CDK4 / 6 degraders for treating breast cancer

Abstract

Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of breast cancer with a CDK4 / 6 degrader, e.g., a compound of Formula (I). Also provided herein is a method of treating, preventing, or ameliorating one or more symptoms of breast cancer with a CDK4 / 6 degrader in combination with an estrogen receptor antagonist.

Description

Attorney Docket No: 127A057WO01 CDK4 / 6 DEGRADERS FOR TREATING BREAST CANCER CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Application No. 63 / 661,587, filed June 19, 2024, the disclosure of which is incorporated herein by reference in its entirety. FIELD

[0002] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of breast cancer with a CDK4 / 6 degrader. Also provided herein is a method of treating, preventing, or ameliorating one or more symptoms of breast cancer with a CDK4 / 6 degrader in combination with an estrogen receptor antagonist. BACKGROUND

[0003] Cyclin-dependent kinases (CDKs) are protein kinases that are involved in critical cellular processes, such as a cell cycle. Malumbres et al., Nat. Cell Biol.2009, 11, 1275-6; Ding et al., Int. J. Mol. Sci.2020, 21, 1960. CDKs associate with different cyclins to control different cell cycle transitions in human cells. Uzbekov and Prigent, Cells 2022, 11, 704. There are 20 CDKs and about 30 cyclins in the human. Malumbres et al., Nat. Cell Biol.2009, 11, 1275-6. CDK2 complexed with cyclin E, or CDK4 / CDK6 complexed with cyclin D drives cell-cycle progression from G1 to S phase. Topacio et al., Mol. Cell 2019, 74, 758-70; Uzbekov and Prigent, Cells 2022, 11, 704. Cell cycle dysregulation characterized by aberrant activation of CDKs is a hallmark of cancer. Malumbres and Barbacid, Nat. Rev. Cancer 2009, 9, 153-66; Otto and Sicinski, Nat. Rev. Cancer 2017, 17, 93-115; Ding et al., Int. J. Mol. Sci.2020, 21, 1960.

[0004] Breast cancer is the most common type of cancer and the leading cause of cancer- related deaths in women. Sung et al., CA Cancer J. Clin.2021, 71, 209-49. The four molecular subtypes of breast cancer are classified based on expression of hormone receptors (estrogen and progesterone) and HER2 (and / or Ki67) and have varying prevalence and severity. Goldhirsch et al., Ann. Oncol.2011, 22, 1736-47. HR+ / HER2- breast cancer, the most common subtype (68%), is usually slower growing and responds well to hormone therapy. The Surveillance,Attorney Docket No: 127A057WO01 Epidemiology, and End Results (SEER) Program of National Cancer Institute, 2024. Approximately 6% of female breast cancer cases are first diagnosed as advanced metastatic disease. Id. While early-stage breast cancer is curable, advanced metastatic breast cancer is currently considered incurable with only palliative treatment options available. Id. The estimated 5-year survival rate in the US for women diagnosed with breast cancer is 90.8% when factoring in all disease stages but only 31% for women with metastatic disease. Id.

[0005] Current treatments for advanced metastatic HR+ / HER2- breast cancer include endocrine therapies to inhibit the production or activity of estrogen and targeted therapies in combination with endocrine therapy, such as CDK inhibitors and phosphoinositide 3 kinase (PI3K) inhibitors. Dual CDK4 / 6 inhibitors, abemaciclib, palbociclib, and ribociclib have been approved by the FDA for treating advanced or metastatic hormone receptor positive breast cancer. Sanchez-Martinez et al., Bioorg. Med. Chem. Lett. 2019, 29, 126637; Zhang et al., Am. J. Cancer Res.2021, 11, 1913-35. The efficacy of CDK4 / CDK6 inhibition is, however, limited by innate or acquired resistance. Razavi et al., Cancer Cell 2018, 34, 427-38; Alvarez- Fernandez and Malumbres, Cancer Cell 2020, 37, 514-29; Ogata et al., Breast Cancer 2021, 28, 206-15; Li et al., Cancer Discov.2022, 12, 356-71. CDK4 / 6 inhibitor therapy can effectively reduce resistance to endocrine monotherapy and significantly extend progression-free survival and overall survival in HR+ / HER2- breast cancer patients. Stanciu et al., Diagnostics (Basel) 2023, 13, 987. However, most patients will develop resistance to CDK4 / 6 inhibitors over time (up to 70% of patients after 3 years on therapy). Scheidemann and Shajahan-Haq, Int. J. Mol. Sci.2021, 22, 12292. Given the poor prognosis of advanced metastatic breast cancer and the limitations of current treatments, there is an urgent need for an effective therapy for breast cancer, in particular, HR+ / HER2- breast cancer. SUMMARY OF THE DISCLOSURE

[0006] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of breast cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):Attorney Docket No: 127A057WO01 or an morea a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is C1-6alkylene, C1-6heteroalkylene, or heterocyclylene; L is a bond, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkylene, or heterocyclylene; X is a bond or –C(O)–; Z is C(R5a) or N, wherein R5ais hydrogen or R5; R1is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R2, R3, and R4are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; each R5, R6, R7, and R8is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d,Attorney Docket No: 127A057WO01 –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R9is hydrogen or C1-6 alkyl; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, 2, or 3; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is an integer of 0, 1, 2, 3, or 4; and q is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(O)SRa, –C(NRa)NRbRc, –C(S)Ra, –C(S)ORa, –C(S)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(O)SRa, –OC(NRa)NRbRc, –OC(S)Ra, –OC(S)ORa, –OC(S)NRbRc, –OP(O)(ORb)ORc, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, –NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(O)SRd, –NRaC(NRd)NRbRc, –NRaC(S)Rd, –NRaC(S)ORd, –NRaC(S)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;Attorney Docket No: 127A057WO01 wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)Re, –C(O)ORe, –C(O)NRfRg, –C(O)SRe, –C –C –C –C –OC –OCor6 6 6alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0007] Also provided herein is method of treating breast cancer in a subject, comprising administering to the subject in need thereof (i) a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (ii) a therapeutically effective amount of an estrogen receptor antagonist.

[0008] Additionally provided herein is a method of inhibiting the growth of a cancerous cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0009] Furthermore, provided herein is a method of inducing degradation of a CDK in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.Attorney Docket No: 127A057WO01

[0010] Provided herein is a method of downregulating a CDK in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] Provided herein is a method of inhibiting the phosphorylation of a retinoblastoma protein (RB) in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Provided herein is an enantiomerically pure compound of: (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102R; (R)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108R; (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135R; (R)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123R; (R)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125R; (R)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148R;Attorney Docket No: 127A057WO01 (R)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153R; or (R)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164R; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] Provided herein is an enantiomerically pure compound of: (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102S; (S)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108S; (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135S; (S)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123S; (S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125S; (S)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148S; (S)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153S; orAttorney Docket No: 127A057WO01 (S)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164S; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. DETAILED DESCRIPTION

[0014] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0015] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0017] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0018] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

[0019] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducingAttorney Docket No: 127A057WO01 adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0020] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and / or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0021] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0022] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press,Attorney Docket No: 127A057WO01 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015.

[0023] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0024] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0025] The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20Attorney Docket No: 127A057WO01 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, e.g., butane-1,1-diyl, butane-1,2- diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, e.g., hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, –C(O)CH2–, –C(O)(CH2)2–, –C(O)(CH2)3–, –C(O)(CH2)4–, –C(O)(CH2)5–, –C(O)(CH2)6–, –C(O)(CH2)7–, –C(O)(CH2)8–, –C(O)(CH2)9–, –C(O)(CH2)10–, –C(O)CH2C(O)–, –C(O)(CH2)2C(O)–, –C(O)(CH2)3C(O)–, –C(O)(CH2)4C(O)–, or –C(O)(CH2)5C(O)–.

[0026] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, –OCH3, –OCH2CH3, –CH2OCH3, –NHCH3, –ONHCH3, –NHOCH3, –SCH3, –CH2NHCH2CH3, and –NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, –CH2NHC(O)CH3 and –NHC(O)CH2CH3.

[0027] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one orAttorney Docket No: 127A057WO01 more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, –CH2O–, –CH2CH2O–, –CH2CH2CH2O–, –(CH2)4O–, –(CH2)5O–, –(CH2)6O–, –(CH2)7O–, –(CH2)8O–, –(CH2)9O–, –(CH2)10O–, –CH2OCH2–, –CH2CH2O–, –(CH2CH2O)2–, –(CH2CH2O)3–, –(CH2CH2O)4–, –(CH2CH2O)5–, –CH2NH–, –CH2NHCH2–, –CH2CH2NH–, – CH2CH2CH2NH–, –(CH2)4NH–, –CH2S–, –CH2SCH2–, and –CH2CH2S–. Examples of substituted heteroalkylene groups include, but are not limited to, –C(O)CH2O–, –C(O)(CH2)2O–, –C(O)CH2CH2CH2O–, –C(O)CH2CH2CH2CH2O–, –C(O)(CH2)5O–, –C(O)(CH2)6O–, –C(O)(CH2)7O–, –C(O)(CH2)8O–, –C(O)(CH2)9O–, –C(O)(CH2)10O–, –C(O)CH2OCH2CH2O–, –C(O)CH2O(CH2CH2O)2–, –C(O)CH2O(CH2CH2O)3–, –C(O)CH2O(CH2CH2O)4, –C(O)CH2O(CH2CH2O)5–, –CH2NHC(O)CH2–, –CH2CH2C(O)NH–, –CH2N(CH3)–, –(CH2)2N(CH3)–, –(CH2)3N(CH3)–, or –(CH2)4N(CH3)–.

[0028] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms,Attorney Docket No: 127A057WO01 e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0029] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carbon- carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (–C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (–C≡CCH3) and propargyl (–CH2C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0030] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclo- butyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]- octyl, decalinyl, and adamantyl.

[0031] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with oneAttorney Docket No: 127A057WO01 or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane-1,1-diyl, cyclo- pentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohex-1,4-diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane-1,1-diyl, cycloheptane-1,2- diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline-1,1-diyl, decaline-1,2-diyl, and decaline-1,8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0032] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and / or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0033] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenyl- ethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, andAttorney Docket No: 127A057WO01 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0034] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5- b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,1-b]-thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzo- furanyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5- b]pyridinyl, oxazolo[4,5-c]-pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]-pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thieno- pyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl,Attorney Docket No: 127A057WO01 thieno[3,2-b]pyridinyl, and thieno-[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzo-furanyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phen- anthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0035] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non- aromatic ring system or monovalent polycyclic ring system that contains at least one non- aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4- dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydro- pyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydro- pyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,Attorney Docket No: 127A057WO01 thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0036] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. If a heterocyclylene group containing a nonaromatic heterocyclic ring also contains a heteroaromatic ring, the heterocyclylene group does not have a linkage to the rest of a molecule via its heteroaromatic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazindiyl, 3,4-dihydrobenzo[c][1,2]oxazindiyl, and 3,4-dihydrobenzo[d][1,2]oxazindiyl), dihydrobenzo- thiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydro- isoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrroldiyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydro- isoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0037] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and / or iodo.Attorney Docket No: 127A057WO01

[0038] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (–D), cyano (–CN), halo, imino (=NH), nitro (–NO2), and oxo (=O); (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(O)SRa, –C(NRa)NRbRc, –C(S)Ra, –C(S)ORa, –C(S)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(O)SRa, –OC(NRa)NRbRc, –OC(S)Ra, –OC(S)ORa, –OC(S)NRbRc, –OP(O)(ORb)ORc, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, –NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(O)SRd, –NRaC(NRd)NRbRc, –NRaC(S)Rd, –NRaC(S)ORd, –NRaC(S)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”

[0039] In one embodiment, each Qais independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)Re, –C(O)ORe, –C(O)NRfRg, –C(O)SRe, –C(NRe)NRfRg, –C(S)Re, –C(S)ORe, –C(S)NRfRg, –ORe, –OC(O)Re, –OC(O)ORe, –OC(O)NRfRg, –OC(O)SRe, –OC(NRe)NRfRg, –OC(S)Re, –OC(S)ORe, –OC(S)NRfRg, –OP(O)(ORf)ORg, –OS(O)Re, –OS(O)2Re, –OS(O)NRfRg, –OS(O)2NRfRg, –NRfRg, –NReC(O)Rh, –NReC(O)ORf, –NReC(O)NRfRg, –NReC(O)SRf, –NReC(NRh)NRfRg, –NReC(S)Rh, –NReC(S)ORf, –NReC(S)NRfRg, –NReS(O)Rh, –NReS(O)2Rh, –NReS(O)NRfRg, –NReS(O)2NRfRg, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6Attorney Docket No: 127A057WO01 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0040] In certain embodiments, “optically active” and ”enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.

[0041] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S.

[0042] The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P),Attorney Docket No: 127A057WO01 phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur- 33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36Cl), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, or any oxygen can be18O, as example, where feasible according to the judgment of one of ordinary skill in the art.

[0043] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g.,1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0044] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.

[0045] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H),Attorney Docket No: 127A057WO01 in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.

[0046] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

[0047] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon-12 (12C) and carbon-13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.

[0048] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon-13 at a given position in a molecule in the place of carbon. For example, carbon-13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).

[0049] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performanceAttorney Docket No: 127A057WO01 liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.

[0050] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0051] For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula –C(O)NH– represents both –C(O)NH– and –NHC(O)–.

