PAK4, CSTF2, or CSTF2t protein degraders, pharmaceutical compositions, and therapeutic applications

Abstract

Provided herein are PAK4, CSTF2, or CSTF2T protein degraders, for example, a compound of Formula (I) or (IV), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PAK4, CSTF2, or CSTF2T.

Description

Attorney Docket No.260A003WO01 PAK4, CSTF2, OR CSTF2T PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS, AND THERAPEUTIC APPLICATIONS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the priority of U.S. Provisional Application No.63 / 650,080, filed May 21, 2024; the disclosure of which is incorporated herein by reference in its entirety. FIELD

[0002] Provided herein are PAK4, CSTF2, or CSTF2T protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PAK4, CSTF2, or CSTF2T. BACKGROUND

[0003] PAK4 (p21-activated kinase 4) regulates a wide range of cellular functions and plays an important role in cancer cell motility, proliferation, and survival. Kumar et al., Gene 2017, 605, 20-31; Wang et al., Expert Opin. Ther. Pat.2021, 31, 977-87. PAK4 is often upregulated in a variety of cancer, including breast cancer, esophageal cancer, gastric cancer, gliomas, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and sarcomas. Kumar et al., Gene 2017, 605, 20-31; Rane and Minden, Sem. Cancer Biol.2019, 54, 40-9; Costa and Stromblad, Int. J. Biochem. Cell Biol.2021, 138, 106041. In cancer patients, PAK4 overexpression correlates with poor prognosis, tumor aggressiveness, and metastasis. Kumar et al., Gene 2017, 605, 20-31; Wang et al., Expert Opin. Ther. Pat.2021, 31, 977-87. Small molecule PAK4 inhibitors have been shown to be effective in inhibiting tumor growth. Murray et al., Proc. Natl. Acad. Sci. USA 2010, 107, 9446-51; Rane et al., Sci. Rep. 2017, 7, 42555. However, clinical studies of the first PAK4 inhibitor were terminated due to poor selectivity, cellular activity, or pharmacokinetic properties. Wang et al., Expert Opin. Ther. Pat.2021, 31, 977-87. As of May 2024, no PAK4 inhibitor has received marketing approval. Id.Attorney Docket No.260A003WO01

[0004] Cleavage-stimulating factor subunit 2 (CSTF2) and its tau variant, CSTF2T, are RNA-binding proteins critical for mRNA cleavage and polyadenylation. Ding et al., Cell Cycle 2023, 22, 2622-36. Both CSTF2 and CSTF2T have been implicated in the development and progression of various cancer, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), glioblastoma, and lung cancer. Chen et al., Front. Oncol.2022, 12, 897804; Feng et al., Front. Pharmacol.2022, 13, 852469; Zheng et al., Nat. Commun.2023, 14,6334; Ding et al., Cell Cycle 22, 2622-36; Liu et al. Cancer Biol. Ther. 2023, 24,2216041. Studies demonstrate CSTF2 and its tau variant are frequently upregulated in cancer cells, and their overexpression correlates with poor prognosis, suggesting them as therapeutic targets for cancer treatment. Chen et al., Front. Oncol.2022, 12, 897804; Ding et al., Cell Cycle 2023, 22, 2622-36.

[0005] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 2,041,910 new cancer cases diagnosed and 618,120 cancer deaths in the US alone in 2025. Cancer Facts & Figures 2025. Therefore, there is a need for an effective therapy for cancer treatment. SUMMARY OF THE DISCLOSURE

[0006] Provided herein is a compound of Formula (I): or an enantiomer, or more diastereomers, avariant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A1is heterocyclylene; A2is C6-14 arylene or heteroarylene; A3is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; A4is a bond, C6-14arylene, or heteroarylene; L1and L2are each independently (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–; or (ii) C1-6 alkylene or C1-6 heteroalkylene;Attorney Docket No.260A003WO01 U is C(R3b) or N; V is C(R3c) or N; each R1is independently deuterium, cyano, halo, nitro, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or two R1are linked together to form C1-6 alkylene or C1-6 heteroalkylene; R9is C3-10cycloalkyl, C6-14aryl, heteroaryl, or heterocyclyl; R2aand R2bare each independently hydrogen, deuterium, or C1-6alkyl; or R2aand R2btogether with the C atom to which they are attached form oxo, C3-10 cycloalkylene, or heterocyclylene; R3a, R3b, and R3care 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, –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; R5aand R5bare each independently hydrogen, deuterium, or C1-6alkyl; or R5aand R5btogether to which they are attached form oxo, C3-10cycloalkylene, orheterocyclylene; 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; and m is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, 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, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is furtherAttorney Docket No.260A003WO01 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, –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, –P(O)(Ra)Rd, –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, C2-6alkenyl, 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; 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, –OC(O)NRfRg, –OC(O)SRe, –OC(NRe)NRfRg, –OC(S)Re, –OC(S)ORe, –OC(S)NRfRg, –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, –P(O)(Re)Rg, –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) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, 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 a compound of Formula (IV):Attorney Docket No.260A003WO01 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: A2is C6-14 arylene or heteroarylene; A3is a bond, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; A4is a bond, C6-14arylene, or heteroarylene; L1and L2are each independently a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–; U is C(R3b) or N; V is C(R3c) or N; each R1is independently deuterium, cyano, halo, nitro, C1-6 alkyl, C1-6 heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or two R1are linked together to form C1-6 alkylene or C1-6 heteroalkylene; each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, 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; or two R4are linked together to form a bond, C1-6 alkylene, or C1-6 heteroalkylene; R2aand R2bare each independently hydrogen, deuterium, or C1-6 alkyl; or R2aand R2btogether with the C atom to which they are attached form oxo, C3-10cycloalkylene, or heterocyclylene; R3a, R3b, and R3care 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,Attorney Docket No.260A003WO01 –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; R4ais hydrogen or R4; or R4aand R3bare linked together to form C1-6alkylene or C1-6heteroalkylene; R5aand R5bare each independently hydrogen, deuterium, or C1-6 alkyl; or R5aand R5btogether with the C atom to which they are attached form oxo, C3-10cycloalkylene, or heterocyclylene; R9a, R9b, and R9care 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, –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; or R9aand R9btogether with the carbon atoms to which they are attached form C3-10cycloalkyl, C6-14aryl, heteroaryl, or heterocyclyl; 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; and m is an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; and p and q are each independently an integer of 0, 1, 2, or 3; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, 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,Attorney Docket No.260A003WO01 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, –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, –P(O)(Ra)Rd, –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, C2-6 alkenyl, 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, –OC(O)NRfRg, –OC(O)SRe, –OC(NRe)NRfRg, –OC(S)Re, –OC(S)ORe, –OC(S)NRfRg, –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, –P(O)(Re)Rg, –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, C2-6 alkynyl, C3-10 cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0008] Additionally, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or (IV), 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 anAttorney Docket No.260A003WO01 isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0009] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PAK4, CSTF2, or CSTF2T in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (IV), 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.

[0010] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (IV), 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 growth of a cell, comprising contacting the cell with an effective amount of a compound of Formula (I) or (IV), or an enantiomer, a mixture of enantiomers, 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 a method of inducing degradation of a PAK4, CSTF2, or CSTF2T protein, comprising contacting the protein with an effective amount of a compound of Formula (I) or (IV), 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. DETAILED DESCRIPTION

[0013] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.Attorney Docket No.260A003WO01

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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 reducing 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.

[0019] 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 inAttorney Docket No.260A003WO01 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.

[0020] 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.

[0021] 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, 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, 2nd ed.; Gibson Ed.; CRC Press, 2009.

[0022] 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” orAttorney Docket No.260A003WO01 “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.

[0023] 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, C1-6 alkyl 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 C1-6and branched C3-6alkyl groups are also “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).

[0024] 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, C1-6 alkanediyl 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 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 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 C1-6 and branched C3-6 alkanediyl 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 hexanediylAttorney Docket No.260A003WO01 (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)–.

[0025] 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, C1-6heteroalkyl 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 C1-6 and 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.

[0026] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or 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, C1-6 heteroalkylene 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 C1-6andC3-6heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are notAttorney Docket No.260A003WO01 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)–.

[0027] 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, C2-6alkenyl 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, 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).

[0028] 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 hydrocarbonAttorney Docket No.260A003WO01 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).

[0029] 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 poly- cyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclo- heptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0030] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one 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.,Attorney Docket No.260A003WO01 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).

[0031] 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.

