / or CCNE2) and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by CDK2 and / or CCNE (CCNE1 and / or CCNE2). In an embodiment, the disease pathology is wholly or partially, mediated by CDK2. In an embodiment, the disease pathology is wholly or partially, mediated by CCNE (CCNE1 and / or CCNE2). In an embodiment, the disease pathology is wholly or partially, mediated by CDK2 and CCNE (CCNE1 and / or CCNE2). Such diseases include cancer and other diseases with proliferation disorder.

[0256] In an embodiment, the compounds of Formula A, Formula I, Formula I-A, or Formula I-B inhibit both CDK2 and CCNE (CCNE1 and / or CCNE2). In an embodiment the compounds of Formula A, Formula I, Formula I-A, or Formula I-B inhibit CDK2 (e.g., selectively inhibit CDK2 over CCNE (CCNE1 and / or CCNE2)). In an embodiment the compounds of Formula A, Formula I, Formula I-A, or Formula I-B inhibit CCNE (CCNE1 and / or CCNE2) (e.g., selectively inhibit CCNE (CCNE1 and / or CCNE2) over CDK2).

[0257] In an embodiment, the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula A, Formula I, Formula I-A, or Formula I-B or a salt thereof such that growth of cancerous tumors is inhibited. A compound of Formula A, Formula I, Formula I-A, or Formula I-B, or a compound as recited in any of the claims and described herein, or a salt thereof, can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK2 kinase activity. These include, but are not limited to, disease (e.g., cancers) that are characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2) such as ovarian cancer, uterine carcinosarcoma and breast cancer and p27 inactivation such as breast cancer and melanomas. Accordingly, in an embodiment of the methods, the patient has been previously determined to have an amplification of the cyclin E (CCNE (CCNE1 and / or CCNE2)) gene and / or an expression level of CCNE (CCNE1 and / or CCNE2) in a biological sample obtained from the human subject that is higher than a control expression level of CCNE (CCNE1 and / or CCNE2). In some embodiments, the cancers are characterized by amplification or overexpression of CCNE1. Accordingly, in an embodiment of the methods, the patient has been previously determined to have an amplification of the cyclin El 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 compound of Formula A, Formula I, Formula I-A, orFormula I-B, or a compound as recited in any of the claims and described herein, or a salt thereof, can be used in conjunction with other agents or standard cancer treatments.

[0258] In an 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 compound of Formula A, Formula I, Formula I-A, or Formula I-B, or of a compound as recited in any of the claims and described herein, or of a salt thereof.

[0259] In an embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with CCNE (CCNE1 and / or CCNE2) 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 compound of Formula A, Formula I, Formula I-A, or Formula I-B, or of a compound as recited in any of the claims and described herein, or a salt or a stereoisomer thereof.

[0260] In an embodiment, provided herein is a method of inhibiting and / or degrading CDK2 and / or CCNE (CCNE1 and / or CCNE2), comprising contacting the CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof. In an embodiment, provided herein is a method of inhibiting and / or degrading CDK2, comprising contacting the CDK2 with a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, ora salt thereof. In an embodiment, provided herein is a method of inhibiting and / or degrading CCNE (CCNE1 and / or CCNE2), comprising contacting the CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof. In an embodiment, provided herein is a method of inhibiting and / or degrading CDK2 and CCNE (CCNE1 and / or CCNE2), comprising contacting the CDK2 and CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof.

[0261] In an embodiment, provided herein is a method of inhibiting and / or degrading CDK2 and / or CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof.

[0262] In an embodiment, provided herein is a method for treating cancer. The method includes administering to a patient (in need thereof), a therapeutically effective amount of acompound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof.

[0263] In an embodiment, the cancer is characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2). In an embodiment, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2).

[0264] In an embodiment, provided herein is a method of treating a disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof. In an embodiment, 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 compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof. In an embodiment, provided herein is a method of treating a disease or disorder associated with CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof. In an embodiment, provided herein is a method of treating a disease or disorder associated with CDK2 and CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-A, or Formula I-B, a compound as recited in any of the claims and described herein, or a salt thereof.

[0265] In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is associated with an amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1 . In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31): 12968-12973) K-Ras mutant lung cancers (see Hu, S., et al., Mol Cancer Ther, 2015. 14(11): 2576-85, and cancers with FBW7 mutation and CCNE (CCNE1 and / or CCNE2) overexpression (see Takada, et al., Cancer Res, 2017.77(18): 4881-4893).

[0266] In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serouscystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0267] In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

[0268] In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is an adenocarcinoma, carcinoma, or cystadenocarcinoma. In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0269] In an embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is a cancer.

[0270] In an embodiment, the cancer is characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2). In an embodiment, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2).

[0271] In an embodiment of any of the embodiments described herein, the CCNE is CCNE1. In an embodiment, the CCNE is CCNE2. In an embodiment, the CCNE is CCNE1 and CCNE2.

[0272] In and embodiment, the cancer has primary or acquired resistance to CDK4 / 6 inhibition (e.g., is resistant to treatment with CDK4 / 6 inhibitors).

[0273] In an embodiment, 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 an embodiment, the breast cancer is advanced or metastatic breast cancer.

[0274] Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0275] In an embodiment, the compounds of the invention 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.Selected embodiments Embodiment 1. A compound of Formula A,or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; Y is C(H) or N; LBM is selected from the group consisting of,Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and at least one of Q, J, and W is N; X is C(H) or N; Z is -CH2- or C=O; R1is, independently, for each occurrence, –H or –D; R2is, independently, for each occurrence, –H or –Me; each instance of R3is independently selected from –D, halo, –OH,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2; each instance of R4is independently selected from –D, halo, –OH, and –C1-6alkyl; each instance of Rais independently selected from –H and –C1-6alkyl. r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene. Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene. Embodiment 4. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is C(H).Embodiment 5. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is N. Embodiment 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –H. Embodiment 7. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –D. Embodiment 8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –H. Embodiment 9. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –Me. Embodiment 10. The compound of any one of embodiments 1-9, wherein Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and least two of Q, J, or W is N. Embodiment 11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein X is C(H). Embodiment 12. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein X is N. Embodiment 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-. Embodiment 14. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is C=O. Embodiment 15. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from halo,– C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2. Embodiment 16. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from –F, – Cl,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2.Embodiment 17. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from –F, – Cl, –Me, –Et, –iPr, –O-CH3, –NH2, –NH(CH3), or –N(CH3)2. Embodiment 18. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently –F. Embodiment 19. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from –Me, –Et, –F, –Cl and–OH. Embodiment 20. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein each R4is independently–Me. Embodiment 21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2. Embodiment 22. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 0. Embodiment 23. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 1. Embodiment 24. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 2. Embodiment 25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, or 2. Embodiment 26. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 0. Embodiment 27. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 1. Embodiment 28. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 2.Embodiment 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein LBM is selected from the group consisting of:. Embodiment 30. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein LBM is selected from the group consisting of:. Embodiment 31. A compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; T is C(F) or N; Y is C(H) or N;R1is, independently, for each occurrence, –H or –D; and R2is, independently, for each occurrence, –H or –Me. Embodiment 32. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond tothe sulfonyl and “*” indicates the location of a bond to the methylene. Embodiment 33. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond tothe sulfonyl and “*” indicates the location of a bond to the methylene. Embodiment 34. The compound of any one of embodiments 31-33, or a pharmaceutically acceptable salt thereof, wherein T is C(F). Embodiment 35. The compound of any one of embodiments 31-33, or a pharmaceutically acceptable salt thereof, wherein T is N. Embodiment 36. The compound of any one of embodiments 31-35, or a pharmaceutically acceptable salt thereof, wherein Y is C(H). Embodiment 37. The compound of any one of embodiments 31-35, or a pharmaceutically acceptable salt thereof, wherein Y is N. Embodiment 38. The compound of any one of embodiments 31-37, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –H. Embodiment 39. The compound of any one of embodiments 31-37, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –D. Embodiment 40. The compound of any one of embodiments 31-39, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –H. Embodiment 41. The compound of any one of embodiments 31-39, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –Me.Embodiment 42. The compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-A:Embodiment 43. The compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B:Embodiment 44. The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:,Embodiment 45. A pharmaceutical composition, comprising a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.Embodiment 46. A method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 46.Embodiment 47. The method of embodiment 46, wherein the inhibiting of CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by atleast 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.Embodiment 48. The method of embodiment 46, wherein the inhibiting of CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by atleast 1 -fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.Embodiment 49. A method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 50. The method of embodiment 49, wherein the inhibiting of CDK2 signaling comprises reducing the signaling activity of CDK2 by at least 1%, 2%, 5%,7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.Embodiment 51. The method of embodiment 49, wherein the inhibiting of CDK2 signaling comprises reducing the signaling activity of CDK2 by at least 1 -fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.Embodiment 52. A method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 53. The method of embodiment 52, wherein the inhibiting of CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CCNE (CCNE1 and / or CCNE2) by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.Embodiment 54. The method of embodiment 52, wherein the inhibiting CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CCNE (CCNE1 and / or CCNE2) by at least 1 -fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30- fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.Embodiment 55. A method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 56. The method of embodiment 55, wherein the inhibiting of CDK2 and CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by atleast 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.Embodiment 57. The method of embodiment 55, wherein the inhibiting of CDK2 and CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by atleast 1 -fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.Embodiment 58. A method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)- mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of embodiments 1 -44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 59. The method of embodiment 58, wherein the CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.Embodiment 60. A method of treating a CDK2-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 61. The method of embodiment 60, wherein the CDK2 -mediated disorder is cancer.Embodiment 62. A method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 63. The method of embodiment 62, wherein the CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.Embodiment 64. A method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2)- mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of embodiments 1 -44, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 45.Embodiment 65. The method of embodiment 64, wherein the CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.Embodiment 66. The method of any one of embodiments 59, 63, or 65, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple negative breast cancer (TNBC), hormone -receptor positive (HR+) breast cancer, HER2 positive (HER2+) positive breast cancer).Embodiment 67. The method of any one of embodiments 59, 63, 65, or 66, wherein the cancer is resistant to treatment with CDK 4 / 6 inhibitors.Examples