[0052] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof” has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, aAttorney Docket No: 127A057WO01 mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a diastereomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein.” Compounds

[0053] In one embodiment, provided herein is a compound of Formula (I): or anmore diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is C1-6 alkylene, C1-6 heteroalkylene, or heterocyclylene; L is a bond, C1-6alkylene, C1-6heteroalkylene, C3-10cycloalkylene, or heterocyclylene; X is a bond or –C(O)–; Z is C(R5a) or N, wherein R5ais hydrogen or R5; R1is (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R2, R3, and R4are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d,Attorney Docket No: 127A057WO01 –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; each R5, R6, R7, and R8is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R9is hydrogen or C1-6alkyl; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, 2, or 3; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is an integer of 0, 1, 2, 3, or 4; and q is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(O)SRa, –C(NRa)NRbRc, –C(S)Ra, –C(S)ORa, –C(S)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(O)SRa, –OC(NRa)NRbRc, –OC(S)Ra, –OC(S)ORa, –OC(S)NRbRc, –OP(O)(ORb)ORc, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, –NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(O)SRd, –NRaC(NRd)NRbRc,Attorney Docket No: 127A057WO01 –NRaC(S)Rd, –NRaC(S)ORd, –NRaC(S)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)Re, –C(O)ORe, –C(O)NRfRg, –C(O)SRe, –C(NRe)NRfRg, –C(S)Re, –C(S)ORe, –C(S)NRfRg, –ORe, –OC(O)Re, –OC(O)ORe, Re,alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0054] In another embodiment, provided herein is a compound of Formula (II): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, X, Z, m, n, p, and q are each as defined herein.Attorney Docket No: 127A057WO01

[0055] In yet another embodiment, provided herein is a compound of Formula (III): or an morediastereomers, a tautomer, a two or more tautomers, or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, X, Z, m, n, p, and q are each as defined herein.

[0056] In certain embodiments, in Formula (I), (II), or (III), X is a bond. In certain embodiments, in Formula (I), (II), or (III), X is –C(O)–.

[0057] In one embodiment, provided herein is a compound of Formula (IV): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, Z, m, n, p, and q are each as defined herein.

[0058] In another embodiment, provided herein is a compound of Formula (V):Attorney Docket No: 127A057WO01 or an morediastereomers, a a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, Z, m, n, p, and q are each as defined herein.

[0059] In yet another embodiment, provided herein is a compound of Formula (VI): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, Z, m, n, p, and q are each as defined herein.

[0060] In still another embodiment, provided herein is a compound of Formula (VII):Attorney Docket No: 127A057WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, Z, m, n, p, and q are each as defined herein.

[0061] In certain embodiments, in any one of Formulae (I) to (VII), Z is C(R5a), wherein R5ais as defined herein. In certain embodiments, in any one of Formulae (I) to (VII), Z is N.

[0062] In one embodiment, provided herein is a compound of Formula (VIII): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R5a, A, L, m, n, p, and q are each as defined herein.

[0063] In another embodiment, provided herein is a compound of Formula (IX): or anmore diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R5a, A, L, m, n, p, and q are each as defined herein.Attorney Docket No: 127A057WO01

[0064] In yet another embodiment, provided herein is a compound of Formula (X): or ana a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R5a, A, L, m, n, p, and q are each as defined herein.

[0065] In still another embodiment, provided herein is a compound of Formula (XI): or anmore diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R5a, A, L, m, n, p, and q are each as defined herein.

[0066] In one embodiment, provided herein is a compound of Formula (XII):Attorney Docket No: 127A057WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, m, n, p, and q are each as defined herein.

[0067] In another embodiment, provided herein is a compound of Formula (XIII): or an morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, m, n, p, and q are each as defined herein.

[0068] In yet another embodiment, provided herein is a compound of Formula (XIV): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, m, n, p, and q are each as defined herein.

[0069] In still another embodiment, provided herein is a compound of Formula (XV):Attorney Docket No: 127A057WO01 or an morea a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, L, m, n, p, and q are each as defined herein.

[0070] In certain embodiments, in any one of the formulae provided herein, A is C1-6alkylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is methanediyl, ethanediyl, or propanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is methane-1,1-diyl, ethane-1,2-diyl, or propane-1,3-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is –(CH2)–, –(CH2CH2)–, –(CH2CF2)–, or –(CH2CH2CH2)–. In certain embodiments, in any one of the formulae provided herein, A is –(CH2)–, –(CH2CH2)–, or –(CH2CF2)–. In certain embodiments, in any one of the formulae provided herein, A is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is –(CH2CH2)O–, –(CH2CH2CH2)O–, –(COCH2)O–, –(COCH2CH2)O–, –(CH2CH2NHCOCH2)O–, or –(CH2CH2CH2NHCOCH2)O–.

[0071] In certain embodiments, in any one of the formulae provided herein, A is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substitutedAttorney Docket No: 127A057WO01 with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 7- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is azetidindiyl, piperidindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is azetidin-1,3-diyl, piperidin-1,4- diyl, or piperazin-1,4-diyl, each optionally substituted with one or more substituents Q.

[0072] In certain embodiments, in any one of the formulae provided herein, A is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-azabicyclo[3.2.1]octandiyl, 8-azabicyclo[3.2.1]octandiyl, 2,7-diaza- spiro[3.5]nonandiyl, or 4,7-diazaspiro[2.5]octandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, 2,7-diazaspiro[3.5]nonan- 2,7-diyl, or 4,7-diazaspiro[2.5]octan-4,7-diyl, each optionally substituted with one or more substituents Q.

[0073] In certain embodiments, in any one of the formulae provided herein, A is –(CH2)–, –(CH2CH2)–, –(CH2CF2)–, –(CH2CH2)O–, –(CH2CH2CH2)O–, –(COCH2)O–, –(COCH2CH2)O–,Attorney Docket No: 127A057WO01 –(CH2CH2NHCOCH2)O–, –(CH2CH2CH2NHCOCH2)O–, azetidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, 2,7- diazaspiro[3.5]nonan-2,7-diyl, or 4,7-diazaspiro[2.5]octan-4,7-diyl. In certain embodiments, in any one of the formulae provided herein, A is ethane-1,2-diyl, piperidin-1,4-diyl, or piperazin- 1,4-diyl.

[0074] In certain embodiments, in any one of the formulae provided herein, L is (i) a bond; or (ii) C1-6alkylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is a bond. In certain embodiments, in any one of the formulae provided herein, L is C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is methanediyl, ethanediyl, or propanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is methane-1,1-diyl, ethane-1,2-diyl, or propane-1,3-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is –(CH2)–, –(CH2CH2)–, –(CH2CF2)–, or –(CH2CH2CH2)–. In certain embodiments, in any one of the formulae provided herein, L is –(CH2)–, –(CH2CH2)–, or –(CH2CH2CH2)–. In certain embodiments, in any one of the formulae provided herein, L is C1-6heteroalkylene, optionally substituted with one or more substituents Q.

[0075] In certain embodiments, in any one of the formulae provided herein, L is C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is cyclohexanediyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is cyclohexane-1,3-diyl or cyclohexane-1,4-diyl, each optionally substituted with one or more substituents Q.Attorney Docket No: 127A057WO01

[0076] In certain embodiments, in any one of the formulae provided herein, L is bicyclic C4- 10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is bridged, fused, or spiro C4-10cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is bridged C5-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is fused C4-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is spiro C4-10cycloalkylene, optionally substituted with one or more substituents Q.

[0077] In certain embodiments, in any one of the formulae provided herein, L is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is 7- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is azetidindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is azetidin-1,3-diyl, 3- fluoroazetidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 4-fluoropiperidin-1,4-diyl, morpholin-2,4-diyl, or piperazin-1,4-diyl. In certain embodiments, in any one of the formulae provided herein, L is a bond, methanediyl, ethane-1,2-diyl, or piperidin-1,4-diyl.Attorney Docket No: 127A057WO01

[0078] In certain embodiments, in any one of the formulae provided herein, L is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, L is spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0079] In certain embodiments, in any one of the formulae provided herein, L is a bond, –(CH2)–, –(CH2CH2)–, –(CH2CH2CH2)–, cyclohex-1,3-diyl, cyclohex-1,4-diyl, azetidin-1,3-diyl, 3-fluoroazetidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 4-fluoropiperidin-1,4-diyl, morpholin-2,4-diyl, or piperazin-1,4-diyl.

[0080] In certain embodiments, in any one of the formulae provided herein, R1is C1-6 alkyl, C3-10 cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is C1-6alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is methyl, ethyl, propyl, butyl, or pentyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is ethyl, isopropyl, or pent-3-yl.

[0081] In certain embodiments, in any one of the formulae provided herein, R1is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is monocyclic C3-10cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6alkyl, optionally substituted with one, two, or three substituents Q.

[0082] In certain embodiments, in any one of the formulae provided herein, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substitutedAttorney Docket No: 127A057WO01 with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl. In certain embodiments, in any one of the formulae provided herein, R1is cyclopropyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclobutyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl. In certain embodiments, in any one of the formulae provided herein, R1is cyclohexyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is cycloheptyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bicyclic C4-10cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bridged C5-10cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is fused C4-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is spiro C4-10cycloalkyl, each optionally substituted with one, two, or three substituents Q.Attorney Docket No: 127A057WO01

[0083] In certain embodiments, in any one of the formulae provided herein, R1is heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 3-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 4-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 5- membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is tetrahydrofuryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 6-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is bridged heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is fused heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1is spiro heterocyclyl, optionally substituted with one, two, or three substituents Q.

[0084] In certain embodiments, in any one of the formulae provided herein, R1is ethyl, isopropyl, pent-3-yl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 2-hydroxy- cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxy-2-methylcyclopentyl, 2-hydroxy-2-ethylcyclo- pentyl, 3-hydroxy-2-methylcyclopentyl, 4-hydroxy-2-methylcyclopentyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-fluoro-5-hydroxycyclohexyl, 3-hydroxy-2-methylcyclohexyl, 5-Attorney Docket No: 127A057WO01 hydroxy-2-methylcyclohexyl, 3-hydroxycycloheptyl, or 4-hydroxy-4-methyltetrahydrofuran-3- yl. In certain embodiments, in any one of the formulae provided herein, R1is cyclopentyl.

[0085] In certain embodiments, in any one of the formulae provided herein, R2is (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –OR1a, or –NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is hydrogen. In certain embodiments, in any one of the formulae provided herein, R2is cyano. In certain embodiments, in any one of the formulae provided herein, R2is halo. In certain embodiments, in any one of the formulae provided herein, R2is fluoro, chloro, bromo, or iodo. In certain embodiments, in any one of the formulae provided herein, R2is C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is C1-6alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoromethyl, aminocarbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, or 2-methoxyethyl. In certain embodiments, in any one of the formulae provided herein, R2is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is benzyl. In certain embodiments, in any one of the formulae provided herein, R2is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is oxazol-5-yl.

[0086] In certain embodiments, in any one of the formulae provided herein, R2is –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –OR1a, or –NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)R1aor –C(O)NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)R1a, wherein R1ais C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)C1-6alkyl, optionally substituted with oneAttorney Docket No: 127A057WO01 or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is acetyl. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)OR1a, wherein R1ais hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is hydroxycarbonyl or ethoxycarbonyl. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)NR1bR1c, wherein R1band R1care each independently hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is –C(O)N(C1-6 alkyl)2, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R2is dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R2is –OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –OR1a, wherein R1ais C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is 2-ethoxyethoxy. In certain embodiments, in any one of the formulae provided herein, R2is –NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, in any one of the formulae provided herein, R2is –NR1bR1c, wherein R1band R1care each independently hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2is amino.

[0087] In certain embodiments, in any one of the formulae provided herein, R2is hydrogen, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2- difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoromethyl, amino- carbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-methoxy- ethyl, benzyl, oxazol-5-yl, acetyl, hydroxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, 2-ethoxyethoxy, or amino. In certain embodiments, in any one of the formulae provided herein, R2is acetyl or dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R2is acetyl. In certain embodiments, in any one of the formulae provided herein, R2is dimethylaminocarbonyl.Attorney Docket No: 127A057WO01

[0088] In certain embodiments, in any one of the formulae provided herein, R3is hydrogen, deuterium, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R3is hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R3is hydrogen. In certain embodiments, in any one of the formulae provided herein, R3is deuterium. In certain embodiments, in any one of the formulae provided herein, R3is C1-6alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R3is methyl. In certain embodiments, in any one of the formulae provided herein, R3is hydrogen or methyl.

[0089] In certain embodiments, in any one of the formulae provided herein, R4is hydrogen or deuterium. In certain embodiments, in any one of the formulae provided herein, R4is hydrogen.

[0090] In certain embodiments, in any one of the formulae provided herein, each R5is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R5is deuterium. In certain embodiments, in any one of the formulae provided herein, each R5is independently halo. In certain embodiments, in any one of the formulae provided herein, each R5is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, each R5is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R5is independently methyl, trifluoromethyl, or ethyl.

[0091] In certain embodiments, in any one of the formulae provided herein, each R6is independently deuterium, halo, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R6is deuterium. In certain embodiments, in any one of the formulae provided herein, each R6is independently halo. In certain embodiments, in any one of the formulae provided herein, each R6is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, each R6is independently C1-6 alkyl, optionally substituted with one or more substituents Q. In certainAttorney Docket No: 127A057WO01 embodiments, in any one of the formulae provided herein, each R6is independently methyl, trifluoromethyl, or ethyl.

[0092] In certain embodiments, in any one of the formulae provided herein, each R7is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R7is deuterium. In certain embodiments, in any one of the formulae provided herein, each R7is independently halo. In certain embodiments, in any one of the formulae provided herein, each R7is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, each R7is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R7is independently methyl, trifluoromethyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, each R7is independently fluoro, chloro, methyl, or trifluoromethyl.

[0093] In certain embodiments, in any one of the formulae provided herein, each R8is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R8is deuterium. In certain embodiments, in any one of the formulae provided herein, each R8is independently halo. In certain embodiments, in any one of the formulae provided herein, each R8is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, each R8is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, each R8is independently methyl, trifluoromethyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, each R8is methyl. In certain embodiments, in any one of the formulae provided herein, each R8is independently fluoro, chloro, methyl, or trifluoromethyl.