[0032] The terms “arylene” and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene or phendiyl (including all isomeric forms, e.g., phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, e.g., naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren-1,2-diyl, fluoren-1,3-diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen-1,2-diyl, azulen-1,3-diyl, and azulen-1,8-diyl), anthrylene (including all isomeric forms, e.g., anthr-1,2-diyl, anthr-1,3-diyl, and anthr-1,8-diyl), phenanthrylene (including all isomeric forms, e.g., phenanthr-1,2-diyl, phenanthr-1,3-diyl, and phenanthr-1,8-diyl), pyrenylene (including all isomeric forms, e.g., pyren-1,2-diyl, pyren-1,3-diyl, and pyren-1,8-diyl), biphenylene (including all isomeric forms, e.g., biphen-2,3-diyl, biphen-3,4’-diyl, and biphen-4,4’-diyl), and terphenylene (including allAttorney Docket No.260A003WO01 isomeric forms, e.g., terphen-2,3-diyl, terphen-3,4’-diyl, and terphen-4,4’-diyl). Arylene 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, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, e.g., inden-1,2-diyl, inden-1,5-diyl, and inden-1,7- diyl), indanylene (including all isomeric forms, e.g., indan-1,2-diyl, indan-1,5-diyl, and indan- 1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, e.g., tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl). In certain embodiments, arylene 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- phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenyl- propyl, and 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 bicyclicAttorney Docket No.260A003WO01 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, isobenzofuranyl, 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, 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, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 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 terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For a heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring. Each ring of a heteroarylene 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 lessAttorney Docket No.260A003WO01 and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrroldiyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazoldiyl, triazinediyl, and triazoldiyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-b]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-b]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-b]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridindiyl, imidazo[4,5-b]pyridindiyl, and imidazo[4,5-c]- pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g., imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (i.e., benzo[c]thiendiyl), isoindoldiyl, isoquinolindiyl, naphthyridindiyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7- naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridindiyl, oxazolo[4,5-c]pyridindiyl, oxazolo[5,4-b]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2-b]- pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]- pyrimidindiyl and [1,2,3]thiadiazolo[4,5-d]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-b]pyridindiyl, thieno[2,3-c]pyridindiyl, thieno[3,2-b]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.Attorney Docket No.260A003WO01

[0036] 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, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0037] 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. For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at leastAttorney Docket No.260A003WO01 one bond to the rest of a molecule via its nonaromatic heterocyclic 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), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydro- pyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrroldiyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydro- indoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydro- thiendiyl, 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.

[0038] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and / or iodo.

[0039] 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, arylene, aralkyl, heteroaryl, heteroarylene, 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, C2-6Attorney Docket No.260A003WO01 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, –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, C3-10 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. As used herein, all groups that can be substituted are “optionally substituted.”

[0040] 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, C2-6 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.

[0041] 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 lessAttorney Docket No.260A003WO01 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.

[0042] 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.

[0043] 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), 15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17, 18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), 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), deuteriumAttorney Docket No.260A003WO01 (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.

[0044] 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.

[0045] 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.

[0046] 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), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is ahydrogen isotope having a natural abundance of about 0.0156%.

[0047] 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 containAttorney Docket No.260A003WO01 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%).

[0048] 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%.

[0049] 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%).

[0050] 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 performance 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 aboutAttorney Docket No.260A003WO01 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.

[0051] 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.

[0052] 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)–.

[0053] 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, 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; (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 mixture of enantiomers, aAttorney Docket No.260A003WO01 diastereomer, 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

[0054] In one embodiment, provided herein is a compound of Formula (I): or an enantiomer,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: A1is heterocyclylene; A2is C6-14arylene or heteroarylene; A3is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; A4is a bond, C6-14 arylene, or heteroarylene; L1and L2are each independently (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–; or (ii) C1-6alkylene or C1-6heteroalkylene; U is C(R3b) or N; V is C(R3c) or N; each R1is independently deuterium, cyano, halo, nitro, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or two R1are linked together to form C1-6 alkylene or C1-6 heteroalkylene; R9is C3-10cycloalkyl, C6-14aryl, heteroaryl, or heterocyclyl; R2aand R2bare each independently hydrogen, deuterium, or C1-6 alkyl; or R2aand R2btogether with the C atom to which they are attached form oxo, C3-10 cycloalkylene, or heterocyclylene; R3a, R3b, and R3care 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,Attorney Docket No.260A003WO01 –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; R5aand R5bare each independently hydrogen, deuterium, or C1-6alkyl; or R5aand R5btogether with the C atom to which they are attached form oxo, C3-10cycloalkylene, or heterocyclylene; 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; and m is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, 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, C6-14 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, –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, –P(O)(Ra)Rd, –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, C2-6 alkenyl, 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;Attorney Docket No.260A003WO01 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, –OC(O)NRfRg, –OC(O)SRe, –OC(NRe)NRfRg, –OC(S)Re, –OC(S)ORe, –OC(S)NRfRg, –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, –P(O)(Re)Rg, –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) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0055] In certain embodiments, R9is C3-10cycloalkyl, C6-14aryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is bridged C5-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bicyclo[1.1.1]pentanyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bicyclo[1.1.1]pentan-1-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9is fused C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is spiro C4-10 cycloalkyl, optionally substituted with one or more substituents Q.

[0056] In certain embodiments, R9is C6-14aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bicyclic C8-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is C7-15aralkyl,Attorney Docket No.260A003WO01 optionally substituted with one or more substituents Q.

[0057] In certain embodiments, R9is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is pyridin-2-yl, pyridin- 5-yl, pyrimidin-2-yl, pyrimidin-5-yl, or pyrazin-2-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is pyridin-2-yl, pyrimidin-2-yl, or pyrazin-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, heteroaryl, or heterocyclyl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0058] In certain embodiments, R9is bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 5,5- , 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is benzo[d]imidazolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, or 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is benzo[d]imidazolyl, benzo[d]isoxazolyl, indazolyl, furo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]- pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, or 6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is benzo[d]imidazol-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo[3,4- d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, or 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-Attorney Docket No.260A003WO01 2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo[3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, or 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl, each optionally substituted with one or more substituents Q.

[0059] In certain embodiments, R9is 6,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9is quinazolinyl, pyrido[2,3-d]- pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido[3,2-b][1,4]oxazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is quinazolinyl, 5,6,7,8-tetrahydroquinazolinyl, pyrido[2,3-d]pyrimidinyl, 3,4-dihydro-2H- pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl, 6,7-dihydro-5H-pyrano[2,3- d]pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido[3,2-b][1,4]-oxazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is quinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4- dihydropyrido[3,2-b][1,4]oxazin-6-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3- d]pyrimidin-2-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]- pyridin-7-yl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido[3,2-b][1,4]oxazin-6-yl, each optionally substituted with one or more substituents Q.

[0060] In certain embodiments, R9is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 6- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is 7-membered heterocyclyl, optionally substituted with one or more substituents Q.Attorney Docket No.260A003WO01

[0061] In certain embodiments, R9is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9is spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0062] In certain embodiments, R9is bicyclo[1.1.1]pentanyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, benzo[d]imidazolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]- pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, quinazolinyl, pyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido[3,2- b][1,4]oxazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is bicyclo[1.1.1]pentanyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, benzo[d]- imidazolyl, benzo[d]isoxazolyl, indazolyl, furo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, 6,7-dihydro- 5H-pyrrolo[3,4-d]pyrimidinyl, quinazolinyl, 5,6,7,8-tetrahydroquinazolinyl, pyrido[2,3-d]- pyrimidinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido- [3,2-b][1,4]oxazinyl, each optionally substituted with one or more substituents Q.

[0063] In certain embodiments, R9is pyridin-2-yl, pyridin-5-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, benzo[d]imidazol-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo[3,4- d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl, quinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydro- pyrido[3,2-b][1,4]oxazin-6-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R9is benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol- 6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo[3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]- pyrimidin-2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]-pyridin-7-yl, 6,7- dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido-Attorney Docket No.260A003WO01 [3,2-b][1,4]oxazin-6-yl, each optionally substituted with one or more substituents Q.

[0064] In certain embodiments, R9is isopropylbicyclo[1.1.1]pentan-1-yl, 4-isopropyl- phenyl, 2-isopropylpyridin-5-yl, 5-isopropylpyridin-2-yl, 5-isopropylpyrazin-2-yl, pyrimidin-2- yl, 4-cyanopyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-chloropyrimidin-2-yl, 4-methylpyrimidin-2- yl, 5-methylpyrimidin-2-yl, 4-isopropylpyrimidin-2-yl, 5-isopropylpyrimidin-2-yl, 4-(hydroxy- methyl)pyrimidin-2-yl, 5-(hydroxymethyl)pyrimidin-2-yl, 5-(aminomethyl)pyrimidin-2-yl, 4- (trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-(1-methylcyclopropyl)- pyrimidin-2-yl, 4-phenylpyrimidin-2-yl, 4-(3-cyanophenyl)pyrimidin-2-yl, 4-(4-cyano-2,6- dimethylbenzyl)pyrimidin-2-yl, 4-(pyridin-3-yl)pyrimidin-2-yl, 5-(oxeten-3-yl)pyrimidin-2-yl, 4- morpholinopyrimidin-2-yl, 4-piperazin-1-ylpyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5- isopropoxypyrimidin-2-yl, 4-(benzyloxy)pyrimidin-2-yl, 5-(piperidin-4-ylmethoxy)pyrimidin-2- yl, 5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl, 4-aminopyrimidin-2-yl, 4-((2-hydroxy- ethyl)amino)pyrimidin-2-yl, 4-((cyclopropylmethyl)amino)pyrimidin-2-yl, 4-aminocarbonyl- pyrimidin-2-yl, 2-(dimethylphosphoryl)phenyl)pyrimidin-2-yl, 5-chloro-4-((2-(dimethyl- phosphoryl)phenyl)amino)pyrimidin-2-yl, 5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)- pyrimidin-2-yl, or 2-isopropylpyrimidin-5-yl.