[0276] In order that the invention(s) described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Abbreviations General anhy. anhydrous aq. aqueous satd. saturated min(s) minute(s) hr(s) hour(s) mL milliliter mmol millimole(s) mol mole(s) MS mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography HPLC high-performance liquid chromatography Me methyl i-Pr iso-propyl t-Bu tert-butyl Ph phenyl Et ethyl Bz benzoyl Spectrum Hzhertz δ chemical shift J coupling constant s singlet d doublet t triplet q quartetm multiplet br broad qd quartet of doublets dquin doublet of quintets dd doublet of doublets dt doublet of triplets Solvents and Reagents (i-PrO)4Ti titanium tetraisopropoxide 9-BBN 9-borabicyclo[3.3.1]nonane AcCl acetyl chloride ACN Acetonitrile AcOH acetic acid ADDP 1,1′-(azodicarbonyl)dipiperidine AlaOH alanine BHT 2,6-di-t-butyl-4-methylphenoxide BINAP 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl Boc t-butoxycarbonyl BSA Bovine Serum Albumin Bu butyl BzCl benzoyl chloride CHCl3chloroform CsF cesium fluoride DAST Diethylaminosulfurtrifluoride DCC dicyclohexylcarbodiimide DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene DTT DL-DithiothreitolEt2O diethyl ether Et3N triethylamine EtMgBr ethylmagnesium bromide EtOAc ethyl acetate EtOAc ethyl acetate EtOH ethyl alcohol H2SO4sulfuric acid HCl hydrochloric acid i-PrMgCl Isopropylmagnesium chloride K2CO3potassium carbonate KOH potassium hydroxide LAH Lithium Aluminium Hydride LDA lithium diisopropylamide LDH Lactate Dehydrogenase LiHMDS lithium hexamethyldisilylamide LiOH.H2O lithium hydroxide hydrates MAD methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide) MeCN acetonitrile MeCN acetonitrile MeOH methyl alcohol MTBE methyl tert-butyl ether Na2CO3sodium carbonate Na2S2O3sodium thiosulfate Na2SO4sodium sulfate Na2SO4sodium sulfate NaBH4sodium borohydride NaBH4sodium borohydride NADH β-Nicotinamide adenine dinucleotide, reduced NaHCO3sodium bicarbonate NaOH sodium hydroxide NBS N-bromosuccinimide NH4Cl ammonium chloride PCC pyridinium chlorochromatePd(t-Bu3P)2bis(tri-tert-butylphosphine)palladium(0) PE petroleum ether PEP Phospho(enol)pyruvic acid Py pyridine RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl TBAF tetra-n-butylammonium fluoride TBS t-butyldimethylsilyl TBSCl tert-Butyl(chloro)dimethylsilane t-BuOK potassium tert-butoxide tBuXPhos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Ti(OiPr)4tetraisopropoxytitanium TMS trimethylsilyl TMSCF3(Trifluoromethyl)trimethylsilane Ts p-toluenesulfonyl Xphos Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane Chemistry examples

[0277] The exemplary compounds described herein were prepared according to synthetic procedures and methods known to those skilled in the art. The structural and physicochemical data for exemplary compounds 1 to 12 are provided in Table 2.

[0278] Example 1: 1-(7-fluoro-6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A. Ethyl 3-[(4-amino-3-fluorophenyl)sulfanyl]benzoate (1b). To a solution of 1a (3 g, 17.835 mmol, 1 equiv) and 2-fluoro-4-iodoaniline (4.44 g, 18.727 mmol, 1.05 equiv) in ethanol (50 mL) were added potassium phosphate tribasic (9.46 g, 44.588 mmol, 2.5 equiv) and Pd(PPh3)4(2.06 g, 1.784 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%formic acid water in acetonitrile, 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1b (1.5 g, 28.87%) as a brown solid. LCMS (ESI, m / z): [M+H]+292.1. Step B. Ethyl 3-((4-amino-3-fluorophenyl)sulfonyl)benzoate (1c). To a stirred solution of 1b (1.5 g, 5.149 mmol, 1 equiv) in anhydrous dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.67 g, 15.447 mmol, 3 equiv) at 0 °C and stirred for 1 h. Desired product could be detected by LCMS. The reaction was quenched with Na2SO3aqueous at 0 °C. The aqueous layer was extracted with dichloromethane (2x50 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 3) to afford 1c (1.5 g, 90.10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+324.0. Step C. ethyl 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzoate (1d). To a solution of 1c (1.5 g, 4.654 mmol, 1 equiv) and CI-1 (2207.27 mg, 5.585 mmol, 1.2 equiv) in 1,4-dioxane (0.4 mL) were added cesium carbonate (4548.71 mg, 13.962 mmol, 3 equiv) and RuPhos (434.32 mg, 0.931 mmol, 0.2 equiv), Pd 2(dba)3 (426.15 mg, 0.465 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 4) to afford 1d (2.5 g, 84.24%) as a yellow solid. LCMS (ESI, m / z): [M+H]+638.2. Step D. (3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)methanol (1e). To a stirred solution of 1d (1 g, 1.568 mmol, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was added diisobutyl aluminium hydride (1 mol / L in n-hexane) (6 mL, 6 mmol, 3.8 equiv) at 0 °C and stirred for 1h. Desired product could be detected by LCMS. The reaction was quenched with Anhydrous sodium sulfate.10water at 0 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 2) to afford 1e (750 mg, 80.29%) as a white solid. LCMS (ESI, m / z): [M+H]+596.2 Step E.3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f). To a stirred solution of 1e (350 mg, 58.53%) in anhydrous dichloromethane (15.00 mL) was added manganese dioxide (525.43 mg, 6.042 mmol, 6 equiv) at 25 °C and stirred for 16 h. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2 / 3) to afford 1f (350 mg, 58.53%) as a white solid. LCMS (ESI, m / z): [M+H]+594.2Step F.1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)piperidin-4- yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1g) To a stirred solution of 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f, 130 mg, 0.219 mmol, 1 equiv) ,1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinane-2,4- dione (CI-10, 86.03 mg, 0.263 mmol, 1.2 equiv), acetic acid (3.95 mg, 0.066 mmol, 0.3 equiv) in anhydrous N,N-dimethylformamide (3 mL) and stirred for 1h at 40 °C. Then sodium cyanoborohydride (41.28 mg, 0.657 mmol, 3 equiv) was added and the mixtu re was stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (1g, 100 mg, 45.43%) as a colorless oil. LCMS (ESI, m / z): [M+H]+923.4 Step G.1-(7-fluoro-6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 1) To a stirred solution of 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (1g, 95 mg, 0.110 mmol, 1 equiv) in anhydrous dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C and stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% ammonium bicarbonate in acetonitrile, 40% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 1-(7-fluoro-6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4- yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 1, 7.3 mg, 7.73%). LCMS (ESI, m / z): [M+H]+851.3