[0094] In certain embodiments, in any one of the formulae provided herein, R9is hydrogen. In certain embodiments, in any one of the formulae provided herein, R9is C1-6 alkyl, optionally substituted with one or more substituents Q.

[0095] In certain embodiments, in any one of the formulae provided herein, R5ais hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R5ais hydrogen. In certainAttorney Docket No: 127A057WO01 embodiments, in any one of the formulae provided herein, R5ais deuterium. In certain embodiments, in any one of the formulae provided herein, R5ais halo. In certain embodiments, in any one of the formulae provided herein, R5ais fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R5ais fluoro. In certain embodiments, in any one of the formulae provided herein, R5ais C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R5ais methyl or ethyl. In certain embodiments, in any one of the formulae provided herein, R5ais hydrogen or fluoro.

[0096] In certain embodiments, in any one of the formulae provided herein, m is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, m is an integer of 0. In certain embodiments, in any one of the formulae provided herein, m is an integer of 1. In certain embodiments, in any one of the formulae provided herein, m is an integer of 2.

[0097] In certain embodiments, in any one of the formulae provided herein, n is an integer of 0, 1, 2, 3, or 4. In certain embodiments, in any one of the formulae provided herein, n is an integer of 0. In certain embodiments, in any one of the formulae provided herein, n is an integer of 1. In certain embodiments, in any one of the formulae provided herein, n is an integer of 2. In certain embodiments, in any one of the formulae provided herein, n is an integer of 3. In certain embodiments, in any one of the formulae provided herein, n is an integer of 4.

[0098] In certain embodiments, in any one of the formulae provided herein, p is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, p is an integer of 0. In certain embodiments, in any one of the formulae provided herein, p is an integer of 1. In certain embodiments, in any one of the formulae provided herein, p is an integer of 2.

[0099] In certain embodiments, in any one of the formulae provided herein, q is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, q is an integer of 0. In certain embodiments, in any one of the formulae provided herein, q is an integer of 1. In certain embodiments, in any one of the formulae provided herein, q is an integer of 2.

[0100] In one embodiment, in any one of the formulae provided herein, R1is C3-10 cycloalkyl, optionally substituted with one or more substituents Q; R2is –C(O)R1aor –C(O)NR1bR1c, wherein R1a, R1b, and R1care each as defined herein;Attorney Docket No: 127A057WO01 R3is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q; and R4is hydrogen.

[0101] In another embodiment, in any one of the formulae provided herein, R1is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q; R2is –C(O)R1aor –C(O)NR1bR1c, wherein R1a, R1b, and R1care each independently C1-6 alkyl, optionally substituted with one or more substituents Q; R3is hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q; and R4is hydrogen.

[0102] In yet another embodiment, in any one of the formulae provided herein, R1is cyclopentyl; R2is acetyl or dimethylaminocarbonyl; R3is hydrogen or methyl; and R4is hydrogen.

[0103] In one embodiment, in any one of the formulae provided herein, R1is C3-10 cycloalkyl, optionally substituted with one or more substituents Q; R2is –C(O)R1aor –C(O)NR1bR1c, wherein R1a, R1b, and R1care each as defined herein; R3is hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q; R4is hydrogen; R5a, if present, is hydrogen or halo; A is C1-6alkylene or heterocyclylene, each optionally substituted with one or more substituents Q; and L is (i) a bond; or (ii) C1-6alkylene or heterocyclylene, each optionally substituted with one or more substituents Q.

[0104] In another embodiment, in any one of the formulae provided herein, R1is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q; R2is –C(O)R1aor –C(O)NR1bR1c, wherein R1a, R1b, and R1care each independently C1-6alkyl, optionally substituted with one or more substituents Q; R3is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q; R4is hydrogen;Attorney Docket No: 127A057WO01 R5a, if present, is hydrogen or halo; A is C1-6 alkylene or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q; and L is (i) a bond; or (ii) C1-6 alkylene or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q.

[0105] In yet another embodiment, in any one of the formulae provided herein, R1is monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q; R2is –C(O)R1aor –C(O)NR1bR1c, wherein R1a, R1b, and R1care each independently C1-6 alkyl, optionally substituted with one or more substituents Q; R3is hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q; R4is hydrogen; R5a, if present, is hydrogen or halo; A is C1-6alkylene or 6-membered heterocyclylene, each optionally substituted with one or more substituents Q; and L is (i) a bond; or (ii) C1-6 alkylene or 6-membered heterocyclylene, each optionally substituted with one or more substituents Q.

[0106] In yet another embodiment, in any one of the formulae provided herein, R1is cyclopentyl; R2is acetyl or dimethylaminocarbonyl; R3is hydrogen or methyl; and R4is hydrogen; R5a, if present, is hydrogen or fluoro; A is ethanediyl, piperidindiyl, or piperazindiyl; and L is a bond, methanediyl, ethanediyl, piperidindiyl, or piperazindiyl.

[0107] In still another embodiment, in any one of the formulae provided herein, R1is cyclopentyl; R2is acetyl or dimethylaminocarbonyl; R3is hydrogen or methyl; and R4is hydrogen;Attorney Docket No: 127A057WO01 R5a, if present, is hydrogen or fluoro; A is ethane-1,2-diyl, piperidin-1,4-diyl, or piperazin-1,4-diyl; and L is a bond, methane-1,1-diyl, ethane-1,2-diyl, or piperidin-1,4-diyl.

[0108] In one embodiment, provided herein is: 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)cyclohexyl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A101; 7- 4-yl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102; 7-piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A103; 7-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A104;Attorney Docket No: 127A057WO01 7- 1-yl)propyl)-piperazin- - carboxamide A105; 7- -3-yl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A106; 7-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A107; 7-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A108;Attorney Docket No: 127A057WO01 7- -piperidin-4-yl)piperazin- - 6- carboxamide A109; 7- yl)propyl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A110; 7--1'-yl)- pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A111; 7--4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A112;Attorney Docket No: 127A057WO01 7- -[1,4'-- - 6- carboxamide A113; 7- yl)cyclo-hexyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A114; 7-yl)cyclo- hexyl)piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A115; 7-4- yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-arboxamide A116;Attorney Docket No: 127A057WO01 7- 1-yl)-piperidin- - carboxamide A117; 7- yl)methyl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A118 7-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A119; 7-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A120;Attorney Docket No: 127A057WO01 7- 4-yl)methyl)-piperazin-1-yl) - 6-carboxamide A121; 7- 4-fluoro-[1,4'-bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A122; 7-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A123; 7-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A124;Attorney Docket No: 127A057WO01 7- 1-yl)ethyl)-piperazin-1- - 6-carboxamide A125; 7- 1-yl)ethyl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A126; 7-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A127; 7-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A128;Attorney Docket No: 127A057WO01 7- -1-yl)-pyridin-2-yl) - A129; 7- 3-yl)phen-ethyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A130; 7-4-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A131; 7-1-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A132;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A133; 7- bipiperidin]-1'-yl) - A134; 7-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135; 7-4-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A136; 7-3-yl)methyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A137;Attorney Docket No: 127A057WO01 7- 3-yl)methyl)-piperazin-1-yl) - 6-carboxamide A138; 7- 3-yl)ethyl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A139; 7-3-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A140; 7-- piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A141;Attorney Docket No: 127A057WO01 7- -piperidin-4- - d]-pyrimidine- 6-carboxamide A142; 7- -azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine-6- carboxamide A143; 7-- azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine-6- carboxamide A144; 7-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A145;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(1-(3-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A146; 7- [1,4'-bipiperidin]-1'-yl)pyridin- - A147; 7- bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A148; 7-bipiperidin]-1'- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A149; 7-azetidin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A150;Attorney Docket No: 127A057WO01 7- 1-yl)-piperidin-1- - 6-carboxamide A151; 7- 1-yl)-piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A152; 7-1- yl)piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A153; 7-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A154;Attorney Docket No: 127A057WO01 7- 1-yl)methyl)-4-- 6- carboxamide A155; 7- 1-yl)methyl)-4-fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A156; 7-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A157; 7-piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine-6- carboxamide A158;Attorney Docket No: 127A057WO01 7- piperidin-4-yl)-ethyl) - - 6- carboxamide A159; 2-( ethyl)-piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A160; 2-(ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A161; 7-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A162;Attorney Docket No: 127A057WO01 7- piperidin-4-yl)ethyl) - - 6- carboxamide A163; 7- piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine-6- carboxamide A164; 7-4-fluoro-[1,4'- bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A165; or 7--piperidin-4- yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine-6- carboxamide A166;Attorney Docket No: 127A057WO01 or an morediastereomers, a a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0109] In another embodiment, provided herein is: 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)phenyl)piperidine-2,6-dione B101; 3-(3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropoxy)phenyl)piperidine-2,6-dione B102; N-(2-(4-[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B103;Attorney Docket No: 127A057WO01 N-(2- d]pyrimidin-2-yl)amino) - - (trifluoromethyl)phenoxy)acetamide B104; N-(2-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B105; N-(2-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B106; N-(3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B107;Attorney Docket No: 127A057WO01 N- d]pyrimidin-2-yl) - - (trifluoromethyl)phenoxy)acetamide B108; N-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B109; N-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B110; 3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)piperidine-2,6-dione B111;Attorney Docket No: 127A057WO01 3-(4-(2-(4- [2,3-d]-pyrimidin-2-yl) 2,6-dione B112; 3-(4-(2- [2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)phenyl)piperidine-2,6-dione B113; 3-(3-((4-[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)piperidine-2,6-dione B114; 3-(3-(2-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6-dione B115;Attorney Docket No: 127A057WO01 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)phenyl)piperidine-2,6-dione B116; 3-(4-(3- [2,3-d]-pyrimidin-2-yl) 2,6-dione B117; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propoxy)phenyl)piperidine-2,6-dione B118; 3-(4-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione B119; 3-(4-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B120;Attorney Docket No: 127A057WO01 3-(4-( [2,3-d]-pyrimidin-2- piperidine-2,6- dione B121; 3-(3-(4- [2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione B122; 3-(3-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123; 3-(3-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)piperidine-2,6- dione B124;Attorney Docket No: 127A057WO01 3-(4- [2,3-d]-pyrimidin-2- piperidine-2,6- dione B125; [2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B126; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)phenyl)piperidine-2,6- dione B127;[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)phenyl)piperidine-2,6- dione B128;Attorney Docket No: 127A057WO01 3-(4- [2,3-d]-pyrimidin-2- 2,6- dione B129; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B130; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)piperidine-2,6- dione B131;Attorney Docket No: 127A057WO01 3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)ethyl)phenyl)piperidine-2,6-dione B132; 3-(4- [2,3-d]-pyrimidin-2- -piperidine- 2,6-dione B133;[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B134; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)propoxy)phenyl)piperidine-2,6- dione B135;Attorney Docket No: 127A057WO01 3- d]-pyrimidin- - - 2,6- dione B136;d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)piperazin-1-yl)phenyl)piperidine-2,6- dione B137; 3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)piperazin-1-yl)phenyl)-piperidine- 2,6-dione B138;Attorney Docket No: 127A057WO01 3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)piperidin-1-yl)phenyl)-piperidine- 2,6-dione B139; 3- [2,3-d]-pyrimidin- 2,6- dione B140; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)propoxy)phenyl)piperidine-2,6- dione B141; 3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B142;Attorney Docket No: 127A057WO01 3-(4-(2-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6- dione B143; 3-(4- [2,3-d]-pyrimidin-2- - - 2,6-dione B144; 3-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)morpholino)phenyl)piperidine-2,6- dione B145; 3-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)morpholino)phenyl)piperidine-2,6- dione B146;Attorney Docket No: 127A057WO01 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B147; 3-(4-(4- [2,3-d]-pyrimidin-2- piperidine-2,6- dione B148; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidine-2,6- dione B149; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)- piperidine-2,6-dione B150;Attorney Docket No: 127A057WO01 3-(4-(3-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)piperidine-2,6-dione B151; 3-(4- [2,3-d]pyrimidin-2-yl)amino) - - 3-(4-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153; 3-(4-[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6-dione B154; 3-(3-(1'-[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione B155;Attorney Docket No: 127A057WO01 3-(3-(4- [2,3-d]-pyrimidin-2-yl) 2,6-dione B156; 3-(3-(1'-[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6-dione B157; 3-(4-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B158; 3-(4-(1-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B159;Attorney Docket No: 127A057WO01 3-(3-(1- [2,3-d]-pyrimidin-2-yl) piperidine-2,6- dione B160; 3-(3-(4- [2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B161; 3-(4-(1-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B162; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B163;Attorney Docket No: 127A057WO01 3-(3-(4- [2,3-d]-pyrimidin-2- piperidine-2,6- dione B164; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-1-yl)ethyl)phenyl)piperidine-2,6-dione B165; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B166;[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B167;Attorney Docket No: 127A057WO01 3-(4- d]-pyrimidin-2- - - 2,6-dione B168; 3-(4-(2-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6- dione B169; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidine-2,6- dione B170; 3-(4-(2-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B171;Attorney Docket No: 127A057WO01 3-(3- [2,3-d]-pyrimidin- - phenyl)- piperidine-2,6-dione B172; 3-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B173; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B174; O O 3-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)methyl)phenyl)piperidine-2,6- dione B175;Attorney Docket No: 127A057WO01 3-(3-((3- [2,3-d]-pyrimidin-2-yl) piperidine-2,6- dione B176; 3-(3-(2-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6- dione B177; 3-(4-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B178;[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B179;Attorney Docket No: 127A057WO01 3-(4-(2- [2,3-d]-pyrimidin-2- - phenyl)- piperidine-2,6-dione B180; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2,6-dione B181; 3-(4-((1-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2,6-dione B182;Attorney Docket No: 127A057WO01 3-(3-((1-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2,6-dione B183; 3-(4- [2,3-d]-pyrimidin-2- - phenyl)- piperidine-2,6-dione B184; 3-(3-(1-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2,6-dione B185; 3-(3-(8-([2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.2.1]octan-3-yl)- phenyl)piperidine-2,6-dione B186;Attorney Docket No: 127A057WO01 3-(3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2,6-dione B187; (S)-3- [2,3-d]-pyrimidin-2-yl) -3-methyl- piperidine-2,6-dione B188; (R)-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)-3-methyl- piperidine-2,6-dione B189; (S)-3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)-3-methyl-piperidine- 2,6-dione B190;Attorney Docket No: 127A057WO01 (R)-3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)-3-methyl-piperidine- 2,6-dione B191;[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2,6-dione B192; 3-(3-(1-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2,6-dione B193;Attorney Docket No: 127A057WO01 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-2-fluorophenyl)piperidine-2,6- dione B194; 3-(4-(4- [2,3-d]-pyrimidin-2-yl) - piperidine-2,6- dione B195; 3-(4-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-2-chlorophenyl)piperidine-2,6- dione B196; 3-(4-(4-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-3-chlorophenyl)piperidine-2,6- dione B197;Attorney Docket No: 127A057WO01 3-(4-(3- [2,3-d]-pyrimidin-2-yl) 2,6-dione B198; 3-(3-(4-[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluorophenyl)- piperidine-2,6-dione B199; 3-(5-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)- piperidine-2,6-dione B200;Attorney Docket No: 127A057WO01 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)- piperidine-2,6-dione B201; 3-(4- [2,3-d]-pyrimidin-2- - - piperidine-2,6-dione B202; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)- piperidine-2,6-dione B203; 3-(3-[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-4-fluoropiperidin-1-yl)phenyl)- piperidine-2,6-dione B204;Attorney Docket No: 127A057WO01 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-fluorophenyl)- piperidine-2,6-dione B205; or 3-(4- [2,3-d]-pyrimidin-2- - octan- phenyl)- piperidine-2,6-dione B206; or anmore diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0110] In yet another embodiment, provided herein is: 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A108; or 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135;Attorney Docket No: 127A057WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0111] In yet another embodiment, provided herein is an enantiomerically pure compound of: (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102R; (R)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108R; or (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135R; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0112] In yet another embodiment, provided herein is an enantiomerically pure compound of: (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102S; (S)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108S; or (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135S; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.Attorney Docket No: 127A057WO01