[0065] In certain embodiments, R9is 4-(1-methylimidazol-2-yl)phenyl, 4-chloropyridin- 2-yl, 6-chloropyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6- isopropylpyridin-2-yl, 2-isopropylpyridin-5-yl, 5-cyclopropylpyridin-2-yl, 5-(1-methylimidazol- 2-yl)pyridin-2-yl, 5-(4-methyl-1,2,4-triazol-3-yl)pyridin-2-yl, 4-cyclopropylpyrimidin-2-yl, 5- cyclopropylpyrimidin-2-yl, 5-(1-methylimidazol-2-yl)pyrimidin-2-yl, 5-(tetrahydropyran-4-yl)- pyrimidin-2-yl, or 4-methoxypyrimidin-2-yl.

[0066] In certain embodiments, R9is 4-fluoro-1-isopropyl-2-methylbenzo[d]imidazol-6- yl, pyrrolo[2,3-d]pyrimidin-2-yl, 7-methylpyrrolo[2,3-d]pyrimidin-2-yl, 7-benzylpyrrolo[2,3-d]- pyrimidin-2-yl, 1-methylpyrazolo[3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 1- methylpyrazolo[4,3-d]pyrimidin-5-yl, 1-(4-methoxybenzyl)-3-methylpyrazolo-[4,3-d]pyrimidin- 5-yl, pyrido[2,3-d]pyrimidin-2-yl, quinazolin-2-yl, 7-methoxyquinazolin-2-yl, 8-methoxy- quinazolin-2-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl, (R)-7-ethyl-8-isopropyl-5-methyl- 6-oxo-5,6,7,8-tetrahydropteridin-2-yl, or 2,2-dimethyl-3-oxo-3,4-dihydropyrido[3,2-b][1,4]-Attorney Docket No.260A003WO01 oxazin-6-yl.

[0067] In certain embodiments, R9is 3-methylbenzo[d]isoxazol-6-yl, 1-methylindazol-5- yl, 1-methylindazol-6-yl, 1,3-dimethylindazol-6-yl, 5-methylfuro[2,3-d]pyrimidin-2-yl, 6,7- dihydropyrrolo[3,4-d]pyrimidin-2-yl, 1-methylpyrrolo[2,3-b]pyridin-6-yl, 7-methylpyrrolo[2,3- d]pyrimidin-2-yl, 1-methylpyrazolo[3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 1- methylpyrazolo[4,3-d]pyrimidin-5-yl, quinazolin-2-yl, 7-methoxyquinazolin-2-yl, 8-methoxy- quinazolin-2-yl, 7-methoxy-4-methylquinazolin-2-yl, 7-methoxy-5-methylquinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, 3,4-dihydropyrano[3,2-c]pyridin-7-yl, 7-methylpyrido[2,3-d]- pyrimidin-2-yl, 7-methoxypyrido[2,3-d]pyrimidin-2-yl, 5,8-dimethyl-7-oxo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl, 3,4-dihydropyrano[2,3-b]pyridin-7-yl, or 6,7-dihydropyrano[2,3-d]- pyrimidin-2-yl.

[0068] In certain embodiments, in Formula (I), A1is heterocyclylene; A2is C6-14 arylene or heteroarylene; A3is C3-10 cycloalkylene, heteroarylene, or heterocyclylene; A4is a bond; L1is a bond; L2is (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–, wherein R1bis as defined herein; or (ii) C1-6alkylene or C1-6heteroalkylene; and R9is C6-14aryl or heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0069] In certain embodiments, in Formula (I), A1is monocyclic or bicyclic heterocyclylene; A2is phendiyl or monocyclic heteroarylene; A3is monocyclic or bicyclic C3-10cycloalkylene, monocyclic heteroarylene, or monocyclic or bicyclic heterocyclylene; A4is a bond; L1is a bond;Attorney Docket No.260A003WO01 L2is (i) a bond, –O–, –NR1b–, or –S–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene; and R9is phenyl, or monocyclic or bicyclic heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phenyl, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0070] In certain embodiments, in Formula (I), A1is 4-, 5-, 6-, or 7-membered heterocyclylene; A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; A4is a bond; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene; and R9is phenyl, or 6-membered, 5,6-fused, or 6,6-fused heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phenyl, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0071] In certain embodiments, in Formula (I), A1is 4-, 5-, 6-, or 7-membered heterocyclylene; A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; A4is a bond; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene; and R9is 6-membered heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phendiyl, heteroaryl,Attorney Docket No.260A003WO01 heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0072] In certain embodiments, in Formula (I), A1is 4-, 5-, 6-, or 7-membered heterocyclylene; A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10 cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; A4is a bond; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6alkylene or C1-6heteroalkylene; and R9is 5,6-fused or 6,6-fused heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0073] In certain embodiments, in Formula (I), A1is azetidindiyl or piperidindiyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phendiyl or pyridindiyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentandiyl, pyridindiyl, azetidindiyl, piperidindiyl, piperazindiyl, 1,4-diazepandiyl, 8-azabicyclo[3.2.1]octandiyl, 2-azaspiro[3.3]heptandiyl, or octahydrocyclopenta[c]pyrroldiyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.Attorney Docket No.260A003WO01

[0074] In certain embodiments, in Formula (I), A1is azetidin-1,3-diyl, piperidin-1,3-diyl, or piperidin-1,4-diyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridin-2-yl, pyrimidin-2-yl, or pyrazin-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0075] In certain embodiments, in Formula (I), A1is azetidin-1,3-diyl, 3-fluoroazetidin-1,3-diyl, 3-hydroxyazetidin-1,3-diyl, piperidin-1,3-diyl, 3-fluoropiperidin-1,3-diyl, 3-hydroxypiperidin-1,3-diyl, piperidin-1,4-diyl, 4- fluropiperidin-1,4-diyl, or 4-hydroxypiperidin-1,4-diyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro-[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond;Attorney Docket No.260A003WO01 L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridin-2-yl, pyrimidin-2-yl, or pyrazin-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0076] In certain embodiments, in Formula (I), A1is azetidindiyl or piperidindiyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phendiyl or pyridindiyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentandiyl, pyridindiyl, azetidindiyl, piperidindiyl, piperazindiyl, 1,4-diazepandiyl, 8-azabicyclo[3.2.1]octandiyl, 2-azaspiro[3.3]heptandiyl, or octahydrocyclopenta[c]pyrroldiyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is benzo[d]imidazolyl, benzo[d]isoxazolyl, indazolyl, furo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]- pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, quinazolinyl, 5,6,7,8-tetrahydro- quinazolinyl, pyrido[2,3-d]pyrimidinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H- pyrano[3,2-c]pyridinyl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido-[3,2-b][1,4]oxazinyl, each further optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0077] In certain embodiments, in Formula (I), A1is azetidin-1,3-diyl, piperidin-1,3-diyl, or piperidin-1,4-diyl, each optionallyAttorney Docket No.260A003WO01 substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo- [3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin- 2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 3,4- dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]-pyridin-7-yl, 6,7-dihydro- 5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido-[3,2-b]- [1,4]oxazin-6-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0078] In certain embodiments, in Formula (I), A1is azetidin-1,3-diyl, 3-fluoroazetidin-1,3-diyl, 3-hydroxyazetidin-1,3-diyl, piperidin-1,3-diyl, 3-fluoropiperidin-1,3-diyl, 3-hydroxypiperidin-1,3-diyl, piperidin-1,4-diyl, 4- fluropiperidin-1,4-diyl, or 4-hydroxypiperidin-1,4-diyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro-[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, eachAttorney Docket No.260A003WO01 optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; A4is a bond; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo- [3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin- 2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 3,4- dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]-pyridin-7-yl, 6,7-dihydro- 5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido-[3,2-b]- [1,4]oxazin-6-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0079] In another embodiment, provided herein is a compound of Formula (II): or an morea a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R9a, R9b, and R9care 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, each optionally substituted with one or more substituents Q; 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,Attorney Docket No.260A003WO01 –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; or R9aand R9btogether with the carbon atoms to which they are attached form C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R1, R1a, R1b, R1c, R1d, R2a, R2b, R3a, R5a, R5b, A1, A2, A3, A4, L1, L2, U, V, and m are each as defined herein.

[0080] In certain embodiments, A3is (i) a bond; or (ii) C3-10 cycloalkylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is (i) a bond; or (ii) heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q.

[0081] In certain embodiments, A3is a bond. In certain embodiments, A3is C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, or cyclohexane-1,4-diyl, each optionally substituted with one or more substituents Q.