[0279] Example 2: 1-(6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A. Ethyl 3-[(4-amino-3-fluorophenyl)sulfanyl]benzoate (1b). To a solution of 1a (3 g, 17.835 mmol, 1 equiv) and 2-fluoro-4-iodoaniline (4.44 g, 18.727 mmol, 1.05 equiv) in ethanol (50 mL) were added potassium phosphate tribasic (9.46 g, 44.588 mmol, 2.5 equiv) and Pd(PPh3)4(2.06 g, 1.784 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%formic acid water in acetonitrile, 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1b (1.5 g, 28.87%) as a brown solid. LCMS (ESI, m / z): [M+H]+292.1.Step B. ethyl 3-((4-amino-3-fluorophenyl)sulfonyl)benzoate (1c). To a stirred solution of 1b (1.5 g, 5.149 mmol, 1 equiv) in anhydrous dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.67 g, 15.447 mmol, 3 equiv) at 0 °C and stirred for 1 h. Desired product could be detected by LCMS. The reaction was quenched with Na2SO3aqueous at 0 °C. The aqueous layer was extracted with dichloromethane (2x50 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 3) to afford 1c (1.5 g, 90.10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+324.0. Step C. ethyl 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzoate (1d). To a solution of 1c (1.5 g, 4.654 mmol, 1 equiv) and CI-1 (2207.27 mg, 5.585 mmol, 1.2 equiv) in 1,4-dioxane (0.4 mL) were added cesium carbonate (4548.71 mg, 13.962 mmol, 3 equiv) and RuPhos (434.32 mg, 0.931 mmol, 0.2 equiv), Pd2(dba)3(426.15 mg, 0.465 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 4) to afford 1d (2.5 g, 84.24%) as a yellow solid. LCMS (ESI, m / z): [M+H]+638.2. Step D. (3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)methanol (1e). To a stirred solution of 1d (1 g, 1.568 mmol, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was added diisobutyl aluminium hydride (1 mol / L in n-hexane) (6 mL, 6 mmol, 3.8 equiv) at 0 °C and stirred for 1h. Desired product could be detected by LCMS. The reaction was quenched with Anhydrous sodium sulfate.10water at 0 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 2) to afford 1e (750 mg, 80.29%) as a white solid. LCMS (ESI, m / z): [M+H]+596.2 Step E.3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f). To a stirred solution of 1e (350 mg, 58.53%) in anhydrous dichloromethane (15.00 mL) was added manganese dioxide (525.43 mg, 6.042 mmol, 6 equiv) at 25 °C and stirred for 16 h. Desired product could be detected by LCMS. The resulting mixture was filtered and thefilter cake was washed with dichloromethane (3x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2 / 3) to afford 1f (350 mg, 58.53%) as a white solid. LCMS (ESI, m / z): [M+H]+594.2 Step F.1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)piperidin-4- yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2g) To a stirred solution of 3-[4-({7-[1-(1-ethoxyethyl)pyrazol-4-yl]-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl}amino)-3-fluorobenzenesulfonyl]benzaldehyde (1f, 130 mg, 0.219 mmol, 1 equiv) ,1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinane-2,4- dione (CI-10, 86.03 mg, 0.263 mmol, 1.2 equiv), acetic acid (3.95 mg, 0.066 mmol, 0.3 equiv) in anhydrous N,N-dimethylformamide (3 mL) and stirred for 1h at 40 °C. Then sodium cyanoborohydride (41.28 mg, 0.657 mmol, 3 equiv) was added and the mixture was stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (2g, 100 mg, 45.43%) as a colorless oil. LCMS (ESI, m / z): [M+H]+905.4 Step G.1-(6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 2) To a stirred solution of 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (2g, 95 mg, 0.110 mmol, 1 equiv) in anhydrous dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C and stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% ammonium bicarbonate in acetonitrile, 40% to 60% gradient in 30 min;detector, UV 254 nm. This resulted in 1-(6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 2, 7.3 mg, 7.73%). LCMS (ESI, m / z): [M+H]+833.2

[0280] Example 3: 1-(6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A. Ethyl 3-[(4-amino-3-fluorophenyl)sulfanyl]benzoate (1b). To a solution of 1a (3 g, 17.835 mmol, 1 equiv) and 2-fluoro-4-iodoaniline (4.44 g, 18.727 mmol, 1.05 equiv) in ethanol (50 mL) were added potassium phosphate tribasic (9.46 g, 44.588 mmol, 2.5 equiv) and Pd(PPh3)4(2.06 g, 1.784 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%formic acid water in acetonitrile, 40%to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1b (1.5 g, 28.87%) as a brown solid. LCMS (ESI, m / z): [M+H]+292.1. Step B. ethyl 3-((4-amino-3-fluorophenyl)sulfonyl)benzoate (6c). To a stirred solution of 1b (1.5 g, 5.149 mmol, 1 equiv) in anhydrous dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.67 g, 15.447 mmol, 3 equiv) at 0 °C and stirred for 1 h. Desired product could be detected by LCMS. The reaction was quenched with Na2SO3aqueous at 0 °C. The aqueous layer was extracted with dichloromethane (2x50 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 3) to afford 1c (1.5 g, 90.10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+324.0. Step C. ethyl 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzoate (1d). To a solution of 1c (1.5 g, 4.654 mmol, 1 equiv) and CI-1 (2207.27 mg, 5.585 mmol, 1.2 equiv) in 1,4-dioxane (0.4 mL) were added cesium carbonate (4548.71 mg, 13.962 mmol, 3 equiv) and RuPhos (434.32 mg, 0.931 mmol, 0.2 equiv), Pd2(dba)3(426.15 mg, 0.465 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 4) to afford 1d (2.5 g, 84.24%) as a yellow solid. LCMS (ESI, m / z): [M+H]+638.2. Step D. (3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)methanol (1e). To a stirred solution of 1d (1 g, 1.568 mmol, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was added diisobutyl aluminium hydride (1 mol / L in n-hexane) (6 mL, 6 mmol, 3.8 equiv) at 0 °C and stirred for 1h. Desired product could be detected by LCMS. The reaction was quenched with Anhydrous sodium sulfate.10water at 0 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 2) to afford 1e (750 mg, 80.29%) as a white solid. LCMS (ESI, m / z): [M+H]+596.2Step E.3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f). To a stirred solution of 1e (350 mg, 58.53%) in anhydrous dichloromethane (15.00 mL) was added manganese dioxide (525.43 mg, 6.042 mmol, 6 equiv) at 25 °C and stirred for 16 h. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2 / 3) to afford 1f (350 mg, 58.53%) as a white solid. LCMS (ESI, m / z): [M+H]+594.2 Step F.1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)piperidin-4- yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (3g) To a stirred solution of 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f, 130 mg, 0.219 mmol, 1 equiv) ,1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinane-2,4- dione (CI-10, 86.03 mg, 0.263 mmol, 1.2 equiv), acetic acid (3.95 mg, 0.066 mmol, 0.3 equiv) in anhydrous N,N-dimethylformamide (3 mL) and stirred for 1h at 40 °C. Then sodium cyanoborohydride (41.28 mg, 0.657 mmol, 3 equiv) was added and the mixtu re was stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (3g, 100 mg, 45.43%) as a colorless oil. LCMS (ESI, m / z): [M+H]+923.5 Step G.1-(7-fluoro-6-(1-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 3) To a stirred solution of 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (3g, 95 mg, 0.110 mmol, 1 equiv) in anhydrous dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C and stirred for 1H.The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% ammonium bicarbonate in acetonitrile, 40% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 1-(7-fluoro-6-(1-((3-((3-fluoro-4-((8-isopropoxy-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 3, 7.3 mg, 7.73%). LCMS (ESI, m / z): [M+H]+853.3

[0281] Example 4: 1-(6-(1-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A. Ethyl 3-[(4-amino-3-fluorophenyl)sulfanyl]benzoate (1b). To a solution of 1a (3 g, 17.835 mmol, 1 equiv) and 2-fluoro-4-iodoaniline (4.44 g, 18.727 mmol, 1.05 equiv) in ethanol (50 mL) were added potassium phosphate tribasic(9.46 g, 44.588 mmol, 2.5 equiv) and Pd(PPh3)4(2.06 g, 1.784 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%formic acid water in acetonitrile, 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1b (1.5 g, 28.87%) as a brown solid. LCMS (ESI, m / z): [M+H]+292.1. Step B. ethyl 3-((4-amino-3-fluorophenyl)sulfonyl)benzoate (1c). To a stirred solution of 1b (1.5 g, 5.149 mmol, 1 equiv) in anhydrous dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.67 g, 15.447 mmol, 3 equiv) at 0 °C and stirred for 1 h. Desired product could be detected by LCMS. The reaction was quenched with Na2SO3aqueous at 0 °C. The aqueous layer was extracted with dichloromethane (2x50 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 3) to afford 1c (1.5 g, 90.10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+324.0. Step C. ethyl 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzoate (1d). To a solution of 1c (1.5 g, 4.654 mmol, 1 equiv) and CI-1 (2207.27 mg, 5.585 mmol, 1.2 equiv) in 1,4-dioxane (0.4 mL) were added cesium carbonate (4548.71 mg, 13.962 mmol, 3 equiv) and RuPhos (434.32 mg, 0.931 mmol, 0.2 equiv), Pd2(dba)3(426.15 mg, 0.465 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 90 °C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 4) to afford 1d (2.5 g, 84.24%) as a yellow solid. LCMS (ESI, m / z): [M+H]+638.2. Step D. (3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)methanol (1e). To a stirred solution of 1d (1 g, 1.568 mmol, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was added diisobutyl aluminium hydride (1 mol / L in n-hexane) (6 mL, 6 mmol, 3.8 equiv) at 0 °C and stirred for 1h. Desired product could be detected by LCMS. The reaction was quenched with Anhydrous sodium sulfate.10water at 0 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure The residue was purified bysilica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 2) to afford 1e (750 mg, 80.29%) as a white solid. LCMS (ESI, m / z): [M+H]+596.2 Step E.3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f). To a stirred solution of 1e (350 mg, 58.53%) in anhydrous dichloromethane (15.00 mL) was added manganese dioxide (525.43 mg, 6.042 mmol, 6 equiv) at 25 °C and stirred for 16 h. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2 / 3) to afford 1f (350 mg, 58.53%) as a white solid. LCMS (ESI, m / z): [M+H]+594.2 Step F.1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)piperidin-4- yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (4g) To a stirred solution of 3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzaldehyde (1f, 130 mg, 0.219 mmol, 1 equiv) ,1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinane-2,4- dione (CI-10, 86.03 mg, 0.263 mmol, 1.2 equiv), acetic acid (3.95 mg, 0.066 mmol, 0.3 equiv) in anhydrous N,N-dimethylformamide (3 mL) and stirred for 1h at 40 °C. Then sodium cyanoborohydride (41.28 mg, 0.657 mmol, 3 equiv) was added and the mixtu re was stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (4g, 100 mg, 45.43%) as a colorless oil. LCMS (ESI, m / z): [M+H]+907.0 Step G.1-(6-(1-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)piperidin- 4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 4) To a stirred solution of 1-(6-(1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (4g, 95 mg, 0.110 mmol, 1 equiv) in anhydrous dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C and stirred for 1H. The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% ammonium bicarbonate in acetonitrile, 40% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 1-(6-(1-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl- d2)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (Example 4, 7.3 mg, 7.73%). LCMS (ESI, m / z): [M+H]+836.9