[0113] In yet another embodiment, provided herein is: 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125; 3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153; or 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0114] In yet another embodiment, provided herein is an enantiomerically pure compound of: (R)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123R; (R)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125R; (R)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148R;Attorney Docket No: 127A057WO01 (R)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153R; or (R)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164R; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0115] In still another embodiment, provided herein is an enantiomerically pure compound of: (S)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123S; (S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125S; (S)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148S; (S)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153S; or (S)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164S; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0116] In certain embodiments, an enantiomerically pure R-enantiomer is substantially free of its S-enantiomer. In certain embodiments, an enantiomerically pure R-enantiomer comprises from about 90 to about 100% of the R-enantiomer and from about 0% to about 10% of its S-Attorney Docket No: 127A057WO01 enantiomer. In certain embodiments, an enantiomerically pure R-enantiomer comprises from about 95 to about 100% of the R-enantiomer and from about 0 to about 5% of its S-enantiomer. In certain embodiments, an enantiomerically pure R-enantiomer comprises from about 98 to about 100% of the R-enantiomer and from about 0 to about 2% of its S-enantiomer. In certain embodiments, enantiomerically pure R-enantiomer comprises from about 99 to about 100% of the R-enantiomer and from about 0 to about 1% of its S-enantiomer. In certain embodiments, enantiomerically pure R-enantiomer comprises from about 99.5 to about 100% of the R- enantiomer and from about 0 to about 0.5% of its S-enantiomer.

[0117] In certain embodiments, an enantiomerically pure S-enantiomer is substantially free of its R-enantiomer. In certain embodiments, an enantiomerically pure S-enantiomer comprises from about 90 to about 100% of the S-enantiomer and from about 0% to about 10% of its R- enantiomer. In certain embodiments, an enantiomerically pure S-enantiomer comprises from about 95 to about 100% of the S-enantiomer and from about 0 to about 5% of its R-enantiomer. In certain embodiments, an enantiomerically pure S-enantiomer comprises from about 98 to about 100% of the S-enantiomer and from about 0 to about 2% of its R-enantiomer. In certain embodiments, enantiomerically pure S-enantiomer comprises from about 99 to about 100% of the S-enantiomer and from about 0 to about 1% of its R-enantiomer. In certain embodiments, enantiomerically pure S-enantiomer comprises from about 99.5 to about 100% of the S- enantiomer and from about 0 to about 0.5% of its R-enantiomer.

[0118] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to,15N for nitrogen;17O or18O for oxygen, and33S,34S, or36S for sulfur.

[0119] In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 30, no less than about 40, no less than about 50, no less than about 60, no less than about 70, no less than about 80, no less than about 90, no less than about 100, no less than about 200, no less thanAttorney Docket No: 127A057WO01 about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6410 for deuterium and 90 for carbon-13.

[0120] In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0121] In certain embodiments, a compound provided herein has a carbon-13 enrichment factor of no less than about 1.8 (about 2% carbon-13 enrichment), no less than about 4.5 (about 5% carbon-13 enrichment), no less than about 9 (about 10% carbon-13 enrichment), no less than about 18 (about 20% carbon-13 enrichment), no less than about 45 (about 50% carbon-13 enrichment), no less than about 68 (about 75% carbon-13 enrichment), no less than about 72 (about 80% carbon-13 enrichment), no less than about 77 (about 85% carbon-13 enrichment), no less than about 81 (about 90% carbon-13 enrichment), no less than about 86 (about 95% carbon- 13 enrichment), no less than about 87 (about 97% carbon-13 enrichment), no less than about 88 (about 98% carbon-13 enrichment), no less than about 89 (about 99% carbon-13 enrichment), or no less than about 90 (about 99.5% carbon-13 enrichment). The carbon-13 enrichment can beAttorney Docket No: 127A057WO01 determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0122] In certain embodiments, at least one of the atoms of a compound provided herein, as specified as isotopically enriched, has isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound provided herein, as specified as isotopically enriched, have isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In any events, the isotopic enrichment of the isotopically enriched atom of a compound provided herein is no less than the natural abundance of the isotope specified.

[0123] In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound provided herein, as specified as deuterium-enriched, have deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.

[0124] In certain embodiments, at least one of the atoms of a compound provided herein, as specified as13C-enriched, has carbon-13 enrichment of no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound provided herein, as specified as13C-enriched, have carbon-13 enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.Attorney Docket No: 127A057WO01

[0125] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0126] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cis / trans (or Z / E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0127] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0128] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci.1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; Wiley-VCH and VHCA, Zurich, 2011.

[0129] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,Attorney Docket No: 127A057WO01 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid. In certain embodiments, a compound provided herein is a hydrochloride salt. In certain embodiments, a compound provided herein is a p-toluenesulfonate salt. In certain embodiments, a compound provided herein is a di-p- toluenesulfonate salt.

[0130] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)-1,3-propanediol, and tromethamine.

[0131] A compound provided herein may also be provided as a prodrug, which is a functional derivative of a compound, for example, of Formula I and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may beAttorney Docket No: 127A057WO01 easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

[0132] The compounds provided herein can be prepared, isolated, or obtained by any method known to one of ordinary skill in the art, for example, by following the procedures described in WO 2023 / 220640 A1, the disclosure of which is incorporated herein by reference in its entirety. Pharmaceutical Compositions

[0133] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0134] In another embodiment, provided herein is a pharmaceutical composition, comprising any one of compounds A101 to A166, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0135] In yet another embodiment, provided herein is a pharmaceutical composition, comprising any one of compounds B101 to B206, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0136] In yet another embodiment, provided herein is a pharmaceutical composition, comprising compound A102, A108, or A135, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0137] In yet another embodiment, provided herein is a pharmaceutical composition, comprising enantiomerically pure compound A102R, A108R, or A135R, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.Attorney Docket No: 127A057WO01

[0138] In yet another embodiment, provided herein is a pharmaceutical composition, comprising enantiomerically pure compound A102S, A108S, or A135S, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0139] In yet another embodiment, provided herein is a pharmaceutical composition, comprising compound B123, B125, B148, B153, or A164, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0140] In yet another embodiment, provided herein is a pharmaceutical composition, comprising enantiomerically pure compound B123R, B125R, B148R, B153R, or A164R, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0141] In still another embodiment, provided herein is a pharmaceutical composition, comprising enantiomerically pure compound B123S, B125S, B148S, B153S, or A164S, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0142] A pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0143] In one embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form forAttorney Docket No: 127A057WO01 subcutaneous administration. In still another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for topical administration.

[0144] A pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.

[0145] A pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0146] In certain embodiments, a pharmaceutical composition provided herein is formulated as a capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount ranging from about 0.1 to about 1,000, from about 0.2 to about 500, from about 0.5 to about 250, or from about 0.5 to about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount ranging from about 0.1 to about 1,000 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount ranging from about 0.2 to about 500 mg per capsule. In certainAttorney Docket No: 127A057WO01 embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount ranging from about 0.5 to about 250 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount ranging from about 0.5 to about 100 mg per capsule.

[0147] In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount of about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 10, about 15, about 20, about 25, about 50, about 75, or about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein in an amount of about 1, about 2.5, about 5, about 10, about 25, about 50, or about 100 mg per capsule. Methods of Treatment

[0148] In one embodiment, provided herein is method of treating, preventing, or ameliorating one or more symptoms of breast cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0149] In certain embodiments, the breast cancer is characterized by CDK4 or CDK6 overexpression. In certain embodiments, the breast cancer is characterized by CDK4 overexpression. In certain embodiments, the breast cancer is characterized by CDK6 overexpression. In certain embodiments, the breast cancer is characterized by CDK4 and CDK6 (CDK4 / 6) overexpression.

[0150] In certain embodiments, the breast cancer is characterized by CDK4 or CDK6 upregulation. In certain embodiments, the breast cancer is characterized by CDK4 upregulation. In certain embodiments, the breast cancer is characterized by CDK6 upregulation. In certain embodiments, the breast cancer is characterized by CDK4 / 6 upregulation.Attorney Docket No: 127A057WO01

[0151] In certain embodiments, the breast cancer is advanced. In certain embodiments, the breast cancer is incurable. In certain embodiments, the breast cancer is metastatic. In certain embodiments, the breast cancer is recurrent. In certain embodiments, the breast cancer is relapsed. In certain embodiments, the breast cancer is refractory. In certain embodiments, the breast cancer is refractory to a standard therapy. In certain embodiments, the breast cancer is intolerant of a standard therapy. In certain embodiments, the breast cancer is drug-resistant.

[0152] In certain embodiments, the breast cancer is resistant to a CDK inhibitor. In certain embodiments, the breast cancer is cancer with intrinsic resistance to a CDK inhibitor. In certain embodiments, the breast cancer is cancer with acquired resistance to a CDK inhibitor.

[0153] In certain embodiments, the breast cancer is resistant to a CDK4 inhibitor. In certain embodiments, the breast cancer is cancer with intrinsic resistance to a CDK4 inhibitor. In certain embodiments, the breast cancer is cancer with acquired resistance to a CDK4 inhibitor.

[0154] In certain embodiments, the breast cancer is resistant to a CDK6 inhibitor. In certain embodiments, the breast cancer is cancer with intrinsic resistance to a CDK6 inhibitor. In certain embodiments, the breast cancer is cancer with acquired resistance to a CDK6 inhibitor.

[0155] In certain embodiments, the breast cancer is resistant to a CDK4 / 6 inhibitor. In certain embodiments, the breast cancer is cancer with intrinsic resistance to a CDK4 / 6 inhibitor. In certain embodiments, the breast cancer is cancer with acquired resistance to a CDK4 / 6 inhibitor.

[0156] In certain embodiments, the breast cancer is resistant to abemaciclib, palbociclib, or ribociclib. In certain embodiments, the breast cancer is resistant to abemaciclib. In certain embodiments, the breast cancer is cancer with intrinsic resistance to abemaciclib. In certain embodiments, the breast cancer is cancer with acquired resistance to abemaciclib. In certain embodiments, the breast cancer is resistant to palbociclib. In certain embodiments, the breast cancer is cancer with intrinsic resistance to palbociclib. In certain embodiments, the breast cancer is cancer with acquired resistance to palbociclib. In certain embodiments, the breast cancer is resistant to ribociclib. In certain embodiments, the breast cancer is cancer with intrinsicAttorney Docket No: 127A057WO01 resistance to ribociclib. In certain embodiments, the breast cancer is cancer with acquired resistance to ribociclib.

[0157] In certain embodiments, the breast cancer is hormone receptor-positive (HR+) breast cancer. In certain embodiments, the breast cancer is hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+ / HER2-) breast cancer. In certain embodiments, the breast cancer is triple negative breast cancer.

[0158] In certain embodiments, the breast cancer is histologically confirmed HR+ / HER2- breast cancer. In certain embodiments, the breast cancer is advanced HR+ / HER2- breast cancer. In certain embodiments, the breast cancer is metastatic HR+ / HER2- breast cancer. In certain embodiments, the breast cancer is locally advanced HR+ / HER2- breast cancer.

[0159] In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to a CDK inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to a CDK inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to a CDK inhibitor.

[0160] In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to a CDK4 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to a CDK4 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to a CDK4 inhibitor.

[0161] In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to a CDK6 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to a CDK6 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to a CDK6 inhibitor.