[0082] In certain embodiments, A3is bicyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is bridged, fused, or spiro C4-10cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is bridged C5-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is bicyclo[1.1.1]pentanediyl, optionally substituted with one or more substituents Q. In certain embodiments, A3is bicyclo[1.1.1]pentan-1,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, A3is fused C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is spiro C4-10 cycloalkylene, optionally substituted with one or more substituents Q.

[0083] In certain embodiments, A3is C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is phendiyl, optionally substituted with one orAttorney Docket No.260A003WO01 more substituents Q. In certain embodiments, A3is phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is bicyclic C8-14arylene, optionally substituted with one or more substituents Q.

[0084] In certain embodiments, A3is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is pyridindiyl, pyrimidindiyl, or pyrazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is pyridin-2,5-diyl, optionally substituted with one or more substituents Q.

[0085] In certain embodiments, A3is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 5,5- , 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is 5,5- fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0086] In certain embodiments, A3is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 3-, 4-, 5-, 6-, or 7- membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 7-membered heterocyclylene, optionally substituted with one or moreAttorney Docket No.260A003WO01 substituents Q. In certain embodiments, A3is 1,4-diazepandiyl, optionally substituted with one or more substituents Q. In certain embodiments, A3is 1,4-diazepan-1,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, A3is azetidindiyl, pyrrolidindiyl, piperidindiyl, piperazindiyl, or azepandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-dyl, piperidin-1,4-dyl, or piperazin-1,4-diyl, each optionally substituted with one or more substituents Q.

[0087] In certain embodiments, A3is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, A3is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A3is 8-azabicyclo[3.2.1]octandiyl, octahydrocyclopenta[c]pyrroldiyl, or 2-azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is 8-azabicyclo[3.2.1]octan-3,8-diyl, octahydrocyclopenta[c]pyrrol-2,5-diyl, or 2-azaspiro[3.3]heptan-2,6-diyl, each optionally substituted with one or more substituents Q.

[0088] In certain embodiments, A3is cyclopentanediyl, cyclohexanediyl, cyclo- hexanediyl, bicyclo[1.1.1]pentanediyl, phendiyl, pyridindiyl, azetidindiyl, pyrrolidindiyl, piperidindiyl, piperidindiyl, piperazindiyl, 8-azabicyclo[3.2.1]octandiyl, octahydrocyclopenta- [c]pyrroldiyl, or 2-azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A3is cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, bicyclo[1.1.1]pentan-1,3-diyl, phen-1,3-diyl, phen-1,4-diyl, pyridin-2,5- diyl, azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-dyl, piperidin-1,4-dyl, piperazin-1,4- diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, octahydrocyclopenta[c]pyrrol-2,5-diyl, or 2-aza- spiro[3.3]heptan-2,6-diyl, each optionally substituted with one or more substituents Q.

[0089] In certain embodiments, A3is bicyclo[1.1.1]pentandiyl, pyridindiyl, azetidindiyl, piperidindiyl, piperazindiyl, 1,4-diazepandiyl, 8-azabicyclo[3.2.1]octandiyl, 2-azaspiro[3.3]-Attorney Docket No.260A003WO01 heptandiyl, or octahydrocyclopenta[c]pyrroldiyl, each optionally substituted with one or more substituents Q, in one embodiment, one or two substituents, each of which is independently fluoro or hydroxyl. In certain embodiments, A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5- diyl, azetidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan- 1,4-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, 2-azaspiro-[3.3]heptan-2,6-diyl, or octahydrocyclo- penta[c]pyrrol-2,5-diyl, each optionally substituted with one or more substituents Q, in one embodiment, one or two substituents, each of which is independently fluoro or hydroxyl.

[0090] In yet another embodiment, provided herein is a compound of Formula (III): 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: Y is C(R7a) or N; Z is C(R7b) or N; each R7is 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, each optionally substituted with one or more substituents Q; 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; or two R7are linked together to form a bond, C1-6 alkylene, or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q; and R7aand R7bare each independently hydrogen or R7;Attorney Docket No.260A003WO01 s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; t and u are each independently an integer of 0, 1, 2, or 3; and R1, R1a, R1b, R1c, R1d, R2a, R2b, R3a, R5a, R5b, R9a, R9b, R9c, A1, A2, A4, L1, L2, U, V, and m are each as defined herein.

[0091] In certain embodiments, A1is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, A1is 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 7-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is azetidindiyl, pyrrolidindiyl, piperidindiyl, piperazindiyl, or azepandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A1is azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-dyl, piperidin- 1,4-dyl, or piperazin-1,4-diyl, each optionally substituted with one or more substituents Q.

[0092] In certain embodiments, A1is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, A1is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, A1is 8-azabicyclo[3.2.1]octandiyl, octahydrocyclopenta[c]pyrroldiyl, or 2-azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A1is 8-azabicyclo[3.2.1]octan-3,8-diyl, octahydrocyclopenta[c]pyrrol-2,5-diyl, or 2-azaspiro[3.3]heptan-2,6-diyl, each optionally substituted with one or more substituents Q.

[0093] In certain embodiments, A1is azetidindiyl, pyrrolidindiyl, piperidindiyl,Attorney Docket No.260A003WO01 piperazindiyl, azepandiyl, 8-azabicyclo[3.2.1]octandiyl, octahydrocyclopenta[c]pyrroldiyl, or 2- azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A1is azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-dyl, piperidin-1,4-dyl, piperazin-1,4-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, octahydrocyclopenta[c]pyrrol-2,5-diyl, or 2-azaspiro[3.3]heptan-2,6-diyl, each optionally substituted with one or more substituents Q.

[0094] In certain embodiments, A1is azetidindiyl or piperidindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A1is azetidindiyl or piperidindiyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl. In certain embodiments, A1is azetidin-1,3-diyl, piperidin-1,3- diyl, or piperidin-1,4-diyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl.

[0095] In yet another 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: each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; 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; or two R4are linked together toAttorney Docket No.260A003WO01 form a bond, C1-6 alkylene, or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q; R4ais hydrogen or R4; or R4aand R3bare linked together to form C1-6alkylene or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; p and q are each independently an integer of 0, 1, 2, or 3; and R1, R1a, R1b, R1c, R1d, R2a, R2b, R3a, R5a, R5b, R9a, R9b, R9c, A2, A3, A4, L1, L2, U, V, and m are

[0096] In yet another embodiment, provided herein is a compound of Formula (V): 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, R4, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A2, A4, L1, L2, U, V, Y, Z, m, n, p, q, s, t, and u are each as defined herein.

[0097] In certain embodiments, A2is C6-14arylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, A2is phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, A2is bicyclic C8-14 arylene, optionally substituted with one or more substituents Q.

[0098] In certain embodiments, A2is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A2is 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is 6-membered heteroarylene, optionally substitutedAttorney Docket No.260A003WO01 with one or more substituents Q. In certain embodiments, A2is pyridindiyl, pyrimidindiyl, or pyrazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A2is pyridin-2,5-diyl, optionally substituted with one or more substituents Q.

[0099] In certain embodiments, A2is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is 5,5- , 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A2is 5,5- fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A2is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0100] In certain embodiments, A2is phendiyl or pyridindiyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl. In certain embodiments, A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl.

[0101] In yet another embodiment, provided herein is a compound of Formula (VI): or anor a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X is C(R6a) or N; each R6is 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, each optionally substituted with one or more substituents Q; 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,Attorney Docket No.260A003WO01 –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; R6ais hydrogen or R6; r is an integer of 0, 1, 2, or 3; and R1, R4, R7, R1a, R1b, R1c, R1d, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A4, L1, L2, U, V, Y, Z, m, n, p, q, s, t, and u are each as defined herein.

[0102] In yet another embodiment, provided herein is a compound of Formula (VII): 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, R4, R6, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A4, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, and u are each as defined herein.

[0103] In still another embodiment, provided herein is a compound of Formula (VIII): R3a( 1R9cO R )mN U or anor a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A4, L1, L2, U, V, Y, Z, m, n, p, q, r, s, t, and u are eachAttorney Docket No.260A003WO01 as defined herein.

[0104] In certain embodiments, A4is a bond.

[0105] In one embodiment, provided herein is a compound of Formula (IX): or an enantiomer, aor 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, R9, R2a, R2b, R3a, R5a, R5b, A1, A2, A3, L1, L2, U, V, and m are each as defined herein.