[0282] Example 5: 1-(6-{4-[(1S)-1-[3-(3-fluoro-4-{[8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]amino}benzenesulfonyl)phenyl]ethyl]piperazin-1- yl}-1-methylindazol-3-yl)-1,3-diazinane-2,4-dioneStep A.1-(3-((4-amino-3-fluorophenyl)thio)phenyl)ethan-1-one (5b). To a stirred mixture of 5a (7 g, 28.450 mmol, 1 equiv) and 4-amino-3- fluorobenzenethiol (4.89 g, 34.140 mmol, 1.2 equiv) in 2,2,2-trifluoroethanol (70 mL) was added Pd(PPh3)4(3.29 g, 2.845 mmol, 0.1 equiv) and potassium phosphate tribasic (9.06 g, 42.675 mmol, 1.5 equiv) . The resulting mixture was stirred for 1 h at 90 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:8) to afford 5b (7.1 g, 91.68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+262.3. Step B.1-(3-((4-amino-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5c). To a stirred mixture of 5b (6 g, 22.961 mmol, 1 equiv) in dichloromethane (60 mL) was added m-chloroperoxybenzoic acid (13.98 g, 68.883 mmol, 3 equiv, 85%) . The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with sodium thiosulfate at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(10:1) to afford 5c (5.2 g, 75.13%) as a white solid. LCMS (ESI, m / z): [M+H]+294.3. Step C.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5d). To a stirred mixture of 5c (3.56 g, 12.144 mmol, 1.2 equiv) and CI-1 (4 g, 10.120 mmol, 1.00 equiv) in dioxane (40 mL) was added Pd2(dba)3(0.93 g, 1.012 mmol, 0.1 equiv) and RuPhos (0.47 g, 1.012 mmol, 0.1 equiv) and cesium carbonate (6.59 g, 20.240 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 100 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:1) to afford 5d (7.9 g, 80.93%) as a white solid. LCMS (ESI, m / z): [M+H]+608.7. Step D.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-ol (5e). To a stirred mixture of 5d (6 g, 9.874 mmol, 1 equiv) in ethanol (60 mL) was added sodium borohydride (0.45 g, 11.849 mmol, 1.2 equiv) in portions at 0 °C. Theresulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 5e (4.3 g, 60.29%) as a colorless oil. LCMS (ESI, m / z): [M+H]+610.7. Step E.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f). To a stirred mixture of 5e (1 g, 1.640 mmol, 1 equiv) in dichloromethane (10 mL) was added trimethylamine (0.66 g, 6.560 mmol, 4 equiv) and methanesulfonic anhydride (0.57 g, 3.280 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5f (1 g, NaN) as a white solid. LCMS (ESI, m / z): [M+H]+688.8. Step F.1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (5g) To a stirred mixture of 1-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]-1,3-diazinane-2,4- dione hydrocholoride (CI-10, 47.75 mg, 0.145 mmol, 1 equiv) and potassium carbonate (120.57 mg, 0.870 mmol, 6 equiv) in acetonitrile (2 mL) was added 1-(3-((4-((7-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f, 100 mg, 0.145 mmol, 1 equiv) and potassium iodide (24.14 mg, 0.145 mmol, 1 equiv) . The resulting mixture was stirred for 1 h at 60 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with methanol / dichloromethane (1:20) to afford 1-(6-(4-(3-((4-((7- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (5g, 80 mg, 53.25%) as a white solid. LCMS (ES, m / z): [M+H]+936.1. Step G.1-(6-(4-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (Example 5) To a stirred solution of 1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (50 mg, 0.054 mmol, 1 equiv) in acetonitrile (5 mL) was added HCl (gas) in 1,4-dioxane (1 mL) . The resulting mixture was stirred for 0.5 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase Combi-Flash, eluted with acetonitrile: water (0.5% ammonium bicarbonate) = 30% - 60%. This resulted in 1-(6-(4-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1- yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 5, 10 mg, 21.53%). LCMS (ES, m / z): [M+H]+864.0.

[0283] Example 6: 1-(6-{4-[(1S)-1-[3-(3-fluoro-4-{[8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]amino}benzenesulfonyl)phenyl]ethyl]piperazin-1- yl}-1-methylindazol-3-yl)-1,3-diazinane-2,4-dioneStep A.1-(3-((4-amino-3-fluorophenyl)thio)phenyl)ethan-1-one (5b). To a stirred mixture of 5a (7 g, 28.450 mmol, 1 equiv) and 4-amino-3- fluorobenzenethiol (4.89 g, 34.140 mmol, 1.2 equiv) in 2,2,2-trifluoroethanol (70 mL) was added Pd(PPh3)4(3.29 g, 2.845 mmol, 0.1 equiv) and potassium phosphate tribasic (9.06 g, 42.675 mmol, 1.5 equiv) . The resulting mixture was stirred for 1 h at 90 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:8) to afford 5b (7.1 g, 91.68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+262.1. Step B.1-(3-((4-amino-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5c). To a stirred mixture of 5b (6 g, 22.961 mmol, 1 equiv) in dichloromethane (60 mL) was added m-chloroperoxybenzoic acid (13.98 g, 68.883 mmol, 3 equiv, 85%) . The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with sodium thiosulfate at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(10:1) to afford 5c (5.2 g, 75.13%) as a white solid. LCMS (ESI, m / z): [M+H]+294.1. Step C.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5d). To a stirred mixture of 5c (3.56 g, 12.144 mmol, 1.2 equiv) and CI-1 (4 g, 10.120 mmol, 1.00 equiv) in dioxane (40 mL) was added Pd2(dba)3(0.93 g, 1.012 mmol, 0.1 equiv) and RuPhos (0.47 g, 1.012 mmol, 0.1 equiv) and cesium carbonate (6.59 g, 20.240 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 100 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:1) to afford 5d (7.9 g, 80.93%) as a white solid. LCMS (ESI, m / z): [M+H]+608.2. Step D.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-ol (5e). To a stirred mixture of 5d (6 g, 9.874 mmol, 1 equiv) in ethanol (60 mL) was added sodium borohydride (0.45 g, 11.849 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 5e (4.3 g, 60.29%) as a colorless oil. LCMS (ESI, m / z): [M+H]+610.2. Step E.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f). To a stirred mixture of 5e (1 g, 1.640 mmol, 1 equiv) in dichloromethane (10 mL) was added trimethylamine (0.66 g, 6.560 mmol, 4 equiv) and methanesulfonic anhydride (0.57 g, 3.280 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with dichloromethane. The combined organic layerswere dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5f (1 g, NaN) as a white solid. LCMS (ESI, m / z): [M+H]+688.2. Step F.1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (6g) To a stirred mixture of 1-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]-1,3-diazinane-2,4- dione hydrocholoride (CI-10, 47.75 mg, 0.145 mmol, 1 equiv) and potassium carbonate (120.57 mg, 0.870 mmol, 6 equiv) in acetonitrile (2 mL) was added 1-(3-((4-((7-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f, 100 mg, 0.145 mmol, 1 equiv) and potassium iodide (24.14 mg, 0.145 mmol, 1 equiv) . The resulting mixture was stirred for 1 h at 60 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with methanol / dichloromethane (1:20) to afford 1-(6-(4-(3-((4-((7- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-7-fluoro-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (6g, 80 mg, 53.25%) as a white solid. LCMS (ES, m / z): [M+H]+952.4. Step G.1-(7-fluoro-6-(4-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 6) To a stirred solution of 1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (50 mg, 0.054 mmol, 1 equiv) in acetonitrile (5 mL) was added HCl (gas) in 1,4- dioxane (1 mL) . The resulting mixture was stirred for 0.5 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed - phase Combi-Flash, eluted with acetonitrile: water (0.5% ammonium bicarbonate) = 30% - 60%. This resulted in 1-(7-fluoro-6-(4-(3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 6, 10 mg, 21.53%). LCMS (ES, m / z): [M+H]+880.3.