[0162] In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to a CDK4 / 6 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to a CDK4 / 6 inhibitor. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to a CDK4 / 6 inhibitor.Attorney Docket No: 127A057WO01

[0163] In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to abemaciclib, palbociclib, or ribociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to abemaciclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to abemaciclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to abemaciclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to palbociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to palbociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to palbociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer resistant to ribociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with intrinsic resistance to ribociclib. In certain embodiments, the breast cancer is HR+ / HER2- breast cancer with acquired resistance to ribociclib.

[0164] In certain embodiments, the subject has failed a prior therapy. In certain embodiments, the subject has failed a prior CDK inhibitor therapy. In certain embodiments, the subject has failed a prior CDK4 inhibitor therapy. In certain embodiments, the subject has failed a prior CDK6 inhibitor therapy. In certain embodiments, the subject has failed a prior CDK4 / 6 inhibitor therapy. In certain embodiments, the subject has failed a prior abemaciclib, palbociclib, or ribociclib therapy. In certain embodiments, the subject has failed a prior abemaciclib therapy. In certain embodiments, the subject has failed a prior therapy. In certain embodiments, the subject has failed a prior palbociclib therapy. In certain embodiments, the subject has failed a prior ribociclib therapy.

[0165] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a woman. In certain embodiments, the subject is a premenopausal human. In certain embodiments, the subject is a postmenopausal human.

[0166] In certain embodiments, the therapeutically effective amount of a compound provided herein (i.e., a CDK4 / 6 degrader) is ranging from about 0.01 to about 10 mg / kg per day, from about 0.02 to about 5 mg / kg per day, from about 0.05 to about 2 mg / kg per day, or from about 0.1 to about 1 mg / kg per day. In one embodiment, the therapeutically effective amount of aAttorney Docket No: 127A057WO01 compound provided herein is ranging from about 0.01 to about 10 mg / kg per day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.02 to about 5 mg / kg per day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.05 to about 2 mg / kg per day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 1 mg / kg per day. In still another embodiment, the therapeutically effective amount of a compound provided herein is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / kg per day.

[0167] In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 1 to about 500 mg per day, from about 2 to about 200 mg per day, from about 5 to about 100 mg per day, or from about 10 mg to about 100 mg per day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 1 to about 500 mg per day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 2 to about 200 mg per day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 5 to about 100 mg per day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 10 to about 100 mg per day. In still another embodiment, the therapeutically effective amount of a compound provided herein is about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, or about 200 mg per day.

[0168] Depending on the disease to be treated and the subject’s condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.

[0169] In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet anotherAttorney Docket No: 127A057WO01 embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.

[0170] A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets, capsules, or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by a method known in the art such as evaluation of subject’s symptoms, physical examination, visualization of the cancer that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0171] A compound provided herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous, i.e., every day, or intermittently. In certain embodiments, a compound provided herein is administered once daily (QD). In certain embodiments, a compound provided herein is administered twice daily (BID). In certain embodiments, a compound provided herein is administered three times daily (TID). In certain embodiments, a compound provided herein is administered four times daily (QID).

[0172] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0173] In certain embodiments, a compound provided herein is cyclically administered to a subject to be treated. Cycling therapy involves the administration of the compound for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to the compound, avoid or reduce the side effects of the compound, and / or improves the efficacy of the compound.Attorney Docket No: 127A057WO01

[0174] Consequently, in one embodiment, a compound provided herein is administered for a cycle of about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, or about ten weeks, with a rest period of about 1 day to about four weeks. In one embodiment, a compound provided herein is administered for a cycle of three weeks, four weeks, five weeks, or six weeks with a rest period of 1, 3, 5, 7, 9, 12, or 14. In certain embodiments, the rest period is 7 days. In certain embodiments, the rest period is 14 days. In certain embodiments, the rest period is a period that is sufficient for bone marrow recovery. The frequency, number, and length of dosing cycles can be increased or decreased.

[0175] In certain embodiments, a compound provided herein is administered for three weeks in a 28-day cycle. In certain embodiments, a compound provided herein is administered daily for three weeks in a 28-day cycle. In certain embodiments, a compound provided herein is administered once daily (QD) for three weeks in a 28-day cycle.

[0176] In certain embodiments, a compound provided herein is administered for four weeks in a 28-day cycle. In certain embodiments, a compound provided herein is administered daily for four weeks in a 28-day cycle. In certain embodiments, a compound provided herein is administered once daily (QD) for four weeks in a 28-day cycle.

[0177] In certain embodiments, a compound provided herein is administered for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, a compound provided herein is administered daily for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, a compound provided herein is administered once daily for three weeks in a 28- day cycle with a 7-day rest period.

[0178] In certain embodiments, the subject is treated with a compound provided herein from about 1 to about 60, from about 2 to about 48, from about 2 to 36, from about 4 to about 24 cycles, or from about 4 to about 12 cycles. In certain embodiments, the subject is treated with a compound provided herein from about 1 to about 60 cycles. In certain embodiments, the subject is treated with a compound provided herein from about 2 to about 48 cycles. In certain embodiments, the subject is treated with a compound provided herein from about 2 to 36 cycles. In certain embodiments, the subject is treated with a compound provided herein from about 4 toAttorney Docket No: 127A057WO01 about 24 cycles. In certain embodiments, the subject is treated with a compound provided herein from about 4 to about 12 cycles.

[0179] In certain embodiments, a method provided herein further comprises administering to the subject in need thereof a therapeutically effective amount of an estrogen receptor antagonist.

[0180] Thus, in one embodiment, provided herein is method of treating, preventing, or ameliorating one or more symptoms of breast cancer in a subject, comprising administering to the subject in need thereof (i) a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (ii) a therapeutically effective amount of an estrogen receptor antagonist.

[0181] In certain embodiments, the estrogen receptor antagonist is a selective estrogen receptor degrader. In certain embodiments, the estrogen receptor antagonist is amcenestrant, brilanestrant, camizestrant, elacestrant, fulvestrant, fulvestrant 3-boronic acid, giredestrant, imlunestrant, rintodestrant, or vepdegestrant. In certain embodiments, the estrogen receptor antagonist is fulvestrant.

[0182] In another embodiment, provided herein is method of treating, preventing, or ameliorating one or more symptoms of breast cancer in a subject, comprising administering to the subject in need thereof (i) a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (ii) a therapeutically effective amount of fulvestrant.

[0183] In certain embodiments, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.1 to about 100 mg / kg per day, from about 0.2 to about 50 mg / kg per day, from about 0.5 to about 20 mg / kg per day, or from about 1 to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.1 to about 100 mg / kg per day. InAttorney Docket No: 127A057WO01 another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.2 to about 50 mg / kg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.5 to about 20 mg / kg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 1 to about 10 mg / kg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / kg per day. In still another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg / kg per day.

[0184] In certain embodiments, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 10 to about 5,000 mg per day, from about 20 to about 2,000 mg per day, from about 50 to about 1,000 mg per day, from about 100 mg to about 1,000 mg per day, or from about 100 mg to about 500 mg per day. In one embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 10 to about 5,000 mg per day. In another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 20 to about 2,000 mg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 50 to about 1,000 mg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 100 to about 1,000 mg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 100 to about 500 mg per day. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000 mg per day. In still another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, or about 2,000 mg per day.Attorney Docket No: 127A057WO01

[0185] In certain embodiments, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.1 mg / kg once every 28 days to about 100 mg / kg twice every 28 days, from about 0.2 mg / kg once every 28 days to about 50 mg / kg twice every 28 days, from about 0.5 mg / kg once every 28 days to about 25 mg / kg twice every 28 days, or from about 1 mg / kg once every 28 days to about 20 mg / kg twice every 28 days. In one embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.1 mg / kg once every 28 days to about 100 mg / kg twice every 28 days. In another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.2 mg / kg once every 28 days to about 50 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 0.5 mg / kg once every 28 days to about 25 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 1 mg / kg once every 28 days to about 20 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg / kg twice every 28 days. In still another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / kg once every 28 days.

[0186] In certain embodiments, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 10 mg once every 28 days to about 5,000 mg twice every 28 days, from about 20 mg once every 28 days to about 2,000 mg twice every 28 days, from about 50 mg once every 28 days to about 1,000 mg twice every 28 days, or from about 100 mg once every 28 days to about 1,000 mg twice every 28 days. In one embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 10 mg once every 28 days to about 5,000 mg twice every 28 days. In another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 20 mg once every 28 days to about 2,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is ranging from about 50 mg once every 28 days to about 1,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of anAttorney Docket No: 127A057WO01 estrogen receptor antagonist described herein is ranging from about 100 mg once every 28 days to about 1,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 100, about 250, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg twice every 28 days. In still another embodiment, the therapeutically effective amount of an estrogen receptor antagonist described herein is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1,000 mg once every 28 days.

[0187] In certain embodiments, the therapeutically effective amount of fulvestrant is ranging from about 0.1 mg / kg once every 28 days to about 100 mg / kg twice every 28 days, from about 0.2 mg / kg once every 28 days to about 50 mg / kg twice every 28 days, from about 0.5 mg / kg once every 28 days to about 25 mg / kg twice every 28 days, or from about 1 mg / kg once every 28 days to about 20 mg / kg twice every 28 days. In one embodiment, the therapeutically effective amount of fulvestrant is ranging from about 0.1 mg / kg once every 28 days to about 100 mg / kg twice every 28 days. In another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 0.2 mg / kg once every 28 days to about 50 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 0.5 mg / kg once every 28 days to about 25 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 1 mg / kg once every 28 days to about 20 mg / kg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg / kg twice every 28 days. In still another embodiment, the therapeutically effective amount of fulvestrant is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / kg once every 28 days.

[0188] In certain embodiments, the therapeutically effective amount of fulvestrant is ranging from about 10 mg once every 28 days to about 5,000 mg twice every 28 days, from about 20 mg once every 28 days to about 2,000 mg twice every 28 days, from about 50 mg once every 28 days to about 1,000 mg twice every 28 days, or from about 100 mg once every 28 days to about 1,000 mg twice every 28 days. In one embodiment, the therapeutically effective amount of fulvestrant is ranging from about 10 mg once every 28 days to about 5,000 mg twice every 28Attorney Docket No: 127A057WO01 days. In another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 20 mg once every 28 days to about 2,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 50 mg once every 28 days to about 1,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is ranging from about 100 mg once every 28 days to about 1,000 mg twice every 28 days. In yet another embodiment, the therapeutically effective amount of fulvestrant is about 100, about 250, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg twice every 28 days. In still another embodiment, the therapeutically effective amount of fulvestrant is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1,000 mg once every 28 days.

[0189] Depending on the disease to be treated and the subject’s condition, an estrogen receptor antagonist described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.

[0190] In one embodiment, an estrogen receptor antagonist described herein is administered orally. In another embodiment, an estrogen receptor antagonist described herein is administered parenterally. In yet another embodiment, an estrogen receptor antagonist described herein is administered intravenously. In yet another embodiment, an estrogen receptor antagonist described herein is administered intramuscularly. In yet another embodiment, an estrogen receptor antagonist described herein is administered subcutaneously. In still another embodiment, an estrogen receptor antagonist described herein is administered topically.

[0191] An estrogen receptor antagonist described herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets, capsules, or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. An estrogen receptor antagonist described herein and a compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by a method known in the art such as evaluation of subject’s symptoms, physicalAttorney Docket No: 127A057WO01 examination, visualization of the cancer that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0192] An estrogen receptor antagonist described herein can be administered once daily (QD), once every 14 days, once every 28 days, or twice every 28 days; or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In certain embodiments, an estrogen receptor antagonist described herein is administered once daily (QD). In certain embodiments, an estrogen receptor antagonist described herein is administered once every 14 days. In certain embodiments, an estrogen receptor antagonist described herein is administered once every 28 days. In certain embodiments, an estrogen receptor antagonist described herein is administered twice every 28 days. In certain embodiments, an estrogen receptor antagonist described herein is administered twice daily (BID). In certain embodiments, an estrogen receptor antagonist described herein is administered three times daily (TID). In certain embodiments, an estrogen receptor antagonist described herein is administered four times daily (QID).

[0193] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific estrogen receptor antagonist and CDK degrader employed, the metabolic stability and length of action of the estrogen receptor antagonist and CDK degrader, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the severity of the particular condition, and the host undergoing therapy.

[0194] In certain embodiments, an estrogen receptor antagonist described herein is cyclically administered in combination with a compound (i.e., a CDK4 / 6 degrader) provided herein to a subject to be treated. Cycling therapy involves the administration of the estrogen receptor antagonist and compound for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one or more of the therapies, and / or improves the efficacy of one or more of the therapies.

[0195] Consequently, in one embodiment, an estrogen receptor antagonist described herein and a compound provided herein are administered for a cycle of about one week, about twoAttorney Docket No: 127A057WO01 weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, or about ten weeks, with a rest period of about 1 day to about four weeks. In one embodiment, an estrogen receptor antagonist described herein and a compound provided herein are administered for a cycle of three weeks, four weeks, five weeks, or six weeks with a rest period of 1, 3, 5, 7, 9, 12, or 14. In certain embodiments, the rest period is 7 days. In certain embodiments, the rest period is 14 days. In certain embodiments, the rest period is a period that is sufficient for bone marrow recovery. The frequency, number, and length of dosing cycles can be increased or decreased.

[0196] In certain embodiments, an estrogen receptor antagonist described herein and a compound provided herein are administered for four weeks in a 28-day cycle. In certain embodiments, an estrogen receptor antagonist described herein and a compound provided herein are each administered daily for four weeks in a 28-day cycle. In certain embodiments, an estrogen receptor antagonist described herein and a compound provided herein are each administered once daily for four weeks in a 28-day cycle.

[0197] In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered daily for four weeks in a 28-day cycle. In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered once daily for four weeks in a 28-day cycle.

[0198] In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered daily for three weeks in a 28-day cycle. In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered once daily for three weeks in a 28-day cycle.