[0106] In certain embodiments, in Formula (IX), A1is heterocyclylene; A2is C6-14 arylene or heteroarylene; A3is C3-10 cycloalkylene, heteroarylene, or heterocyclylene; L1is a bond; L2is (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene; and R9is C6-14aryl or heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0107] In certain embodiments, in Formula (IX), A1is monocyclic or bicyclic heterocyclylene; A2is phendiyl or monocyclic heteroarylene; A3is monocyclic or bicyclic C3-10 cycloalkylene, monocyclic heteroarylene, or monocyclic or bicyclic heterocyclylene; L1is a bond; L2is (i) a bond, –O–, –NR1b–, or –S–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6heteroalkylene; andAttorney Docket No.260A003WO01 R9is phenyl, or monocyclic or bicyclic heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phenyl, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0108] In certain embodiments, in Formula (IX), A1is 4-, 5-, 6-, or 7-membered heterocyclylene; A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10 cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene; and R9is phenyl, or 6-membered, 5,6-fused, or 6,6-fused heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phenyl, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0109] In certain embodiments, in Formula (IX), A1is 4-, 5-, 6-, or 7-membered heterocyclylene; A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6alkylene or C1-6 heteroalkylene; and R9is 6-membered heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0110] In certain embodiments, in Formula (IX), A1is 4-, 5-, 6-, or 7-membered heterocyclylene;Attorney Docket No.260A003WO01 A2is phendiyl or 6-membered heteroarylene; A3is monocyclic or bicyclic C3-10 cycloalkylene, 6-membered heteroarylene, or monocyclic or bicyclic heterocyclylene; L1is a bond; L2is (i) a bond, –O–, or –NR1b–, wherein R1bis as defined herein; or (ii) C1-6 alkylene or C1-6heteroalkylene; and R9is 5,6-fused or 6,6-fused heteroaryl; wherein each alkylene, heteroalkylene, cycloalkylene, phendiyl, heteroaryl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

[0111] In certain embodiments, in Formula (IX), A1is azetidindiyl or piperidindiyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phendiyl or pyridindiyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentandiyl, pyridindiyl, azetidindiyl, piperidindiyl, piperazindiyl, 1,4-diazepandiyl, 8-azabicyclo[3.2.1]octandiyl, 2-azaspiro[3.3]heptandiyl, or octahydrocyclopenta[c]pyrroldiyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0112] In certain embodiments, in Formula (IX), A1is azetidin-1,3-diyl, piperidin-1,3-diyl, or piperidin-1,4-diyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substitutedAttorney Docket No.260A003WO01 with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridin-2-yl, pyrimidin-2-yl, or pyrazin-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0113] In certain embodiments, in Formula (IX), A1is azetidin-1,3-diyl, 3-fluoroazetidin-1,3-diyl, 3-hydroxyazetidin-1,3-diyl, piperidin-1,3-diyl, 3-fluoropiperidin-1,3-diyl, 3-hydroxypiperidin-1,3-diyl, piperidin-1,4-diyl, 4- fluropiperidin-1,4-diyl, or 4-hydroxypiperidin-1,4-diyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro-[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is phenyl, pyridin-2-yl, pyrimidin-2-yl, or pyrazin-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.Attorney Docket No.260A003WO01

[0114] In certain embodiments, in Formula (IX), A1is azetidindiyl or piperidindiyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phendiyl or pyridindiyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentandiyl, pyridindiyl, azetidindiyl, piperidindiyl, piperazindiyl, 1,4-diazepandiyl, 8-azabicyclo[3.2.1]octandiyl, 2-azaspiro[3.3]heptandiyl, or octahydrocyclopenta[c]pyrroldiyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is benzo[d]imidazolyl, benzo[d]isoxazolyl, indazolyl, furo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]- pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, quinazolinyl, 5,6,7,8-tetrahydro- quinazolinyl, pyrido[2,3-d]pyrimidinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H- pyrano[3,2-c]pyridinyl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido-[3,2-b][1,4]oxazinyl, each further optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0115] In certain embodiments, in Formula (IX), A1is azetidin-1,3-diyl, piperidin-1,3-diyl, or piperidin-1,4-diyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or hydroxyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro orAttorney Docket No.260A003WO01 hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo- [3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin- 2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 3,4- dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]-pyridin-7-yl, 6,7-dihydro- 5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido-[3,2-b]- [1,4]oxazin-6-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0116] In certain embodiments, in Formula (IX), A1is azetidin-1,3-diyl, 3-fluoroazetidin-1,3-diyl, 3-hydroxyazetidin-1,3-diyl, piperidin-1,3-diyl, 3-fluoropiperidin-1,3-diyl, 3-hydroxypiperidin-1,3-diyl, piperidin-1,4-diyl, 4- fluropiperidin-1,4-diyl, or 4-hydroxypiperidin-1,4-diyl; A2is phen-1,3-diyl, phen-1,4-diyl, or pyridin-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro, chloro, or methyl; A3is bicyclo[1.1.1]pentan-1,3-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, piperidin- 1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, 1,4-diazepan-1,4-diyl, 8-azabicyclo[3.2.1]octan- 3,8-diyl, 2-azaspiro-[3.3]heptan-2,6-diyl, or octahydrocyclopenta[c]pyrrol-2,5-diyl, each optionally substituted with one or two substituents, each of which is independently fluoro or hydroxyl; L1is a bond; L2is a bond, –CH2–, –CF2–, –O–, or –NH–; and R9is benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2-yl, pyrazolo- [3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin- 2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2-yl, 3,4- dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]-pyridin-7-yl, 6,7-dihydro-Attorney Docket No.260A003WO01 5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido-[3,2-b]- [1,4]oxazin-6-yl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano or halo; (ii) C1-6alkyl, C1-6heteroalkyl, or heteroaryl, each further optionally substituted with one, two, or three substituents Qa; or (iii) –OR1a, wherein R1ais as defined herein.

[0117] In another embodiment, provided herein is a compound of Formula (X): 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, R2a, R2b, R3a, R5a, R5b, R9a, R9b, R9c, A1, A2, A3, L1, L2, U, V, and m are each as defined herein.

[0118] In yet another embodiment, provided herein is a compound of Formula (XI): or anthereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A2, A3, L1, L2, U, V, m, n, p, and q are each as defined herein.

[0119] In yet another embodiment, provided herein is a compound of Formula (XII):Attorney Docket No.260A003WO01or an a a a 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, R4, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A2, L1, L2, U, V, Y, Z, m, n, p, q, s, t, and u are each as defined herein.

[0120] In yet another embodiment, provided herein is a compound of Formula (XIII): 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, R4, R6, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, and u are each as defined herein.

[0121] In yet another embodiment, provided herein is a compound of Formula (XIV): or anthereof; orAttorney Docket No.260A003WO01 a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, and u are each as defined herein.

[0122] In still another embodiment, provided herein is a compound of Formula (XV): 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, R4, R6, R7, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, Y, Z, m, n, p, q, r, s, t, and u are each as defined herein.

[0123] In certain embodiments, A4is C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, A4is phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, A4is bicyclic C8-14arylene, optionally substituted with one or more substituents Q

[0124] In certain embodiments, A4is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A4is 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is pyridindiyl, pyrimidindiyl, or pyrazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, A4is pyridin-2,5-diyl, optionally substituted with one or more substituents Q.

[0125] In certain embodiments, A4is bicyclic heteroarylene, optionally substituted withAttorney Docket No.260A003WO01 one or more substituents Q. In certain embodiments, A4is 5,5- , 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, A4is 5,5- fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, A4is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0126] In one embodiment, provided herein is a compound of Formula (XVI): 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: each R8is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; 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; v is an integer of 0, 1, 2, or 3; and R1, R9, R1a, R1b, R1c, R1d, R2a, R2b, R3a, R5a, R5b, A1, A2, A3, L1, L2, U, V, and m are each as defined herein.

[0127] In another embodiment, provided herein is a compound of Formula (XVII):Attorney Docket No.260A003WO01or an a a a 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, R8, R2a, R2b, R3a, R5a, R5b, R9a, R9b, R9c, A1, A2, A3, L1, L2, U, V, m, and v are each as defined herein.

[0128] In yet another embodiment, provided herein is a compound of Formula (XVIII): 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, R4, R8, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A2, A3, L1, L2, U, V, m, n, p, q, and v are each as defined herein.

[0129] In yet another embodiment, provided herein is a compound of Formula (XIX): or anor a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R7, R8, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, A2, L1, L2, U, V, Y, Z, m, n, p, q, s, t, u, and v are eachAttorney Docket No.260A003WO01 as defined herein.

[0130] In yet another embodiment, provided herein is a compound of Formula (XX): 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, R4, R6, R7, R8, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, u, and v are each as defined herein.

[0131] In yet another embodiment, provided herein is a compound of Formula (XXI): R3aO(R1)mor anor a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R7, R8, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, u, and v are each as defined herein.

[0132] In still another embodiment, provided herein is a compound of Formula (XXII):Attorney Docket No.260A003WO01or an a a a 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, R4, R6, R7, R8, R2a, R2b, R3a, R4a, R5a, R5b, R9a, R9b, R9c, L1, L2, U, V, Y, Z, m, n, p, q, r, s, t, u, and v are each as defined herein.

[0133] In certain embodiments, L1is a bond. In certain embodiments, L1is –C(O)–. In certain embodiments, L1is –O–. In certain embodiments, L1is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is methanediyl, optionally substituted with one or more substituents Q. In certain embodiments, L1is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is methanediyloxy or ethanediyloxy, each optionally substituted with one or more substituents Q. In certain embodiments, L1is methanediyloxy or ethane-1,2-diyloxy, each optionally substituted with one or more substituents Q.

[0134] In certain embodiments, L1is (i) a bond, –C(O)–, or –O–; or (ii) C1-6 alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, L1is a bond, –C(O)–, –O–, methanediyl, methanediyloxy, or ethane-1,2-diyloxy.