[0284] Example 7: 1-(6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dioneStep A.1-(3-((4-amino-3-fluorophenyl)thio)phenyl)ethan-1-one (5b). To a stirred mixture of 5a (7 g, 28.450 mmol, 1 equiv) and 4-amino-3- fluorobenzenethiol (4.89 g, 34.140 mmol, 1.2 equiv) in 2,2,2-trifluoroethanol (70 mL) was added Pd(PPh3)4(3.29 g, 2.845 mmol, 0.1 equiv) and potassium phosphate tribasic (9.06 g, 42.675 mmol, 1.5 equiv) . The resulting mixture was stirred for 1 h at 90 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:8) to afford 5b (7.1 g, 91.68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+262.1.Step B.1-(3-((4-amino-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5c). To a stirred mixture of 5b (6 g, 22.961 mmol, 1 equiv) in dichloromethane (60 mL) was added m-chloroperoxybenzoic acid (13.98 g, 68.883 mmol, 3 equiv, 85%) . The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with sodium thiosulfate at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(10:1) to afford 5c (5.2 g, 75.13%) as a white solid. LCMS (ESI, m / z): [M+H]+294.1. Step C.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5d). To a stirred mixture of 5c (3.56 g, 12.144 mmol, 1.2 equiv) and CI-1 (4 g, 10.120 mmol, 1.00 equiv) in dioxane (40 mL) was added Pd2(dba)3(0.93 g, 1.012 mmol, 0.1 equiv) and RuPhos (0.47 g, 1.012 mmol, 0.1 equiv) and cesium carbonate (6.59 g, 20.240 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 100 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:1) to afford 5d (7.9 g, 80.93%) as a white solid. LCMS (ESI, m / z): [M+H]+608.2. Step D.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-ol (5e). To a stirred mixture of 5d (6 g, 9.874 mmol, 1 equiv) in ethanol (60 mL) was added sodium borohydride (0.45 g, 11.849 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 5e (4.3 g, 60.29%) as a colorless oil. LCMS (ESI, m / z): [M+H]+610.2.Step E.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f). To a stirred mixture of 5e (1 g, 1.640 mmol, 1 equiv) in dichloromethane (10 mL) was added trimethylamine (0.66 g, 6.560 mmol, 4 equiv) and methanesulfonic anhydride (0.57 g, 3.280 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5f (1 g, NaN) as a white solid. LCMS (ESI, m / z): [M+H]+688.2. Step F.1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (5g) To a stirred mixture of 1-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]-1,3-diazinane-2,4- dione hydrocholoride (CI-10, 47.75 mg, 0.145 mmol, 1 equiv) and potassium carbonate (120.57 mg, 0.870 mmol, 6 equiv) in acetonitrile (2 mL) was added 1-(3-((4-((7-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f, 100 mg, 0.145 mmol, 1 equiv) and potassium iodide (24.14 mg, 0.145 mmol, 1 equiv) . The resulting mixture was stirred for 1 h at 60 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with methanol / dichloromethane (1:20) to afford 1-(6-(4-(3-((4-((7- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (5g, 80 mg, 53.25%) as a white solid. LCMS (ES, m / z): [M+H]+906.4. Step G.1-(6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (Example 7) To a stirred solution of 1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (50 mg, 0.054 mmol, 1 equiv) in acetonitrile (5 mL) was added HCl (gas) in 1,4-dioxane (1 mL) . The resulting mixture was stirred for 0.5 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase Combi-Flash, eluted with acetonitrile: water (0.5% ammonium bicarbonate) = 30% - 60%. This resulted in 1-(6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (Example 7, 10 mg, 21.53%). LCMS (ES, m / z): [M+H]+848.3.

[0285] Example 8: 1-(7-fluoro-6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A.1-(3-((4-amino-3-fluorophenyl)thio)phenyl)ethan-1-one (5b). To a stirred mixture of 5a (7 g, 28.450 mmol, 1 equiv) and 4-amino-3- fluorobenzenethiol (4.89 g, 34.140 mmol, 1.2 equiv) in 2,2,2-trifluoroethanol (70 mL) was added Pd(PPh3)4(3.29 g, 2.845 mmol, 0.1 equiv) and potassium phosphate tribasic (9.06 g, 42.675 mmol, 1.5 equiv) . The resulting mixture was stirred for 1 h at 90 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:8) to afford 5b (7.1 g, 91.68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+262.1. Step B.1-(3-((4-amino-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5c). To a stirred mixture of 5b (6 g, 22.961 mmol, 1 equiv) in dichloromethane (60 mL) was added m-chloroperoxybenzoic acid (13.98 g, 68.883 mmol, 3 equiv, 85%) . The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with sodium thiosulfate at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(10:1) to afford 5c (5.2 g, 75.13%) as a white solid. LCMS (ESI, m / z): [M+H]+294.1. Step C.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-one (5d). To a stirred mixture of 5c (3.56 g, 12.144 mmol, 1.2 equiv) and CI-1 (4 g, 10.120 mmol, 1.00 equiv) in dioxane (40 mL) was added Pd2(dba)3(0.93 g, 1.012 mmol, 0.1 equiv) and RuPhos (0.47 g, 1.012 mmol, 0.1 equiv) and cesium carbonate (6.59 g, 20.240 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 100 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate (1:1) to afford 5d (7.9 g, 80.93%) as a white solid. LCMS (ESI, m / z): [M+H]+608.2. Step D.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethan-1-ol (5e). To a stirred mixture of 5d (6 g, 9.874 mmol, 1 equiv) in ethanol (60 mL) was added sodium borohydride (0.45 g, 11.849 mmol, 1.2 equiv) in portions at 0 °C. Theresulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 5e (4.3 g, 60.29%) as a colorless oil. LCMS (ESI, m / z): [M+H]+610.2. Step E.1-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f). To a stirred mixture of 5e (1 g, 1.640 mmol, 1 equiv) in dichloromethane (10 mL) was added trimethylamine (0.66 g, 6.560 mmol, 4 equiv) and methanesulfonic anhydride (0.57 g, 3.280 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5f (1 g, NaN) as a white solid. LCMS (ESI, m / z): [M+H]+688.2. Step F.1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (6g) To a stirred mixture of 1-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]-1,3-diazinane-2,4- dione hydrocholoride (CI-10, 47.75 mg, 0.145 mmol, 1 equiv) and potassium carbonate (120.57 mg, 0.870 mmol, 6 equiv) in acetonitrile (2 mL) was added 1-(3-((4-((7-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3- fluorophenyl)sulfonyl)phenyl)ethyl methanesulfonate (5f, 100 mg, 0.145 mmol, 1 equiv) and potassium iodide (24.14 mg, 0.145 mmol, 1 equiv) . The resulting mixture was stirred for 1 h at 60 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with methanol / dichloromethane (1:20) to afford 1-(6-(4-(3-((4-((7- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3-dimethylpiperazin-1-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (6g, 80 mg, 53.25%) as a white solid. LCMS (ES, m / z): [M+H]+952.4. Step G.1-(7-fluoro-6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 8) To a stirred solution of 1-(6-(4-(3-((4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)benzyl)-3,3- dimethylpiperazin-1-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (50 mg, 0.054 mmol, 1 equiv) in acetonitrile (5 mL) was added HCl (gas) in 1,4- dioxane (1 mL) . The resulting mixture was stirred for 0.5 h at 0 °C. Desired product could be detected by LCMS. The reaction was quenched with triethylamine at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed - phase Combi-Flash, eluted with acetonitrile: water (0.5% ammonium bicarbonate) = 30% - 60%. This resulted in 1-(7-fluoro-6-(4-((3-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)phenyl)methyl-d2)-3,3- dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 8, 10 mg, 21.53%). LCMS (ES, m / z): [M+H]+882.3.