[0199] In certain embodiments, an estrogen receptor antagonist described herein and a compound provided herein are each administered for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, an estrogen receptor antagonist described herein and a compound provided herein are each administered daily for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, an estrogen receptor antagonist described herein andAttorney Docket No: 127A057WO01 a compound provided herein are each administered once daily for three weeks in a 28-day cycle with a 7-day rest period.

[0200] In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered daily for three weeks in a 28-day cycle with a 7-day rest period. In certain embodiments, an estrogen receptor antagonist described herein is administered once or twice every 28 days and a compound provided herein is administered once daily for three weeks in a 28-day cycle with a 7-day rest period.

[0201] In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 1 to about 60, from about 2 to about 48, from about 2 to 36, or from about 4 to about 24 cycles, or from about 4 to about 12 cycles. In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 1 to about 60 cycles. In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 2 to about 48 cycles. In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 2 to 36 cycles. In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 4 to about 24 cycles. In certain embodiments, the subject is treated with an estrogen receptor antagonist described herein and a compound provided herein from about 4 to about 12 cycles.

[0202] In one embodiment, provided herein is a method of inhibiting the growth of a cancerous cell, comprising contacting the cancerous cell with an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.Attorney Docket No: 127A057WO01

[0203] In another embodiment, provided herein is a method of inducing degradation of a CDK in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0204] In certain embodiments, the CDK is a CDK4 or CDK6. In certain embodiments, the CDK is a CDK4. In certain embodiments, the CDK is a CDK4 complexed with a cyclin. In certain embodiments, the CDK is a CDK4 complexed with a cyclin D. In certain embodiments, the CDK is a CDK4 complexed with a cyclin D1. In certain embodiments, the CDK is a CDK4 complexed with a cyclin D2. In certain embodiments, the CDK is a CDK4 complexed with a cyclin D3. In certain embodiments, the CDK is a CDK6. In certain embodiments, the CDK is a CDK6 complexed with a cyclin. In certain embodiments, the CDK is a CDK6 complexed with a cyclin D. In certain embodiments, the CDK is a CDK6 complexed with a cyclin D1. In certain embodiments, the CDK is a CDK6 complexed with a cyclin D2. In certain embodiments, the CDK is a CDK6 complexed with a cyclin D3.

[0205] In yet another embodiment, provided herein is a method of downregulating a CDK6 in a cell, comprising contacting the cell with an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0206] In still another embodiment, provided herein is a method of inhibiting the phosphorylation of a retinoblastoma protein (RB) in a cell, comprising contacting the cell with an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0207] In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is a cell of breast cancer described herein.Attorney Docket No: 127A057WO01

[0208] A compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[0209] In certain embodiments, provided herein is a kit which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein.

[0210] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.

[0211] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0212] The disclosure will be further understood by the following non-limiting examples.Attorney Docket No: 127A057WO01 EXAMPLES

[0213] As used herein, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: mg (milligrams); mL (milliliters); h (hour or hours); and min (minute or minutes). Example 1 CDK4 / 6 Protein Degradation

[0214] MDA-MB-231 cells were cultured in DMEM media supplemented with 10% fetal bovine serum and 5% streptomycin and penicillin. The cells were plated in a 6-well plate at 500,000 cells / well in the culturing media. After overnight incubation, the cells were treated with DMSO (control) or a compound at 10 nM, 100 nM and 1 µM for 6 h at 37 ºC under 5% CO2. The media was then removed, and the cells were washed with 1 x PBS. The cells were scraped in 1 x PBS and centrifuged to collect the cell pellets, which were lysed with an IP lysis buffer solution and centrifuged. The lysates were stored at -80 ºC until protein quantification.

[0215] A protein assay was conducted to determine lysate protein concentration, and loading samples were prepared to run on a JESS SIMPLE WESTERN automated blot system or SDS- PAGE for western blot analysis. For western blot analysis, the whole cell protein extracts were separated on a 4-12% SDS-polyacrylamide gel, transferred to nitrocellulose, blocked with LI- COR INTERCEPT® (PBS) blocking buffer for 1 h at room temperature. Primary antibodies (CDK2 rabbit mAb, CDK4 rabbit mAb, CDK6 rabbit mAb, β-actin mouse mAb, RB mouse mAb, and phospho-RB ser 807 / 811 rabbit mAb) were prepared in an INTERCEPT® (PBS) blocking buffer and added to blots after the blocking step. After overnight incubation at 4 ºC with the primary antibodies, the blots were washed with 0.1% TWEEN-PBS and treated with secondary antibody solutions (IRDYE® 680RD goat anti-rabbit and IRDYE® 800CW goat anti- mouse secondary antibody in the INTERCEPT® (PBS) blocking buffer) for 1 h at room temperature. The blots were washed with 0.1% TWEEN PBS and then imaged with ODYSSEY® CLx.Attorney Docket No: 127A057WO01

[0216] For the JESS PROTENSIMPLE analysis, the whole cell protein extracts were analyzed at a concentration of 1 mg / mL and separated using 12-230k Da separation module. The same primary antibodies were used, and JESS anti-rabbit, anti-mouse and anti-mouse NIR detection modules were used. The signals were detected by the JESS machine and analyzed with the COMPASS software.

[0217] The results are summarized in Tables 1 and 2, where “A” represents a percentage degradation value of no less than 50%; “B” represents a percentage degradation value of less than 50% and no less than 25%; “C” represents a percentage degradation value of less than 25% and no less than 10%; and “D” represents a percentage degradation value of less than 10%; where “A’” represents a DC50value of no greater than 5 nM; “B’” represents a DC50value of greater than 5 nM and no greater than 25 nM; “C’” represents a DC50 value of greater than 25 nM and no greater than 100 nM; and “D’” represents a DC50 value of greater than 100 nM; and where “A”” represents a Dmaxvalue of no less than 80%; “B”” represents a Dmaxvalue of less than 80% and no less than 60%; “C”” represents a Dmax value of less than 60% and no less than 40%; and “D”” represents a Dmax value of less than 40%. TABLE 1. Effect of CDK4 / 6 Degraders on CDK Degradation CDK2 CDK4 CDK6 Compd. No. 1 M 01 M 1 M 01 M 1 M 01 MAttorney Docket No: 127A057WO01 CDK2 CDK4 CDK6 Compd. No. 1 µM 0.1 µM 1 µM 0.1 µM 1 µM 0.1 µMAttorney Docket No: 127A057WO01 CDK2 CDK4 CDK6 Compd. No. 1 µM 0.1 µM 1 µM 0.1 µM 1 µM 0.1 µMAttorney Docket No: 127A057WO01 CDK2 CDK4 CDK6 Compd. No. 1 µM 0.1 µM 1 µM 0.1 µM 1 µM 0.1 µMAttorney Docket No: 127A057WO01 CDK2 CDK4 CDK6 Compd. No. 1 µM 0.1 µM 1 µM 0.1 µM 1 µM 0.1 µMAttorney Docket No: 127A057WO01 CDK2 CDK4 CDK6 Compd. No. 1 µM 0.1 µM 1 µM 0.1 µM 1 µM 0.1 µMCDK4 CDK6 Compd. No. DC50 (nM) Dmax (%) DC50 (nM) Dmax (%)Cell Viability Assays

[0218] MCF-7 (ER+ / HER2-) and MDA-MB-231 (TNBC) cells were cultured in DMEM media supplemented with 10% fetal bovine serum and 5% streptomycin and penicillin. T47D (ER+ / HER2-) and ZR751 (ER+ / HER2-) cells were cultured in RPMI media supplemented with 10% fetal bovine serum and 5% streptomycin and penicillin. The cells were plated in a 96-well plate at 500 cells / well (MCF-7), 150 cells / well (MDA-MB-231), 600 cells / well (T47D), or 1,000 cells / well (ZR751). After overnight incubation, the cells were treated with DMSO (control) or a compound in triplicate at 9 concentrations starting at 5 µM and proceeding at a 1:3 dilution rate until the last concentration at 0.76 nM. The cells were incubated at 37 ºC under 5% CO2 for 10 days. The media was changed and the compound was replenished twice during the 10-day incubation. On the final day of the experiment, 100 μL of media was removed from each experimental well and replaced with 100 μL of CTG. The plates were then incubated on an orbital shaker protected from light for 10 min and then incubated in the dark without shaking for 10 min. The signals were detected by the JESS machine and analyzed with the COMPASS software. The plates were then run on a CLARIOSTAR plate reader using a 96 well luminescenceAttorney Docket No: 127A057WO01 protocol with a 1 second acquisition time. The data were analyzed using a nonlinear regression (four parameter model) in GRAPHPAD PRISM™ to generate IC50values.

[0219] The results are summarized in Table 3, where “A” represents an IC50 value of no greater than 10 nM; “B” represents an IC50value of greater than 10 nM and no greater than 50 nM; “C” represents an IC50 value of greater than 50 nM and no greater than 150 nM; and “D” represents an IC50 value of greater than 150 nM. TABLE 3. Effect of CDK4 / 6 Degraders on Cell Proliferation IC50 (nM) Compd. No. MCF-7 T47D ZR751 MDA-MB-231xamp e Inhibition of pRB Phosphorylation

[0220] MCF-7 (ER+ / HER2-) and MDA-MB-231 (TNBC) cells were cultured in DMEM media supplemented with 10% fetal bovine serum and 5% streptomycin and penicillin. The cells were plated in black walled 384 well plates at 8,000 cells / well (MCF-7) or 10,000 cells / well (MDA-MB-231). After overnight incubation, the cells were treated with DMSO (control) or a compound in duplicate at 9 concentrations starting at 10 µM and proceeding at a 1:3 dilution rate until the last concentration at 1.52 nM for 24 h at 37 ºC under 5% CO2. Media was then removed and 4% PFA (50 µL) was added to each well. After the plates were incubated at room temperature on a rotator for 20 min, the PFA was removed and the cells were washed with PBS, followed by two 10-min incubations with 0.1% Triton X-100 in PBS at room temperature on a rotator. LI-COR INTERCEPT® (PBS) blocking buffer was then added to each well and the plates were incubated at room temperature on a rotator for 90 min. Primary antibodies (RBAttorney Docket No: 127A057WO01 mouse mAb, and phospho-RB ser 807 / 811 rabbit mAb) in an INTERCEPT® (PBS) blocking buffer were added. After overnight incubation at 4 ºC with the primary antibodies, the plates were washed five times with 0.1% Tween 20 in PBS with a five-minute incubation per wash. The plates were then incubated in secondary antibody solutions (IRDYE® 680RD goat anti- rabbit and IRDYE® 800CW goat anti-mouse secondary antibody in the INTERCEPT® (PBS) blocking buffer) for 1 h at room temperature and protected from light. After incubation with secondary antibody, the plates were washed five times with 0.1% Tween 20 in PBS with a five- minute incubation per wash all protected from light. The plates were then imaged using an ODYSSEY® CLx. The fluorescence intensities were acquired using an image studio software and analyzed using a nonlinear regression (four parameter model) in GRAPHPAD PRISM™ to generate IC50 values.

[0221] The results are summarized in Table 4, where “A” represents an IC50 value of no greater than 10 nM; “B” represents an IC50value of greater than 10 nM and no greater than 50 nM; “C” represents an IC50 value of greater than 50 nM and no greater than 150 nM; and “D” represents an IC50 value of greater than 150 nM. TABLE 4. Effect of CDK4 / 6 Degraders on pRB Phosphorylation Inhibition IC50 (nM) Compd. No. MCF 7 MDA MB 231Example 4 Xenograft Mouse Models

[0222] MCF-7 (ER+ / HER2-) cells were inoculated subcutaneously in the right flank of the female Balb / c nude mice. Upon tumor establishment, the mice were each dosed orally (QD)Attorney Docket No: 127A057WO01 with a compound at a given dose. Tumor volumes were measured twice weekly with tumor growth inhibition (TGI) or regression rates calculated based on tumor volume measurements on Day 28 post start of the treatments. Results are summarized in Table 5 below. TABLE 5. Anticancer Effects of CDK4 / 6 Degraders in a Xenograft Model of Breast Cancer Compd. No. Dose TGI (%) Regression (%) A102 30 mg / kg QD 6.3p Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of a CDK4 / 6 Degrader in Subjects with Advanced and / or Metastatic Breast Cancer

[0223] This is a multicenter, nonrandomized, open-label clinical study evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of a CDK4 / 6 degrader as a monotherapy and / or in combination with fulvestrant in subjects with HR+ / HER2- advanced and / or metastatic breast cancer. The study includes a dose escalation part (Part A), followed by a dose expansion (Part B).

[0224] During dose escalation (Part A), the CDK4 / 6 degrader is initially dose escalated alone and then explored in combination with fulvestrant. The dose escalation scheme for the monotherapy is based on an accelerated titration design (ATD) with single participant cohorts followed by expansion to cohorts of ≥ 3 participants and transition to a Bayesian Optimal Interval (BOIN) design. Liu and Yuan, J. R. Stat. Soc. Ser. C Appl. Stat.2015, 64, 507-23. Part A determines the maximum tolerated dose (MTD) / maximum evaluable dose (MED) of the CDK4 / 6 degrader. Part B determines the preliminary efficacy of the CDK4 / 6 degrader.Attorney Docket No: 127A057WO01

[0225] Approximately 82 eligible subjects are enrolled and nonrandomly assigned initially to Part A (dose escalation; ~36 subjects) and later to Part B (dose expansion; ~46 subjects). During dose escalation (Part A), the CDK4 / 6 degrader is administered orally QD in a 28-day treatment cycle. Administration of the CDK4 / 6 degrader continues until disease progression, death, intolerance to trial intervention, or withdrawal of consent. For a combination therapy, fulvestrant (500 mg) is administered by intramuscular injection on Days 1 and 15 in Cycle 1 and every 28 days thereafter, unless the subjects are receiving stable doses of fulvestrant prior to dosing of the CDK4 / 6 degrader. During dose escalation (Part A), depending on the emerging safety profile, an intermittent dosing schedule with 21 days QD of the CDK4 / 6 degrader followed by 7 days off in 28-day cycles can be employed. Flaherty et al., Clin. Cancer Res.2012, 18, 568-76; Infante et al., Clin. Cancer Res.2016, 22, 5696-705.