[0135] In certain embodiments, L2is a bond. In certain embodiments, L2is –O–. In certain embodiments, L2is –N(R1b)–, wherein R1bis as defined herein. In certain embodiments, L2is –N(R1b)–, wherein R1bis hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)-or –N(CH3)–. In certain embodiments, L2is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is methanediyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is methanediyl or difluoromethanediyl.

[0136] In certain embodiments, L2is (i) a bond, –O–, or –NR1b–, wherein R1bis asAttorney Docket No.260A003WO01 defined herein; or (ii) C1-6 alkylene or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, L2is a bond, –O–, –N(H)–, –N(CH3)–, methanediyl, or difluoromethanediyl.

[0137] In certain embodiments, U is C(R3b), wherein R3bis as defined herein. In certain embodiments, U is C(H). In certain embodiments, U is C(F). In certain embodiments, U is N.

[0138] In certain embodiments, V is C(R3c), wherein R3cis as defined herein. In certain embodiments, V is C(H). In certain embodiments, V is C(F). In certain embodiments, V is N.

[0139] In certain embodiments, U is C(R3b) and V is C(R3c), wherein R3band R3care each as defined herein. In certain embodiments, U and V are each C(H). In certain embodiments, U is C(H) and V is C(F). In certain embodiments, U is C(F) and V is C(H). In certain embodiments, U is C(R3b) and V is N, wherein R3bis as defined herein. In certain embodiments, U is C(H) and V is N. In certain embodiments, U is C(F) and V is N. In certain embodiments, U is N and V is C(R3c), wherein R3cis as defined herein. In certain embodiments, U is N and V is C(H). In certain embodiments, U is N and V is C(F). In certain embodiments, U and V are each N.

[0140] In certain embodiments, Y is C(R7a), wherein R7ais as defined herein. In certain embodiments, Y is C(H). In certain embodiments, Y is N.

[0141] In certain embodiments, Z is C(R7b), wherein R7bis as defined herein. In certain embodiments, Z is C(H). In certain embodiments, Z is N.

[0142] In certain embodiments, Y is C(R7a) and Z is C(R7b), wherein R7aand R7bare each as defined herein. In certain embodiments, Y and Z are each C(H). In certain embodiments, Y is C(R7a) and Z is N, wherein R7ais as defined herein. In certain embodiments, Y is C(H) and Z is N. In certain embodiments, Y is N and Z is C(R7b), wherein R7bis as defined herein. In certain embodiments, Y is N and Z is C(H). In certain embodiments, Y and Z are each N.

[0143] In certain embodiments, R2ais hydrogen. In certain embodiments, R2ais deuterium. In certain embodiments, R2ais C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2ais methyl, optionally substituted with one or moreAttorney Docket No.260A003WO01 substituents Q.

[0144] In certain embodiments, R2bis hydrogen. In certain embodiments, R2bis deuterium. In certain embodiments, R2bis C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis methyl, optionally substituted with one or more substituents Q.

[0145] In certain embodiments, R2aand R2btogether with the C atom to which they are attached form oxo. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bridged, fused, or spiro C4-10cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bridged C5-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form fused C4-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form spiro C4-10cycloalkylene, optionally substituted with one or more substituents Q.

[0146] In certain embodiments, R2aand R2btogether with the C atom to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form 3-, 4-, 5-, 6-, or 7- membered heterocyclylene, each optionally substituted with one or more substituents Q. InAttorney Docket No.260A003WO01 certain embodiments, R2aand R2btogether with the C atom to which they are attached form 3- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0147] In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R2aand R2btogether with the C atom to which they are attached form spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0148] In certain embodiments, R3ais hydrogen. In certain embodiments, R3ais deuterium. In certain embodiments, R3ais halo. In certain embodiments, R3ais fluoro or chloro. In certain embodiments, R3ais fluoro.

[0149] In certain embodiments, R4ais (i) hydrogen, deuterium, or halo; (ii) C1-6 alkyl, optionally substituted with one or more substituents Q; or (iii) –OR1a, wherein R1ais as defined herein. In certain embodiments, R4ais (i) hydrogen, deuterium, or halo; or (ii) –OR1a, wherein R1ais as defined herein. In certain embodiments, R4ais hydrogen, fluoro, or hydroxyl.

[0150] In certain embodiments, R4ais hydrogen. In certain embodiments, R4ais deuterium. In certain embodiments, R4ais halo. In certain embodiments, R4ais fluoro or chloro.Attorney Docket No.260A003WO01 In certain embodiments, R4ais fluoro. In certain embodiments, R4ais C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais methyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais –OR1a, wherein R1ais as defined herein. In certain embodiments, R4ais OH.

[0151] In certain embodiments, R5ais hydrogen. In certain embodiments, R5ais deuterium. In certain embodiments, R5ais C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5ais methyl, optionally substituted with one or more substituents Q.

[0152] In certain embodiments, R5bis hydrogen. In certain embodiments, R5bis deuterium. In certain embodiments, R5bis C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5bis methyl, optionally substituted with one or more substituents Q.

[0153] In certain embodiments, R5aand R5btogether with the C atom to which they are attached form oxo. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bridged, fused, or spiro C4-10cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bridged C5-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form fused C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form spiro C4-10cycloalkylene, optionally substituted with one or moreAttorney Docket No.260A003WO01 substituents Q.

[0154] In certain embodiments, R5aand R5btogether with the C atom to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 3-, 4-, 5-, 6-, or 7- membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 3- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0155] In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the C atom to which they are attached form spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0156] In certain embodiments, R9is not a moiety of a CDK inhibitor. In certain embodiments, R9is not a moiety of a CDK4 inhibitor. In certain embodiments, R9is not aAttorney Docket No.260A003WO01 moiety of a CDK6 inhibitor. In certain embodiments, R9is not any one of unsubstituted and substituted 4-(1H-benzo[d]imidazol-6-yl)pyrimidine-2-yl and 7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidine-2-yl. In certain embodiments, R9is neither 4-(4-fluoro-1-isopropyl-2-methyl-1H- benzo[d]imidazol-6-yl)-5-methylpyrimidin-2-yl nor 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl.

[0157] In certain embodiments, R9ais (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, R9ais hydrogen. In certain embodiments, R9ais deuterium. In certain embodiments, R9ais cyano. In certain embodiments, R9ais halo. In certain embodiments, R9ais fluoro or chloro.

[0158] In certain embodiments, R9ais C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais methyl, ethyl, or propyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais trifluoromethyl. In certain embodiments, R9ais C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais bridged C5-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais fused C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais spiro C4-10 cycloalkyl, optionally substituted with one or more substituents Q.

[0159] In certain embodiments, R9ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais bicyclic C8-14aryl, optionally substituted with oneAttorney Docket No.260A003WO01 or more substituents Q. In certain embodiments, R9ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais benzyl, optionally substituted with one or more substituents Q.

[0160] In certain embodiments, R9ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais imidazolyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais imidazol-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 1-methylimidazol-2-yl. In certain embodiments, R9ais 6- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5,5-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais 6,6- fused heteroaryl, each optionally substituted with one or more substituents Q.

[0161] In certain embodiments, R9ais heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais oxetanyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais oxetan-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais tetrahydropyranyl, optionally substituted with one or moreAttorney Docket No.260A003WO01 substituents Q. In certain embodiments, R9ais tetrahydropyran-4-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0162] In certain embodiments, R9ais bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9ais bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9ais spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0163] In certain embodiments, R9ais –C(O)NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, R9ais –OR1a, wherein R1ais as defined herein. In certain embodiments, R9ais –NR1bR1c, wherein R1band R1care each as defined herein.

[0164] In certain embodiments, R9ais (i) hydrogen, deuterium, cyano, fluoro, or chloro; or (ii) methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, phenyl, pyridinyl, oxetanyl, morpholino, methoxy, propoxy, benzyloxy, amino, aminocarbonyl, or benzo[d]imidazolyl, each optionally substituted with one or more substituents Q.

[0165] In certain embodiments, R9ais hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoromethyl, 1-methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3-yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxyethyl)amino, aminocarbonyl, dimethyl- phosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)amino. In certain embodiments, R9ais hydrogen, cyano, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydropyran-4-yl, or methoxy.

[0166] In certain embodiments, R9bis (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6 alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, R9bisAttorney Docket No.260A003WO01 hydrogen. In certain embodiments, R9bis deuterium. In certain embodiments, R9bis cyano. In certain embodiments, R9bis halo. In certain embodiments, R9bis fluoro or chloro.

[0167] In certain embodiments, R9bis C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis methyl, ethyl, or propyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis trifluoromethyl. In certain embodiments, R9bis C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis bicyclic C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis bridged C5-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis fused C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis spiro C4-10cycloalkyl, optionally substituted with one or more substituents Q.

[0168] In certain embodiments, R9bis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis bicyclic C8-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis benzyl, optionally substituted with one or more substituents Q.