[0286] Example 9: Rel-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl)piperidin- 4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A.1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4- b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (9b). A solution of 9a (471.49 mg, 1.856 mmol, 2 equiv), potassium acetate (182.22 mg, 1.856 mmol, 2 equiv) and Pd(dppf)Cl2(67.93 mg, 0.093 mmol, 0.1 equiv) in dioxane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was washed with 3x10 mL of water. The aqueous layer was extracted with ethyl acetate (3x100 mL). The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(5:1) to afford 9b (180 mg, 52.37%) as a white solid. LCMS (ESI, m / z): [M+H]+371.2. Step B. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9c).To a solution of tert-butyl 2,2-dimethyl-4-(trifluoromethanesulfonyloxy)-3,6- dihydropyridine-1-carboxylate (400 mg, 1.113 mmol, 1 equiv) and 9b (494.51 mg, 1.336 mmol, 1.2 equiv) in dioxane (8 mL) and water (2 mL) were added sodium carbonate (353.92 mg, 3.339 mmol, 3 equiv) and Pd(dppf)Cl2(81.45 mg, 0.111 mmol, 0.1 equiv) . After stirring for 1 at 60°C under a nitrogen atmosphere, The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC / silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 9c (300 mg, 56.45%) as a yellow solid. LCMS (ESI, m / z): [M+H]+426.2. Step C. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (9d). To a stirred solution of 9c (200 mg, 0.441 mmol, 1 equiv) in tetrahydrofuran (5 mL) were added Pd / C (140.78 mg, 1.323 mmol, 3 equiv) under hydrogen atmosphere. The resulting mixture was stirred for 3 hours at 25°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The mixture was concentrated under reduced pressure to get 180 mg crude product and the residue was used for next step d irectly. LCMS (ESI, m / z): [M+H]+428.2. Step D.1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (9e). To a stirred solution of 9d (200 mg, 0.439 mmol, 1 equiv) in dichloromethane (2 mL) were added HCl(gas)in 1,4-dioxane (0.4 mL) under hydrogen atmosphere. The resulting mixture was stirred for 1 hours at 0°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to get 9e (180 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+328.2. Step E. tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (9f). To a stirred solution of 9e (60 mg, 0.281 mmol, 1 equiv) in metanol (2 mL) were added potassium acetate (55.22 mg, 0.562 mmol, 2 equiv) The resulting mixture was stirred for 10 mins at 25°C under nitrogen atmosphere. To the above mixture was added sodium cyanoborohydride (35.36 mg, 0.562 mmol, 2 equiv), acetic acid (50.68 mg, 0.843 mmol, 3 equiv) and 1-[6-(2,2-dimethylpiperidin-4-yl)-1-methylindazol-3-yl]-1,3-diazinane-2,4-dione(99.99 mg, 0.281 mmol, 1 equiv) at 50°C. The resulting mixture was stirred for additional 5 hours at 50°C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the f ollowing conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 5% to 50% gradient in 30 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to afford 9f (60 mg, 36.66%) as a white solid. LCMS (ESI, m / z): [M+H]+525.3. Step F.1-(1-methyl-6-(1-(piperidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4- b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (9g). To a stirred solution of 9f (60 mg, 0.109 mmol, 1 equiv) in acetonitrile (2 mL) were added HCl(gas)in 1,4-dioxane (1 mL, 0.218 mmol). The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to offord 9g (70 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+425.3. Step G: 1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl) piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9) To a stirred solution of TFA (0.3 mL, 4.039 mmol, 51.59 equiv) in CH2Cl2(1 mL) was added 9g (70 mg, 0.078 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was neutralized to pH 8 with saturated NaHCO3(aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl) piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9, 10 mg, 33.17%) as a white solid. LCMS (ESI, m / z): [M+H]+840.3. The rac 1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl)piperidin- 4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9, 60 mg) was separated by prep chiral HPLC with the following conditions (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: methyl tert-butyl ether (10mMNH3-methanol), Mobile Phase B: methanol; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 214 / 289 nm; RT1(min): 14.8; RT2(min): 21.6; Sample Solvent: methanol: dichloromethane=8: 1; Injection Volume: 0.8 mL; Number Of Runs: 3). The prepeak fractions were evaporated to dryness to afford rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9.1, 9.3 mg, 30.81%) as a white solid. LCMS (ESI, m / z): [M+H]+840.3. The postpeak fractions were evaporated to dryness to afford rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl) piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9.2, 10 mg, 33.17%). LCMS (ESI, m / z): [M+H]+840.3.

[0287] Example 10: rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (94) and rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl) piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A.1-(7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10b). A solution of 10a (471.49 mg, 1.856 mmol, 2 equiv), potassium acetate (182.22 mg, 1.856 mmol, 2 equiv) and Pd(dppf)Cl2(67.93 mg, 0.093 mmol, 0.1 equiv) in dioxane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was washed with 3x10 mL of water. The aqueous layer was extracted with ethyl acetate (3x100 mL). The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(5:1) to afford 10b (180 mg, 52.37%) as a white solid. LCMS (ESI, m / z): [M+H]+340.0. Step B. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H- indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10c). To a solution of tert-butyl 2,2-dimethyl-4-(trifluoromethanesulfonyloxy)-3,6- dihydropyridine-1-carboxylate (400 mg, 1.113 mmol, 1 equiv) and 10b (494.51 mg, 1.336mmol, 1.2 equiv) in dioxane (8 mL) and water (2 mL) were added sodium carbonate (353.92 mg, 3.339 mmol, 3 equiv) and Pd(dppf)Cl2(81.45 mg, 0.111 mmol, 0.1 equiv) . After stirring for 1 at 60°C under a nitrogen atmosphere, The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC / silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 10c (300 mg, 56.45%) as a yellow solid. LCMS (ESI, m / z): [M+H]+388.2. Step C. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1- methyl-1H-indazol-6-yl)piperidine-1-carboxylate (10d). To a stirred solution of 10c (200 mg, 0.441 mmol, 1 equiv) in tetrahydrofuran (5 mL) were added Pd / C (140.78 mg, 1.323 mmol, 3 equiv) under hydrogen atmosphere. The resulting mixture was stirred for 3 hours at 25°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The mixture was concentrated under reduced pressure to get 180 mg crude product and the residue was used for next step directly. LCMS (ESI, m / z): [M+H]+445.2. Step D.1-(7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10e). To a stirred solution of 10d (200 mg, 0.439 mmol, 1 equiv) in dichloromethane (2 mL) were added HCl(gas)in 1,4-dioxane (0.4 mL) under hydrogen atmosphere. The resulting mixture was stirred for 1 hours at 0°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to get 10e (180 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+345.2. Step E. tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1- methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (10f). To a stirred solution of 10e (60 mg, 0.281 mmol, 1 equiv) in metanol (2 mL) were added potassium acetate (55.22 mg, 0.562 mmol, 2 equiv) The resulting mixture was stirred for 10 mins at 25°C under nitrogen atmosphere. To the above mixture was added sodium cyanoborohydride (35.36 mg, 0.562 mmol, 2 equiv), acetic acid (50.68 mg, 0.843 mmol, 3 equiv) and 1-[6-(2,2-dimethylpiperidin-4-yl)-1-methylindazol-3-yl]-1,3-diazinane-2,4-dione (99.99 mg, 0.281 mmol, 1 equiv) at 50°C. The resulting mixture was stirred for additional 5 hours at 50°C. The reaction was monitored by LCMS. Desired product could be detected byLCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 5% to 50% gradient in 30 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to affo rd 10f (60 mg, 36.66%) as a white solid. LCMS (ESI, m / z): [M+H]+542.3. Step F.1-(7-fluoro-1-methyl-6-(1-(piperidin-3-ylmethyl)piperidin-4-yl)-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10g). To a stirred solution of 10f (60 mg, 0.109 mmol, 1 equiv) in acetonitrile (2 mL) were added HCl(gas)in 1,4-dioxane (1 mL, 0.218 mmol). The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to offord 10g (70 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+442.3. Step G: 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (Example 10) To a stirred solution of TFA (0.3 mL, 4.039 mmol, 51.59 equiv) in CH2Cl2(1 mL) was added 10g (70 mg, 0.078 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was neutralized to pH 8 with saturated NaHCO3(aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 10, 9.3 mg, 30.81.05%). LCMS (ESI, m / z): [M+H]+857.3.

[0288] Example 11: rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (94) and rel-(R)-1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl) piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A.1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4- b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (9b). A solution of 9a (471.49 mg, 1.856 mmol, 2 equiv), potassium acetate (182.22 mg, 1.856 mmol, 2 equiv) and Pd(dppf)Cl2(67.93 mg, 0.093 mmol, 0.1 equiv) in dioxane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was washed with 3x10 mL of water. The aqueous layer was extracted with ethyl acetate (3x100 mL). The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(5:1) to afford 9b (180 mg, 52.37%) as a white solid. LCMS (ESI, m / z): [M+H]+371.2.Step B. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9c). To a solution of tert-butyl 2,2-dimethyl-4-(trifluoromethanesulfonyloxy)-3,6- dihydropyridine-1-carboxylate (400 mg, 1.113 mmol, 1 equiv) and 9b (494.51 mg, 1.336 mmol, 1.2 equiv) in dioxane (8 mL) and water (2 mL) were added sodium carbonate (353.92 mg, 3.339 mmol, 3 equiv) and Pd(dppf)Cl2(81.45 mg, 0.111 mmol, 0.1 equiv) . After stirring for 1 at 60°C under a nitrogen atmosphere, The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC / silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 9c (300 mg, 56.45%) as a yellow solid. LCMS (ESI, m / z): [M+H]+426.2. Step C. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (9d). To a stirred solution of 9c (200 mg, 0.441 mmol, 1 equiv) in tetrahydrofuran (5 mL) were added Pd / C (140.78 mg, 1.323 mmol, 3 equiv) under hydrogen atmosphere. The resulting mixture was stirred for 3 hours at 25°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The mixture was concentrated under reduced pressure to get 180 mg crude product and the residue was used for next step d irectly. LCMS (ESI, m / z): [M+H]+428.2. Step D.1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (9e). To a stirred solution of 9d (200 mg, 0.439 mmol, 1 equiv) in dichloromethane (2 mL) were added HCl(gas)in 1,4-dioxane (0.4 mL) under hydrogen atmosphere. The resulting mixture was stirred for 1 hours at 0°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to get 9e (180 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+328.2. Step E. tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)piperidin-1-yl)methyl-d2)piperidine-1-carboxylate (11f). To a stirred solution of 9e (60 mg, 0.281 mmol, 1 equiv) in metanol (2 mL) were added potassium acetate (55.22 mg, 0.562 mmol, 2 equiv) The resulting mixture was stirred for 10 mins at 25°C under nitrogen atmosphere. To the above mixture was added sodiumcyanoborohydride (35.36 mg, 0.562 mmol, 2 equiv), acetic acid (50.68 mg, 0.843 mmol, 3 equiv) and 1-[6-(2,2-dimethylpiperidin-4-yl)-1-methylindazol-3-yl]-1,3-diazinane-2,4-dione (99.99 mg, 0.281 mmol, 1 equiv) at 50°C. The resulting mixture was stirred f or additional 5 hours at 50°C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 5% to 50% gradient in 30 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to afford 11f (60 mg, 36.66%) as a white solid. LCMS (ESI, m / z): [M+H]+527.3. Step F.1-(1-methyl-6-(1-(piperidin-3-ylmethyl-d2)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11g). To a stirred solution of 11f (60 mg, 0.109 mmol, 1 equiv) in acetonitrile (2 mL) were added HCl(gas)in 1,4-dioxane (1 mL, 0.218 mmol). The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to offord 11g (70 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+427.3. Step G: 1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl- d2)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (Example 11) To a stirred solution of TFA (0.3 mL, 4.039 mmol, 51.59 equiv) in CH2Cl2(1 mL) was added 11g (70 mg, 0.078 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was neutralized to pH 8 with saturated NaHCO3(aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl-d2)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (Example 11, 10 mg, 33.17%). LCMS (ESI, m / z): [M+H]+842.4