[0226] The ATD portion of dose escalation (Part A) begins with dose level (DL) 1 at 50 mg / day of the CDK4 / 6 degrader. The first participant at DL1 is observed for 28 days for any acute toxicities before subsequent participants are enrolled. Single participant cohorts are enrolled at DL1 and DL2 during the ATD portion. In the absence of a Grade ≥ 2 adverse event (AE), a dose increase from DL1 to DL2 is up to 150%. If a Grade ≥ 2 AE occurs, the current dose level is expanded to ≥ 3 participants and the trial design transitions to BOIN. In the expanded cohorts, the first participant enrolled is observed for 5 days for any acute toxicities before additional participants are enrolled. In the absence of a dose-limiting toxicity (DLT) in the BOIN design, dose escalation uses increments between 33% and 100%. Once the first DLT is observed, subsequent dose escalation increments are ≤ 33%. If the starting dose in the first monotherapy cohort (DL1) is not tolerated, a de-escalated dose are carried out in a cohort of ≥ 3 participants if feasible. The dose escalation scheme for the CDK4 / 6 degrader combination therapy with fulvestrant uses a BOIN design with no accelerated titration. Dose escalation increments for the combination therapy cohorts are determined based on safety data from the monotherapy cohorts and any available safety data from combination therapy cohorts.

[0227] During the BOIN portion of each dose escalation, escalation is based on cohorts of ≥ 3 participants for each dose level. Any cohort that is backfilled may enroll approximately 12 participants (including both escalation and backfill participants) and allows for further exploration of a specific dose during dose escalation.Attorney Docket No: 127A057WO01

[0228] The expansion cohort (Part B) is enrolled using a Bayesian Optimal Phase 2 (BOP2) design. The same schedule of the CDK4 / 6 degrader administration, either QD for 28 days or the intermittent dosing schedule with 21 days QD of the CDK4 / 6 degrader followed by 7 days off in 28-day cycles chosen during dose escalation is used in dose expansion.

[0229] The clinical study enrolls eligible adults (18 years and over) with a current diagnosis of advanced and / or metastatic HR+ / HER2- breast cancer, determined from the most recent tumor sample (primary or metastatic), as per the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guideline recommendations. Subjects who have progressed on prior therapy are considered for enrollment based on prior treatment criteria. Subjects in the expansion cohort must have measurable disease according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) and / or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Subjects with nonmeasurable disease are also allowed to enroll in dose escalation cohorts.

[0230] The clinical study enrolls subjects with HR+ / HER2- breast cancer without visceral crisis who have failed appropriate standard therapies, including CDK4 / 6 inhibitors and endocrine therapies, and where further unmet medical need exists.

[0231] Eligible subjects for the clinical study have metastatic and / or locally advanced HR+ / HER2- breast cancer. The subjects must have histologically confirmed HR+ / HER2- breast cancer determined from the most recent tumor sample (primary or metastatic), as per the ASCO and CAP guideline recommendations. To fulfill the requirement of HR+ disease, breast cancer must express the estrogen receptor with or without co-expression of the progesterone receptor or subjects must have received prior endocrine therapy for at least 6 months. For dose escalation (Part A), eligible subjects must have a measurable disease according to RECIST v1.1 and / or at least 1 lytic or mixed (lytic+ sclerotic) bone lesion that can be assessed by CT or MRI or nonmeasurable disease (including bone lesions). For dose expansion, eligible subjects must have a measurable disease according to RECIST v1.1.

[0232] The preliminary efficacy of the CDK4 / 6 degrader is evaluated by the following endpoints: (i) objective response rate (ORR); (ii) best overall response (CBR); (iii) duration ofAttorney Docket No: 127A057WO01 response (DOR); (iv) time to response (TTR); and (v) progression-free survival (PFS). The preliminary efficacy analyses are performed on the Safety Population and Fulvestrant Efficacy Population.

[0233] The PK parameters of the CDK4 / 6 degrader are determined, including (i) maximum observed plasma concentration (Cmax); (ii) time to maximum plasma concentration (Tmax); (iii) minimum plasma concentration (Cmin); (iv) area under the plasma concentration-time curve (AUC) from time 0 to time t (AUC0-t); (v) AUC from time 0 to 24 hours (AUC0-24); (vi) AUC from 0 to infinity (AUC0-^); (vii) half-life (t1 / 2); (viii) oral clearance (CL / F); (ix) apparent volume of distribution (Vz / F); and (x) accumulation ratio (Racc).

[0234] All subjects who receive at least 1 dose of any trial intervention are evaluated for safety and toxicity. Example 6 Compound Resolution

[0235] Compound A102 is resolved by supercritical fluid chromatography (SFC) on a chiral column (DAICEL CHIRALPAK IA) eluting isocratically with hexane (100%) as Phase A and IPA / ACN (7:3) to afford compounds A102R and A102S. Compounds A108, A135, B123, B125, B148, B153, and B164 are resolved similarly to afford compounds A108R, A108S, A135R, A135S, B123R, B123S, B125R, B125S, B148R, B148S, B153R, B153S, B164R, and B164S. * * * * *

[0236] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

Attorney Docket No: 127A057WO01 What is claimed is:

1. A method of treating, preventing, or ameliorating one or more symptoms of breast cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I): or an morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is C1-6 alkylene, C1-6 heteroalkylene, or heterocyclylene; L is a bond, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkylene, or heterocyclylene; X is a bond or –C(O)–; Z is C(R5a) or N, wherein R5ais hydrogen or R5; R1is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R2, R3, and R4are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; each R5, R6, R7, and R8is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl,Attorney Docket No: 127A057WO01 heteroaryl, or heterocyclyl; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(O)SR1a, –C(NR1a)NR1bR1c, –C(S)R1a, –C(S)OR1a, –C(S)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(O)SR1a, –OC(NR1a)NR1bR1c, –OC(S)R1a, –OC(S)OR1a, –OC(S)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(O)SR1d, –NR1aC(NR1d)NR1bR1c, –NR1aC(S)R1d, –NR1aC(S)OR1d, –NR1aC(S)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R9is hydrogen or C1-6 alkyl; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, 2, or 3; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is an integer of 0, 1, 2, 3, or 4; and q is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(O)SRa, –C(NRa)NRbRc, –C(S)Ra, –C(S)ORa, –C(S)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(O)SRa, –OC(NRa)NRbRc, –OC(S)Ra, –OC(S)ORa, –OC(S)NRbRc, –OP(O)(ORb)ORc, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, –NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(O)SRd, –NRaC(NRd)NRbRc, –NRaC(S)Rd, –NRaC(S)ORd, –NRaC(S)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four,Attorney Docket No: 127A057WO01 substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)Re, –C(O)ORe, –C(O)NRfRg, –C(O)SRe, –C(NRe)NRfRg, –C(S)Re, –C(S)ORe, –C(S)NRfRg, –ORe, –OC(O)Re, –OC(O)ORe, Re,or6 6 6alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

2. The method of claim 1, wherein X is a bond.

3. The method of claim 1, wherein X is –C(O)–.

4. The method of any one of claims 1 to 3, wherein Z is C(R5a).

5. The method of any one of claims 1 to 3, wherein Z is N.

6. The method of any one of claims 1, 2, and 4, wherein the compound is a compound of Formula (VIII):Attorney Docket No: 127A057WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

7. The method of any one of claims 1, 2, and 4, wherein the compound is a compound of Formula (IX): or an morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

8. The method of any one of claims 1, 3, and 4, wherein the compound is a compound of Formula (X): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

9. The method of any one of claims 1, 3, and 4, wherein the compound is a compound of Formula (XI):Attorney Docket No: 127A057WO01 or an morediastereomers, a a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

10. The method of any one of claims 1, 2, and 5, wherein the compound is a compound of Formula (XII): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

11. The method of any one of claims 1, 2, and 5, wherein the compound is a compound of Formula (XIII):Attorney Docket No: 127A057WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

12. The method of any one of claims 1, 3, and 5, wherein the compound is a compound of Formula (XIV): or andiastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

13. The method of any one of claims 1, 3, and 5, wherein the compound is a compound of Formula (XV): or anmore diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

14. The method of any one of claims 1 to 13, wherein A is C1-6 alkylene or heterocyclylene, each optionally substituted with one or more substituents Q.Attorney Docket No: 127A057WO01 15. The method of any one of claims 1 to 14, wherein A is C1-6 alkylene, optionally substituted with one or more substituents Q.

16. The method of any one of claims 1 to 15, wherein A is ethane-1,2-diyl, optionally substituted with one or more substituents Q.

17. The method of any one of claims 1 to 14, wherein A is heterocyclylene, each optionally substituted with one or more substituents Q.

18. The method of any one of claims 1 to 14 and 17, wherein A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.

19. The method of any one of claims 1 to 14, 17, and 18, wherein A is 6-membered heterocyclylene, optionally substituted with one or more substituents Q.

20. The method of any one of claims 1 to 14 and 17 to 19, wherein A is piperidin-1,4- diyl or piperazin-1,4-diyl, each optionally substituted with one or more substituents Q.

21. The method of any one of claims 1 to 13, wherein A is –(CH2)–, –(CH2CH2)–, –(CH2CF2)–, –(CH2CH2)O–, –(CH2CH2CH2)O–, –(COCH2)O–, –(COCH2CH2)O–, –(CH2CH2NHCOCH2)O–, –(CH2CH2CH2NHCOCH2)O–, azetidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, 2,7- diazaspiro[3.5]nonan-2,7-diyl, or 4,7-diazaspiro[2.5]octan-4,7-diyl.

22. The method of any one of claims 1 to 21, wherein L is (i) a bond; or (ii) C1-6 alkylene or heterocyclylene, each optionally substituted with one or more substituents Q.

23. The method of any one of claims 1 to 22, wherein L is a bond.

24. The method of any one of claims 1 to 22, wherein L is C1-6 alkylene, optionally substituted with one or more substituents Q.

25. The method of any one of claims 1 to 22 and 24, wherein L is methane-1,1-diyl or ethane-1,2-diyl, each optionally substituted with one or more substituents Q.Attorney Docket No: 127A057WO01 26. The method of any one of claims 1 to 22, wherein L is heterocyclylene, each optionally substituted with one or more substituents Q.

27. The method of any one of claims 1 to 22 and 26, wherein L is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.

28. The method of any one of claims 1 to 22, 26, and 27, wherein L is 6-membered heterocyclylene, optionally substituted with one or more substituents Q.

29. The method of any one of claims 1 to 22 and 26 to 28, wherein A is piperidin-1,4- diyl, optionally substituted with one or more substituents Q.

30. The method of any one of claims 1 to 21, wherein L is a bond, –(CH2)–, –(CH2CH2)–, –(CH2CH2CH2)–, cyclohex-1,3-diyl, cyclohex-1,4-diyl, azetidin-1,3-diyl, 3- fluoroazetidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 4-fluoropiperidin-1,4-diyl, morpholin-2,4-diyl, or piperazin-1,4-diyl.

31. The method of any one of claims 1 to 30, wherein R1is C1-6alkyl, C3-10cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q.

32. The method of any one of claims 1 to 31, wherein R1is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.

33. The method of any one of claims 1 to 32, wherein R1is monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q.

34. The method of any one of claims 1 to 30, wherein R1is ethyl, isopropyl, pent-3- yl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 2-hydroxycyclopentyl, 3- hydroxycyclopentyl, 2-hydroxy-2-methylcyclopentyl, 2-hydroxy-2-ethylcyclopentyl, 3-hydroxy- 2-methylcyclopentyl, 4-hydroxy-2-methylcyclopentyl, 3-hydroxycyclohexyl, 4-hydroxy- cyclohexyl, 3-fluoro-5-hydroxycyclohexyl, 3-hydroxy-2-methylcyclohexyl, 5-hydroxy-2-methyl- cyclohexyl, 3-hydroxycycloheptyl, or 4-hydroxy-4-methyltetrahydrofuran-3-yl.

35. The method of any one of claims 1 to 34, wherein R1is cyclopentyl, optionally substituted with one or more substituents Q.Attorney Docket No: 127A057WO01 36. The method of any one of claims 1 to 35, wherein R2is (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (iii) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –OR1a, or –NR1bR1c.

37. The method of any one of claims 1 to 36, wherein R2is –C(O)R1a.

38. The method of any one of claims 1 to 37, wherein R2is –C(O)C1-6 alkyl, optionally substituted with one or more substituents Q.

39. The method of any one of claims 1 to 38, wherein R2is acetyl.

40. The method of any one of claims 1 to 36, wherein R2is –C(O)NR1bR1c.

41. The method of any one of claims 1 to 36 and 40, wherein R2is –C(O)N(C1-6alkyl)2, each optionally substituted with one or more substituents Q.

42. The method of any one of claims 1 to 36, 40, and 41, wherein R2is dimethyl- aminocarbonyl.

43. The method of any one of claims 1 to 35, wherein R2is hydrogen, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoromethyl, aminocarbonyl- methyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, benzyl, oxazol-5-yl, acetyl, hydroxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, 2-ethoxyethoxy, or amino.

44. The method of any one of claims 1 to 43, wherein R3is hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q.

45. The method of any one of claims 1 to 44, wherein R3is hydrogen.

46. The method of any one of claims 1 to 44, wherein R3is C1-6alkyl, optionally substituted with one or more substituents Q.

47. The method of any one of claims 1 to 44 and 46, wherein R3is methyl, optionally substituted with one or more substituents Q.Attorney Docket No: 127A057WO01 48. The method of any one of claims 1 to 47, wherein R4is hydrogen.