[0169] In certain embodiments, R9bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis imidazolyl, optionally substituted with one or more substituents Q. InAttorney Docket No.260A003WO01 certain embodiments, R9bis imidazol-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 1-methylimidazol-2-yl. In certain embodiments, R9bis 6- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5,5-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis 6,6- fused heteroaryl, each optionally substituted with one or more substituents Q.

[0170] In certain embodiments, R9bis heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis oxetanyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis oxetan-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis tetrahydropyranyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis tetrahydropyran-4-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0171] In certain embodiments, R9bis bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9bis bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9bis spiro heterocyclyl, optionally substituted with one or moreAttorney Docket No.260A003WO01 substituents Q.

[0172] In certain embodiments, R9bis –C(O)NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, R9bis –OR1a, wherein R1ais as defined herein. In certain embodiments, R9bis –NR1bR1c, wherein R1band R1care each as defined herein.

[0173] In certain embodiments, R9bis (i) hydrogen, deuterium, cyano, fluoro, or chloro; or (ii) methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, phenyl, pyridinyl, oxetanyl, morpholino, methoxy, propoxy, benzyloxy, amino, aminocarbonyl, or benzo[d]imidazolyl, each optionally substituted with one or more substituents Q.

[0174] In certain embodiments, R9bis hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoromethyl, 1-methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3-yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxyethyl)amino, aminocarbonyl, dimethyl- phosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)amino. In certain embodiments, R9bis hydrogen, cyano, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydropyran-4-yl, or methoxy.

[0175] In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form C6-14aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form C6-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form bicyclic C8-14aryl, optionally substituted with one or more substituents Q.

[0176] In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 5- orAttorney Docket No.260A003WO01 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form pyrazolyl or pyrrolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 6- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form pyridinyl, optionally substituted with one or more substituents Q.

[0177] In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form dihydropyrrolyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 6- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9aand R9btogether with the carbon atoms to which they are attached form 7- membered heterocyclyl, optionally substituted with one or more substituents Q.

[0178] In certain embodiments, R9cis (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6 alkyl, C1-6 heteroalkyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c, wherein each R1a, R1b, and R1cis as defined herein. In certain embodiments, R9cis hydrogen. In certain embodiments, R9cis deuterium. In certain embodiments, R9cis cyano. In certain embodiments, R9cis halo. In certain embodiments, R9cis fluoro or chloro.Attorney Docket No.260A003WO01

[0179] In certain embodiments, R9cis C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis methyl, ethyl, or propyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis C1-6heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis trifluoromethyl. In certain embodiments, R9cis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis bridged, fused, or spiro C4-10cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis bridged C5-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis fused C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis spiro C4-10 cycloalkyl, optionally substituted with one or more substituents Q.

[0180] In certain embodiments, R9cis C6-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis bicyclic C8-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis C7-15aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis benzyl, optionally substituted with one or more substituents Q.

[0181] In certain embodiments, R9cis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis imidazolyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis imidazol-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 1-methylimidazol-2-yl. In certain embodiments, R9cis 6- membered heteroaryl, optionally substituted with one or more substituents Q. In certainAttorney Docket No.260A003WO01 embodiments, R9cis bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5,5-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis 6,6- fused heteroaryl, each optionally substituted with one or more substituents Q.

[0182] In certain embodiments, R9cis heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis oxetanyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis oxetan-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis tetrahydropyranyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis tetrahydropyran-4-yl, optionally substituted with one or more substituents Q. IIn certain embodiments, R9cis 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0183] In certain embodiments, R9cis bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R9cis bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R9cis spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0184] In certain embodiments, R9cis –C(O)NR1bR1c, wherein R1band R1care each asAttorney Docket No.260A003WO01 defined herein. In certain embodiments, R9cis –OR1a, wherein R1ais as defined herein. In certain embodiments, R9cis –NR1bR1c, wherein R1band R1care each as defined herein.

[0185] In certain embodiments, R9cis (i) hydrogen, deuterium, cyano, fluoro, or chloro; or (ii) methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, phenyl, pyridinyl, oxetanyl, morpholino, methoxy, propoxy, benzyloxy, amino, aminocarbonyl, or benzo[d]imidazolyl, each optionally substituted with one or more substituents Q.

[0186] In certain embodiments, R9cis hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoromethyl, 1-methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3-yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxyethyl)amino, aminocarbonyl, dimethyl- phosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)amino. In certain embodiments, R9cis hydrogen, cyano, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydropyran-4-yl, or methoxy.

[0187] In certain embodiments, m is an integer of 0, 1, or 2. In certain embodiments, m is an integer of 0. In certain embodiments, m is an integer of 1. In certain embodiments, m is an integer of 2.

[0188] In certain embodiments, n is an integer of 0, 1, or 2. In certain embodiments, n is an integer of 0. In certain embodiments, n is an integer of 1. In certain embodiments, n is an integer of 2.

[0189] In certain embodiments, p is an integer of 0, 1, or 2. In certain embodiments, p is an integer of 0. In certain embodiments, p is an integer of 1. In certain embodiments, p is an integer of 2.

[0190] In certain embodiments, q is an integer of 0, 1, or 2. In certain embodiments, q is an integer of 0. In certain embodiments, q is an integer of 1. In certain embodiments, q is an integer of 2.

[0191] In certain embodiments, p and q are each an integer of 0. In certain embodiments, p and q are each an integer of 1. In certain embodiments, p is an integer of 0 and q is an integerAttorney Docket No.260A003WO01 of 1. In certain embodiments, p is an integer of 0 and q is an integer of 2.

[0192] In certain embodiments, r is an integer of 0, 1, or 2. In certain embodiments, r is an integer of 0. In certain embodiments, r is an integer of 1. In certain embodiments, r is an integer of 2.

[0193] In certain embodiments, s is an integer of 0, 1, or 2. In certain embodiments, s is an integer of 0. In certain embodiments, s is an integer of 1. In certain embodiments, s is an integer of 2.

[0194] In certain embodiments, t is an integer of 0, 1, or 2. In certain embodiments, t is an integer of 0. In certain embodiments, t is an integer of 1. In certain embodiments, t is an integer of 2.

[0195] In certain embodiments, u is an integer of 0, 1, or 2. In certain embodiments, u is an integer of 0. In certain embodiments, u is an integer of 1. In certain embodiments, u is an integer of 2.

[0196] In certain embodiments, t and u are each an integer of 0. In certain embodiments, t and u are each an integer of 1. In certain embodiments, t is an integer of 0 and u is an integer of 1. In certain embodiments, t is an integer of 0 and u is an integer of 2. In certain embodiments, t and u are each an integer of 2.

[0197] In certain embodiments, v is an integer of 0, 1, or 2. In certain embodiments, v is an integer of 0. In certain embodiments, v is an integer of 1. In certain embodiments, v is an integer of 2.

[0198] All combinations of the embodiments provided herein for the groups, R1, R4, R6, R7, R8, R9, R2a, R2b, R3a, R3b, R3c, R4a, R5a, R5b, R6a, R7a, R7b, R9a, R9b, R9c, A1, A2, A3, A4, L1, L2, U, V, X, Y, Z, m, n, p, q, r, s, t, u, and v in formulae described herein, including Formulae (I) to

[0199] In one embodiment, provided herein is a compound of: 3-(5-(1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)- amino)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-Attorney Docket No.260A003WO01 dione A001; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A002; 3-(2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidin-4-yl)benzonitrile A003; 3-(5-(4-hydroxy-1-(4-(4-((4-phenylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A004; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A005; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A006; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropoxypyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A007; 3-(5-(1-(4-(4-((4-(benzyloxy)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A008; 3-(5-(4-hydroxy-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A009; 3-(5-(4-hydroxy-1-(4-(4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A010; 3-(5-(4-hydroxy-1-(4-(4-((4-((2-hydroxyethyl)amino)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A011; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carbonitrile A012; 3-(5-(1-(4-(4-((4-(2-(dimethylphosphoryl)phenyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A013; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile A014; 4-((2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidin-4-yl)methyl)-3,5-dimethyl- benzonitrile A015;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-((5-(hydroxymethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A016; 3-(5-(4-hydroxy-1-(4-(4-((4-morpholinopyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A017; 3-(5-(4-hydroxy-1-(4-(4-((5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)- amino)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A018; 3-(5-(4-hydroxy-1-(4-(4-((4-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A019; 3-(5-(4-hydroxy-1-(4-(4-((4-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A020; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A021; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide A022; 3-(5-(4-hydroxy-1-(4-(4-(pyrimidin-2-ylamino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A023; 3-(5-(4-hydroxy-1-(4-(4-((4-(hydroxymethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A024; 3-(5-(1-(4-(4-((5-(aminomethyl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A025; or 3-(5-(4-hydroxy-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A026; 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.