[0289] Example 12: rel 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl-d2)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(94) and rel 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl- d2)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep A.1-(7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10b). A solution of 10a (471.49 mg, 1.856 mmol, 2 equiv), potassium acetate (182.22 mg, 1.856 mmol, 2 equiv) and Pd(dppf)Cl2(67.93 mg, 0.093 mmol, 0.1 equiv) in dioxane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was washed with 3x10 mL of water. The aqueous layer was extracted with ethyl acetate (3x100 mL). The residue was purified by silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(5:1) to afford 10b (180 mg, 52.37%) as a white solid. LCMS (ESI, m / z): [M+H]+340.0.Step B. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H- indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10c). To a solution of tert-butyl 2,2-dimethyl-4-(trifluoromethanesulfonyloxy)-3,6- dihydropyridine-1-carboxylate (400 mg, 1.113 mmol, 1 equiv) and 10b (494.51 mg, 1.336 mmol, 1.2 equiv) in dioxane (8 mL) and water (2 mL) were added sodium carbonate (353.92 mg, 3.339 mmol, 3 equiv) and Pd(dppf)Cl2(81.45 mg, 0.111 mmol, 0.1 equiv) . After stirring for 1 at 60°C under a nitrogen atmosphere, The reaction progress was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC / silica gel column chromatography, eluted with petrolumn ether / ethyl acetate(1:1) to afford 10c (300 mg, 56.45%) as a yellow solid. LCMS (ESI, m / z): [M+H]+388.2. Step C. tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1- methyl-1H-indazol-6-yl)piperidine-1-carboxylate (10d). To a stirred solution of 10c (200 mg, 0.441 mmol, 1 equiv) in tetrahydrofuran (5 mL) were added Pd / C (140.78 mg, 1.323 mmol, 3 equiv) under hydrogen atmosphere. The resulting mixture was stirred for 3 hours at 25°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The mixture was concentrated under reduced pressure to get 180 mg crude product and the residue was used for next step directly. LCMS (ESI, m / z): [M+H]+445.2. Step D.1-(7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10e). To a stirred solution of 10d (200 mg, 0.439 mmol, 1 equiv) in dichloromethane (2 mL) were added HCl(gas)in 1,4-dioxane (0.4 mL) under hydrogen atmosphere. The resulting mixture was stirred for 1 hours at 0°C under hydrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to get 10e (180 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+345.2. Step E. tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1- methyl-1H-indazol-6-yl)piperidin-1-yl)methyl-d2)piperidine-1-carboxylate (12f). To a stirred solution of 10e (60 mg, 0.281 mmol, 1 equiv) in metanol (2 mL) were added potassium acetate (55.22 mg, 0.562 mmol, 2 equiv) The resulting mixture was stirred for 10 mins at 25°C under nitrogen atmosphere. To the above mixture was added sodiumcyanoborohydride (35.36 mg, 0.562 mmol, 2 equiv), acetic acid (50.68 mg, 0.843 mmol, 3 equiv) and 1-[6-(2,2-dimethylpiperidin-4-yl)-1-methylindazol-3-yl]-1,3-diazinane-2,4-dione (99.99 mg, 0.281 mmol, 1 equiv) at 50°C. The resulting mixture was stirred f or additional 5 hours at 50°C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 5% to 50% gradient in 30 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to afford 12f (60 mg, 36.66%) as a white solid. LCMS (ESI, m / z): [M+H]+544.3. Step F.1-(7-fluoro-1-methyl-6-(1-(piperidin-3-ylmethyl-d2)piperidin-4-yl)-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (12g). To a stirred solution of 12f (60 mg, 0.109 mmol, 1 equiv) in acetonitrile (2 mL) were added HCl(gas)in 1,4-dioxane (1 mL, 0.218 mmol). The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to offord 12g (70 mg) as crude product which was used for next step directly. LCMS (ESI, m / z): [M+H]+444.3. Step G: 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3-yl)methyl- d2)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 12) To a stirred solution of TFA (0.3 mL, 4.039 mmol, 51.59 equiv) in CH2Cl2(1 mL) was added 12g (70 mg, 0.078 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was neutralized to pH 8 with saturated NaHCO3(aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(7-fluoro-6-(1-((1-((3-fluoro-4-((8-isopropoxy- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-3- yl)methyl-d2)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 12, 13.6 mg, 21.05%). LCMS (ESI, m / z): [M+H]+859.4Table 2. Structure, physicochemical data for compounds 1 to 12Biological assays HiBit Assay Protocol for CDK2 1. Materials 1.1 Reagents1.2 Instruments2. Assay procedure Day 1. 1. The culture medium for HEK293-CDK2-Hibit cells was prepared using DMEM with 10% FBS.2. Cells were cultivated in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity. Cells were allowed to reach 80-90% confluence before detaching and splitting.3. Cultivated cells were rinsed in T-75 flasks with 5 mL PBS. Aspirated off. Added 1.5 mL trypsin, and incubated the cells at 37 °C for approximately 5 minutes or until the cells detached and floated.4. Trypsin was inactivated by adding excess serum containing medium.5. Cells were harvested from flask into cell culture medium and then the cell number was counted. HEK293-CDK2-Hibit cells were seeded into 384-well plate (cell density: 1.6x105 cells / well / 50 uL medium) in DMEM medium according to the plate map below and were incubated overnight at 37°C and 5% CO2.Note: Cell Culture Medium: 90% DMEM + 10% FBS +1% Penicillin-Streptomycin LiquidPlate mapDay 2.1. Test compounds were dissolved at 10 mM DMSO stock solution. 45 uL of stock solution was transferred to a 384 pp-plate. A 3 -fold, 10-point dilution was performed via transferring 15 uL compound into 30 uL DMSO by using TECAN liquid handler.2. The plates were spinned at room temperature at 1,000 RPM for 1 minute.3. 50 nL of diluted compound was transferred from compound source plate into the cell plate by Echo.4. After compound treatment for 6 hours, the plate was removed from incubators and equilibrated at room temperature for 15 minutes. The HiBit reagent was prepared, consisting of the following ratios: 10 mL of Nano-Glo®-HiBiT Lytic Buffer, 200 uL of Nano-Glo®-HiBiT Lytic Substrate and 100 uL of LgBiT Protein, mixed thoroughly.20 uL of HiBit reagent was added into each well and the plates were spinned at room temperature at 1,000 RPM for 1 minute to be detected. Then the plates were shaken at 600 RPM at room temperature for 20 minutes, and read by EnVision. 5. The inhibition activity was calculated following the formula below: %Degrader = 100 x (LumHC – LumSample) / (LumHC –LumLC) Note: Where HC was obtained from cells treated with 0.1% DMSO only; LC was obtained from culture medium only. 6. ABS DC50was calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope)) The data from this assay is presented in Table 3, columns 6 and 7. HiBit Assay Protocol for CCNE1 1. Materials 1.1 Reagents1.2 Instruments2. Assay procedure Day 1. 1.The culture medium for HEK293-CCNE1-Hibit cell was prepared using EMEM with 10% FBS. 2. Cells were cultivated in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity. Cells were allowed to reach 80-90% confluence before detaching and splitting. 3. Cultivated cells were rinsed in T-75 flasks with 5 mL PBS. Aspirated off. Added was 1.5 mL trypsin, and incubated the cells at 37 °C for approximately 5 minutes or until the cells detached and floated. 4. Trypsin was inactivated by adding excess serum containing medium. 5. Cells were harvested from flask into cell culture medium and then the cell number was counted. HEK293-CCNE1-Hibit cell were seeded into 384-well plate (cell density: 1.6x105cells / well / 50 uL medium) in EMEM medium according to the plate map below and incubated overnight at 37°C and 5% CO2. Note: Cell Culture Medium: 90% EMEM + 10% FBS +1% Penicillin-Streptomycin LiquidPlate mapDay 2. 1. Test compounds were dissolved at 10 mM DMSO stock solution. 45 uL of stock solution was transferred to a 384 pp-plate. A 3-fold, 10-point dilution was performed via transferring 15 uL compound into 30 uL DMSO by using TECAN liquid handler. 2. The plates were spinned at room temperature at 1,000 RPM for 1 minute. 3.50 nL of diluted compound was transferred from compound source plate into the cell plate by Echo. 4. After compound treatment for 6 hours, the plate was removed from incubators and equilibrated at room temperature for 15 minutes. The HiBit reagent was prepared, consisting of the following ratios: 10 mL of Nano-Glo®-HiBiT Lytic Buffer, 200 uL of Nano-Glo®- HiBiT Lytic Substrate and 100 uL of LgBiT Protein, mixed thoroughly.20 uL of HiBit reagent was added into each well and the plates were spinned at room temperature at 1,000 RPM for 1 minute to be detected. Then the plates were shaken at 600 RPM at room temperature for 20 minutes, and read by EnVision. 5. The inhibition activity was calculated following the formula below: %Degrader = 100 x (LumHC – LumSample) / (LumHC –LumLC) Note: Where HC was obtained from cells treated with 0.1% DMSO only; LC was obtained from culture medium only. 6. ABS DC50was calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope)) The data from this assay is presented in Table 3, columns 2 and 3.HiBit Assay Protocol for CCNE2 3. Materials 3.1 Reagents1.2 Instruments4. Assay procedure Day 1. 1.The culture medium for HEK293-CCNE2-Hibit cell was prepared using EMEM with 10% FBS.2. Cells were cultivated in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity. Cells were allowed to reach 80-90% confluence before detaching and splitting.3. Cultivated cells were rinsed in T-75 flasks with 5 mL PBS. Aspirated off. Added was 1.5 mL trypsin, and incubated the cells at 37 °C for approximately 5 minutes or until the cells detached and floated.4. Trypsin was inactivated by adding excess serum containing medium.5. Cells were harvested from flask into cell culture medium and then the cell number was counted. HEK293-CCNE2-Hibit cell were seeded into 384-well plate (cell density: 1.6xl05cells / well / 50 uL medium) in EMEM medium according to the plate map below and incubated overnight at 37°C and 5% CO2.Note: Cell Culture Medium: 90% EMEM + 10% FBS +1% Penicillin-StreptomycinLiquidPlate mapDay 2.1. Test compounds were dissolved at 10 mM DMSO stock solution. 45 uL of stock solution was transferred to a 384 pp-plate. A 3-fold, 10-point dilution was performed via transferring 15 uL compound into 30 uL DMSO by using TEC AN liquid handler.2. The plates were spinned at room temperature at 1,000 RPM for 1 minute.3. 50 nL of diluted compound was transferred from compound source plate into the cell plate by Echo.4. After compound treatment for 6 hours, the plate was removed from incubators and equilibrated at room temperature for 15 minutes. The HiBit reagent was prepared, consistingof the following ratios: 10 mL of Nano-Glo®-HiBiT Lytic Buffer, 200 uL of Nano-Glo®- HiBiT Lytic Substrate and 100 uL of LgBiT Protein, mixed thoroughly.20 uL of HiBit reagent was added into each well and the plates were spinned at room temperature at 1,000 RPM for 1 minute to be detected. Then the plates were shaken at 600 RPM at room temperature for 20 minutes, and read by EnVision. 5. The inhibition activity was calculated following the formula below: %Degrader = 100 x (LumHC – LumSample) / (LumHC –LumLC) Note: Where HC was obtained from cells treated with 0.1% DMSO only; LC was obtained from culture medium only. 6. ABS DC50was calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope)) The data from this assay is presented in Table 3, columns 4 and 5.