49. The method of any one of claims 1 to 48, wherein R5ais hydrogen, deuterium, or halo.

50. The method of any one of claims 1 to 49, wherein R5ais hydrogen.

51. The method of any one of claims 1 to 49, wherein R5ais halo.

52. The method of any one of claims 1 to 49 and 51, wherein R5ais fluoro.

53. The method of any one of claims 1 to 52, wherein m is an integer of 0.

54. The method of any one of claims 1 to 53, wherein n is an integer of 0.

55. The method of any one of claims 1 to 54, wherein p is an integer of 0.

56. The method of any one of claims 1 to 55, wherein q is an integer of 0.

57. The method of claim 1, wherein the compound is: 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)cyclohexyl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A101; 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102; 7-cyclopentyl-2-((5-(4-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A103; 7-cyclopentyl-2-((5-(4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A104; 7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A105;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[1,4'-bipiperidin]-3-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A106; 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A107; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A108; 7-cyclopentyl-2-((5-(4-(1-(3-(4-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)piperidin-4- yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A109; 7-cyclopentyl-2-((5-(4-(3-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)propyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A110; 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[1,4'-bipiperidin]-1'-yl)- pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A111; 7-cyclopentyl-2-((5-(4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[1,4'-bipiperidin]-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A112; 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)-[1,4'- bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A113; 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)cyclo- hexyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A114; 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)cyclo- hexyl)piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A115;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(1-(3-(3-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-arboxamide A116; 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A117; 7-cyclopentyl-2-((5-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A118 7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A119; 7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A120; 7-cyclopentyl-2-((5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A121; 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenethyl)-4-fluoro-[1,4'- bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A122; 7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A123; 7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A124; 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A125;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A126; 7-cyclopentyl-2-((5-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A127; 7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A128; 7-cyclopentyl-2-((5-(1'-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[4,4'-bipiperidin]-1-yl)- pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A129; 7-cyclopentyl-N,N-dimethyl-2-((5-(4-(1-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phen- ethyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A130; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A131; 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A132; 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)ethyl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A133; 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[1,4'-bipiperidin]- 1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A134; 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135; 7-cyclopentyl-2-((5-(4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A136;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)methyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A137; 7-cyclopentyl-2-((5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)methyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A138; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A139; 7-cyclopentyl-2-((5-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A140; 7-cyclopentyl-2-((5-(4-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)- piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A141; 7-cyclopentyl-2-((5-(4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)- piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A142; 7-cyclopentyl-2-((5-(4-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)- azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A143; 7-cyclopentyl-2-((5-(4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)- azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A144; 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A145; 7-cyclopentyl-2-((5-(4-(1-(3-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)-piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A146; 7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[1,4'-bipiperidin]- 1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A147;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[1,4'-bipiperidin]-1'- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A148; 7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[1,4'-bipiperidin]-1'- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A149; 7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoroazetidin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A150; 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoroazetidin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A151; 7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A152; 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-1-yl)- piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A153; 7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A154; 7-cyclopentyl-2-((5-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A155; 7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A156; 7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)-4- fluoropiperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A157; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A158;Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A159; 2-((5-(4-(2-(1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A160; 2-((5-(4-(2-(1-(2-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A161; 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A162; 7-cyclopentyl-2-((5-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-5-fluorophenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A163; 7-cyclopentyl-2-((5-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-4-fluorophenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A164; 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)-4-fluoro-[1,4'- bipiperidin]-1'-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A165; 7-cyclopentyl-2-((5-(4-(2-(1-(5-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A166; 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)phenyl)piperidine-2,6-dione B101; 3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropoxy)phenyl)piperidine-2,6-dione B102;Attorney Docket No: 127A057WO01 N-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B103; N-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)phenoxy)acetamide B104; N-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B105; N-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamide B106; N-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2-methyl- phenoxy)acetamide B107; N-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2-(trifluoro- methyl)phenoxy)acetamide B108; N-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4-methyl- phenoxy)acetamide B109; N-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoro- methyl)phenoxy)acetamide B110; 3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)piperidine-2,6-dione B111; 3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6-dione B112; 3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)phenyl)piperidine-2,6-dione B113;Attorney Docket No: 127A057WO01 3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)piperidine-2,6-dione B114; 3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6-dione B115; 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)phenyl)piperidine-2,6-dione B116; 3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propoxy)phenyl)piperidine-2,6-dione B117; 3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propoxy)phenyl)piperidine-2,6-dione B118; 3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione B119; 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B120; 3-(4-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)piperidine-2,6- dione B121; 3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione B122; 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123; 3-(3-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)piperidine-2,6- dione B124; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125;Attorney Docket No: 127A057WO01 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B126; 3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)phenyl)piperidine-2,6- dione B127; 3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)phenyl)piperidine-2,6- dione B128; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B129; 3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B130; 3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)piperidine-2,6- dione B131; 3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)ethyl)phenyl)piperidine-2,6-dione B132; 3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)piperazin-1-yl)phenyl)-piperidine- 2,6-dione B133; 3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B134; 3-(4-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)propoxy)phenyl)piperidine-2,6- dione B135;Attorney Docket No: 127A057WO01 3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2yl)amino)pyridin-3-yl)piperazin-1-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)piperidine-2,6- dione B136; 3-(4-(4-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)piperazin-1-yl)phenyl)piperidine-2,6- dione B137; 3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)piperazin-1-yl)phenyl)-piperidine- 2,6-dione B138; 3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)cyclohexyl)piperidin-1-yl)phenyl)-piperidine- 2,6-dione B139; 3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)ethoxy)phenyl)piperidine-2,6- dione B140; 3-(3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)propoxy)phenyl)piperidine-2,6- dione B141; 3-(3-(4-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B142; 3-(4-(2-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6- dione B143; 3-(4-(2-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6-dione B144; 3-(4-((S)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)morpholino)phenyl)piperidine-2,6- dione B145;Attorney Docket No: 127A057WO01 3-(4-((R)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)morpholino)phenyl)piperidine-2,6- dione B146; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B147; 3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148; 3-(4-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidine-2,6- dione B149; 3-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)- piperidine-2,6-dione B150; 3-(4-(3-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)piperidine-2,6-dione B151; 3-(4-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione B152; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153; 3-(4-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6-dione B154; 3-(3-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione B155; 3-(3-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B156; 3-(3-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6-dione B157;Attorney Docket No: 127A057WO01 3-(4-(4-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B158; 3-(4-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B159; 3-(3-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B160; 3-(3-(4-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B161; 3-(4-(1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B162; 3-(3-(1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B163; 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164; 3-(4-(2-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-1-yl)ethyl)phenyl)piperidine-2,6-dione B165; 3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B166; 3-(4-(1-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B167;Attorney Docket No: 127A057WO01 3-(4-((1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[1,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine-2,6-dione B168; 3-(4-(2-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6- dione B169; 3-(3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidine-2,6- dione B170; 3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B171; 3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)piperidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B172; 3-(4-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B173; 3-(3-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)-1,1-difluoroethyl)phenyl)- piperidine-2,6-dione B174; 3-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)methyl)phenyl)piperidine-2,6- dione B175; 3-(3-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)methyl)phenyl)piperidine-2,6- dione B176; 3-(3-(2-(1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6- dione B177;Attorney Docket No: 127A057WO01 3-(4-((1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B178; 3-(3-((1'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[1,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B179; 3-(4-(2-(1-(1-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2,6-dione B180; 3-(3-(2-(1-(1-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2,6-dione B181; 3-(4-((1-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2,6-dione B182; 3-(3-((1-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2,6-dione B183; 3-(4-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2,6-dione B184; 3-(3-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2,6-dione B185; 3-(3-(8-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.2.1]octan-3-yl)- phenyl)piperidine-2,6-dione B186; 3-(3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2,6-dione B187;Attorney Docket No: 127A057WO01 (S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)-3-methyl- piperidine-2,6-dione B188; (R)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)-3-methyl- piperidine-2,6-dione B189; (S)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)-3-methyl-piperidine- 2,6-dione B190; (R)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)-3-methyl-piperidine- 2,6-dione B191; 3-(4-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2,6-dione B192; 3-(3-(1-((1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2,6-dione B193; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-2-fluorophenyl)piperidine-2,6- dione B194; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6- dione B195; 3-(4-(4-(1-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-2-chlorophenyl)piperidine-2,6- dione B196; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)-3-chlorophenyl)piperidine-2,6- dione B197;Attorney Docket No: 127A057WO01 3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)azetidin-1-yl)phenyl)piperidine-2,6-dione B198; 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluorophenyl)- piperidine-2,6-dione B199; 3-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)- piperidine-2,6-dione B200; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)- piperidine-2,6-dione B201; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)- piperidine-2,6-dione B202; 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)- piperidine-2,6-dione B203; 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-4-fluoropiperidin-1-yl)phenyl)- piperidine-2,6-dione B204; 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-fluorophenyl)- piperidine-2,6-dione B205; or 3-(4-(7-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)phenyl)- piperidine-2,6-dione B206; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

58. The method of claim 1, wherein the compound is:Attorney Docket No: 127A057WO01 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102; 7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A108; 7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)piperazin-1- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135; 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123; 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125; 3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148; 3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153; or 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

59. The method of claim 1, wherein the compound is an enantiomerically pure compound of: (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102R;Attorney Docket No: 127A057WO01 (R)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108R; (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135R; (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102S; (S)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108S; (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135S; (R)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123R; (R)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125R; (R)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148R; (R)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153R; (R)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164R;Attorney Docket No: 127A057WO01 (S)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123S; (S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125S; (S)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148S; (S)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153S; or (S)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164S; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

60. The method of any one of claims 1 to 59, wherein the compound is administered orally.

61. The method of any one of claims 1 to 60, wherein the compound is administered as a tablet or capsule.

62. The method of any one of claims 1 to 61, wherein the therapeutically effective amount of the compound is ranging from about 0.01 to about 10 mg / kg per day.

63. The method of any one of claims 1 to 62, wherein the therapeutically effective amount of the compound is ranging from about 1 to about 500 mg per day.

64. The method of any one of claims 1 to 63, further comprising administering to the subject in need thereof a therapeutically effective amount of an estrogen receptor antagonist.Attorney Docket No: 127A057WO01 65. The method of claim 64, wherein the estrogen receptor antagonist is amcenestrant, brilanestrant, camizestrant, elacestrant, fulvestrant 3-boronic acid, giredestrant, imlunestrant, rintodestrant, or vepdegestrant.

66. The method of claim 64 or 65, wherein the estrogen receptor antagonist is administered orally.

67. The method of any one of claims 64 to 66, wherein the therapeutically effective amount of the estrogen receptor antagonist is ranging from about 0.1 to about 100 mg / kg per day.

68. The method of any one of claims 64 to 67, wherein the therapeutically effective amount of the estrogen receptor antagonist is ranging from about 10 to about 5,000 mg per day.

69. The method of claim 63, wherein the estrogen receptor antagonist is fulvestrant.

70. The method of claim 69, wherein fulvestrant is administered intramuscularly.

71. The method of claim 69 or 70, wherein the therapeutically effective amount of fulvestrant is ranging from about 0.1 mg / kg once every 28 days to about 100 mg / kg twice every 28 days.

72. The method of any one of claims 69 to 71, wherein the therapeutically effective amount of fulvestrant is ranging from about 10 mg once every 28 days to about 5,000 mg twice every 28 days.

73. The method of any one of claims 1 to 72, wherein the compound is administered in a cycle.

74. The method of claim 73, wherein one cycle is 28 days.

75. The method of any one of claims 1 to 74, wherein the compound is administered once daily for 28 days in a 28-day cycle.

76. The method of any one of claims 1 to 74, wherein the compound is administered once daily for 21 days in a 28-day cycle with a 7-day rest period.Attorney Docket No: 127A057WO01 77. The method of any one of claims 69 to 76, wherein fulvestrant is administered once or twice every 28 days.

78. The method of any one of claims 1 to 77, wherein the breast cancer is HR+ breast cancer.

79. The method of any one of claims 1 to 78, wherein the breast cancer is HR+ / HER2- breast cancer.

80. The method of any one of claims 1 to 77, wherein the breast cancer is triple negative breast cancer.

81. The method of any one of claims 1 to 80, wherein the breast cancer is advanced breast cancer.

82. The method of any one of claims 1 to 81, wherein the breast cancer is locally advanced breast cancer.

83. The method of any one of claims 1 to 82, wherein the breast cancer is metastatic breast cancer.

84. The method of any one of claims 1 to 83, wherein the breast cancer is characterized by CDK6 overexpression.

85. The method of any one of claims 1 to 84, wherein the breast cancer is characterized by CDK6 upregulation.

86. The method of any one of claims 1 to 85, wherein the breast cancer is resistant to a CDK4 / 6 inhibitor.

87. The method of any one of claims 1 to 86, wherein the breast cancer is resistant to abemaciclib, palbociclib, or ribociclib.

88. The method of any one of claims 1 to 87, wherein the subject is a human.Attorney Docket No: 127A057WO01 89. The method of any one of claims 1 to 88, wherein the subject has failed a prior CDK4 / 6 inhibitor therapy.

90. The method of any one of claims 1 to 89, wherein the subject has failed a prior abemaciclib, palbociclib, or ribociclib therapy.

91. An enantiomerically pure compound of: (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102R; (R)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)-piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108R; (R)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135R; (R)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123R; (R)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125R; (R)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148R; (R)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153R; (R)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164R;Attorney Docket No: 127A057WO01 (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A102S; (S)-7-cyclopentyl-2-((5-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A108S; (S)-7-cyclopentyl-2-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A135S; (S)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B123S; (S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B125S; (S)-3-(4-(4-(2-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione B148S; (S)-3-(4-(4-(1-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione B153S; or (S)-3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6- dione B164S; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

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