[0290] Experiment results are provided in Table 3 below. The symbol “++++” indicates a DC50less than 10 nM or a Dmaxgreater than 75%. The symbol “+++” indicates a DC50in the range of 10 nM to 100 nM or a Dmaxin the range of 50% to 75%. The symbol “++” indicates a DC50in the range of 100 nM to 1000 nM or a Dmaxin the range of 25% to 50%. The symbol “+” indicates a DC50greater than or equal to 1000 nM or a Dmaxless or equal to 25%. Table 3. Biological assay data for compounds 1 to 12

Claims

CLAIMS What is claimed is:

1. A compound of Formula A,or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; Y is C(H) or N; LBM is selected from the group consisting of, , ,Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and at least one of Q, J, and W is N; X is C(H) or N; Z is -CH2- or C=O; R1is, independently, for each occurrence, –H or –D; R2is, independently, for each occurrence, –H or –Me; each instance of R3is independently selected from –D, halo, –OH,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2; each instance of R4is independently selected from –D, halo, –OH, and –C1-6alkyl; each instance of Rais independently selected from –H and –C1-6alkyl. r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A iswhereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is C(H).

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –H.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –D.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –H.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –Me.

10. The compound of any one of claims 1-9, wherein Q, J, and W are each independently selected from C(H) and N, wherein at least one of Q, J, or W is C(H) and least two of Q, J, or W is N.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is C(H).

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is N.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is C=O.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from halo,–C1-6alkyl, –O-C1-6alkyl, and –N(Ra)2.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from –F, –Cl,–C1-6alkyl, –O- C1-6alkyl, and –N(Ra)2.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently selected from –F, –Cl, –Me, –Et, –iPr, – O-CH3, –NH2, –NH(CH3), or –N(CH3)2.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each instance of R3is independently –F.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from –Me, –Et, –F, –Cl and–OH.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein each R4is independently–Me.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 0.

23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 1.

24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein r is 2.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, or 2.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 0.

27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 1.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein s is 2.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein LBM is selected from the group consisting of:.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein LBM is selected from the group consisting of:.

31. A compound of Formula Ior a pharmaceutically acceptable salt thereof, whereinRing A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene; T is C(F) or N; Y is C(H) or N; R1is, independently, for each occurrence, –H or –D; and R2is, independently, for each occurrence, –H or –Me.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

33. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is, whereinindicates the location of a bond to the sulfonyl and “*” indicates the location of a bond to the methylene.

34. The compound of any one of claims 31-33, or a pharmaceutically acceptable salt thereof, wherein T is C(F).

35. The compound of any one of claims 31-33, or a pharmaceutically acceptable salt thereof, wherein T is N.

36. The compound of any one of claims 31-35, or a pharmaceutically acceptable salt thereof, wherein Y is C(H).

37. The compound of any one of claims 31-35, or a pharmaceutically acceptable salt thereof, wherein Y is N.

38. The compound of any one of claims 31-37, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –H.

39. The compound of any one of claims 31-37, or a pharmaceutically acceptable salt thereof, wherein each R1is independently –D.

40. The compound of any one of claims 31-39, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –H.

41. The compound of any one of claims 31-39, or a pharmaceutically acceptable salt thereof, wherein each R2is independently –Me.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-A:

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B:

44. The compound of any one of claims 1 -43, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

45. A pharmaceutical composition, comprising a compound of any one of claims 1 -44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

46. A method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

47. The method of claim 46, wherein the inhibiting of CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

48. The method of claim 46, wherein the inhibiting of CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

49. A method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

50. The method of claim 49, wherein the inhibiting of CDK2 signaling comprises reducing the signaling activity of CDK2 by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

51. The method of claim 49, wherein the inhibiting of CDK2 signaling comprises reducing the signaling activity of CDK2 by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10- fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

52. A method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

53. The method of claim 52, wherein the inhibiting of CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CCNE (CCNE1 and / or CCNE2) by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

54. The method of claim 52, wherein the inhibiting CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CCNE (CCNE1 and / or CCNE2) by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

55. A method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1 -44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

56. The method of claim 55, wherein the inhibiting of CDK2 and CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

57. The method of claim 55, wherein the inhibiting of CDK2 and CCNE (CCNE1 and / or CCNE2) signaling comprises reducing the signaling activity of CDK2 and / or CCNE (CCNE1 and / or CCNE2) by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

58. A method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

59. The method of claim 58, wherein the CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.

60. A method of treating a CDK2 -mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1 -44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

61. The method of claim 60, wherein the CDK2 -mediated disorder is cancer.

62. A method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

63. The method of claim 62, wherein the CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.

64. A method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

65. The method of claim 64, wherein the CDK2 and CCNE (CCNE1 and / or CCNE2)- mediated disorder is cancer.

66. The method of any one of claims 59, 63, or 65, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple negative breast cancer (TNBC), hormone -receptor positive (HR+) breast cancer, HER2 positive (HER2+) positive breast cancer).

67. The method of any one of claims 59, 63, 65, or 66, wherein the cancer is resistant to treatment with CDK 4 / 6 inhibitors.

Images