[0200] In another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(4-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A027; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A028; 3-(5-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)-Attorney Docket No.260A003WO01 1-oxoisoindolin-2-yl)piperidine-2,6-dione A029; 3-(2-(1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A030; 3-(2-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]- pentan-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione A031; 3-(5-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A032; 3-(2-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A033; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A034; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A035; 3-(2-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A036; 3-(2-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A037; 3-(5-(1-((6-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-3-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A038; 3-(5-(1-((5-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A039; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperazin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A040; 3-(5-(1-(4-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A041; 3-(5-(1-(4-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A042; 3-(5-(1-(4-(4-(difluoro(5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A043;Attorney Docket No.260A003WO01 3-(2-((3aR,5r,6aS)-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)piperidine-2,6-dione A044; 3-(5-((S)-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A045; 3-(5-((R)-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A046; 3-(5-(3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A047; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A048; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A049; 3-(6-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A050; 3-(5-(4-hydroxy-1-((1-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)-1H- pyrazol-4-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A051; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A052; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A053; 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A054; 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A055; 3-(5-(4-hydroxy-1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A056; 3-(5-(1-(4-(4-((4-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A057; 3-(5-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A058;Attorney Docket No.260A003WO01 3-(5-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A059; 3-(5-(1-(4-((1R,5S)-3-((5-(oxetan-3-yl)pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]- octan-8-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A060; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A061; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A062; 3-(5-(1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A063; 3-(5-(1-(4-(3-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A064; 3-(5-(1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A065; 3-(5-(1-(4-(4-(4-(1-methyl-1H-imidazol-2-yl)phenoxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A066; 3-(1-oxo-5-(1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A067; 3-(5-(4-hydroxy-1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A068; 3-(1-oxo-5-(1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A069; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A070; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A071; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2- yl)methyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A072; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A073; 3-(5-(1-((5-(4-((5-cyclopropylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)-Attorney Docket No.260A003WO01 methyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A074; 3-(5-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)azetidin-3-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A075; 3-(5-(1-(4-(3-((5-isopropylpyridin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)benzyl)- azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A076; 3-(5-(1-((5-(4-((5-cyclopropylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)- methyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A077; 3-(5-(1-(4-(3-((5-cyclopropylpyridin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A078; 3-(2-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)azetidin-3-yl)- 5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A079; 3-(5-(1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A080; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A081; 3-(2-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- azetidin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A082; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2- yl)methyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A083; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A084; 3-(5-(1-((5-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A085; 3-(5-((R)-1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-3,3- difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A086; 3-(5-((S)-1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-3,3- difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A087; 3-(5-((R)-1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- 3,3-difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A088; 3-(5-((S)-1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- 3,3-difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A089;Attorney Docket No.260A003WO01 5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione A090; 5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione A091; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A092; (S)-3-((R)-5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A093; (S)-3-((R)-5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A094; (S)-3-((R)-5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A095; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A096; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A097; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A098; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A099; or 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A100; 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.

[0201] In yet another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)-2-azaspiro[3.3]- heptan-2-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A101; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyridin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A102; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-Attorney Docket No.260A003WO01 yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A103; (S)-3-((S)-5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A104; 3-(5-(4-hydroxy-1-(4-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- methyl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A105; 3-(2-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A106; 3-(5-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A107; 3-(5-(4-hydroxy-1-((6-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A108; 3-(5-(4-hydroxy-1-((5-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A109; 3-(2-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A110; 3-(5-(4-hydroxy-1-(3-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A111; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methylcyclopropyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A112; 3-(5-(4-hydroxy-1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A113; 3-(5-(4-hydroxy-1-(4-((R)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A114; 3-(5-(4-hydroxy-1-(4-((S)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A115; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)azetidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A116; (S)-3-((R)-2-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A117;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(((5-isopropylpyrimidin-2-yl)amino)methyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A119; 3-(5-(4-hydroxy-1-(4-(5-((5-isopropylpyrimidin-2-yl)amino)hexahydrocyclo- penta[c]pyrrol-2(1H)-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A120; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]- octan-8-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A121; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidine-1-carbonyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A122; 3-(5-(1-(4-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)methyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A124; 3-(5-(1-(4-(((5-isopropylpyrimidin-2-yl)amino)methyl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A125; (S)-3-((R)-2-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione A126; 3-(5-(4-hydroxy-1-(4-(4-((3-isopropylbicyclo[1.1.1]pentan-1-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A127; 3-(5-(4-hydroxy-1-(4-(4-((4-isopropylphenyl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A128; 3-(5-(4-hydroxy-1-(4-(4-((6-isopropylpyridin-3-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A129; 3-(5-(1-(4-(4-(difluoro(5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- 4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A130; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A131; 3-(5-(4-hydroxy-1-(4-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A132; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperazin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A133; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)(methyl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A134;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)piperazin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A135; 3-(5-(4-hydroxy-1-((6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)methyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A136; 3-(5-(4-hydroxy-1-(2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- phenyl)propan-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A137; 3-(6-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A138; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A139; 3-(5-(4-hydroxy-1-(4-(4-((2-isopropylpyrimidin-5-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A140; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A141; 3-(5-(4-hydroxy-1-(3-((S)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A142; 3-(5-(4-hydroxy-1-(3-((R)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A143; 3-(5-(4-hydroxy-1-(4-((S)-3-((5-isopropylpyrimidin-2-yl)amino)pyrrolidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A144; 3-(5-(4-hydroxy-1-(4-((R)-3-((5-isopropylpyrimidin-2-yl)amino)pyrrolidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A145; 3-(5-(4-hydroxy-1-(4-(((1s,4s)-4-((5-isopropylpyrimidin-2-yl)methyl)cyclo- hexyl)oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A146; 3-(5-(4-hydroxy-1-(4-(((1s,4s)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A147; 3-(5-(4-hydroxy-1-(4-(((1r,4r)-4-((5-isopropylpyrimidin-2-yl)methyl)cyclo- hexyl)oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A148; 3-(5-(4-hydroxy-1-(4-(((1r,4r)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A149;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-((1s,4s)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A150; 3-(5-(4-hydroxy-1-(4-((1r,4r)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A151; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]- pentan-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A152; 3-(5-(4-hydroxy-1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A153; 3-(5-(1-(4-(2-((5-isopropylpyrimidin-2-yl)amino)ethoxy)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A154; 3-(5-((3aR,5s,6aS)-5-hydroxy-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A155; 3-(5-((3aR,5r,6aS)-5-hydroxy-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A156; 3-(5-((S)-3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A157; 3-(5-((R)-3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl) -1-oxoisoindolin-2-yl)piperidine-2,6-dione A158; or3- (4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A159; 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.

[0202] In yet another embodiment, provided herein is a compound of: 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- (difluoromethyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A160; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-(difluoro- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A161; 3-(5-(4-(difluoromethyl)-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-Attorney Docket No.260A003WO01 piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A162; 3-(5-(4-(difluoromethyl)-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A163; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A164; 3-(5-(1-(4-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A165; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A166; 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A167; 3-(5-(1-(4-(4-((4-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A168; 3-(5-(4-fluoro-1-((5-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A169; 3-(5-(1-(4-(4-((4-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A170; 3-(5-(1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A171; 3-(5-(4-fluoro-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A172; 3-(5-(4-fluoro-1-(4-(4-((5-methylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A173; 3-(5-(1-(4-(4-((5-methylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A174; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A175; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A176; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A177;Attorney Docket No.260A003WO01 3-(5-(4-fluoro-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A178; 3-(5-(1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A179; 3-(5-(1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A180; 3-(5-(4-fluoro-1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A181; 3-(1-oxo-5-(1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A182; 3-(5-(4-fluoro-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A183; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)- methyl)phenyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile A184; 3-(5-(1-(4-(4-((5-methoxypyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A185; 3-(5-(1-(4-(4-((4-methoxypyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A186; 3-(5-(1-(4-(4-((4-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A187; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)- methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carbonitrile A188; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A189; 3-(1-oxo-5-(1-((5-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A190; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A191; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A192; (S)-3-((R)-3-methyl-5-(1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-Attorney Docket No.260A003WO01 yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A193; (S)-3-((R)-5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A194; 3-(2-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A195; (S)-3-((R)-5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A196; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A197; (S)-3-((R)-3-methyl-1-oxo-5-(1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A198; 3-(5-(1-(4-((S)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A199; or 3-(5-(1-(4-((R)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A200; 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.

[0203] In yet another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A201; 3-(5-(4-hydroxy-1-(4-(4-(quinazolin-2-ylamino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A202; 3-(5-(4-hydroxy-1-(4-(4-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-d]- pyrimidin-5-yl)amino)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A203; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxyquinazolin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A204; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A205; 3-(5-(4-hydroxy-1-(4-(4-((8-methoxyquinazolin-2-yl)amino)piperidin-1-yl)-Attorney Docket No.260A003WO01 benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A206; 3-(5-(1-(4-(4-((1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)piperidin-1-yl)benzyl)- 4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A207; 3-(5-(4-hydroxy-1-(4-(4-(pyrido[2,3-d]pyrimidin-2-ylamino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A208; 3-(5-(4-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A209; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A210; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A211; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A212; 3-(2-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A213; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)oxy)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A214; 3-(5-(1-(4-(4-((5,8-dimethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)- amino)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A215; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxy-5-methylquinazolin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A216; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A217; 3-(5-(4-hydroxy-1-(4-(4-((5-methylfuro[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A218; 3-(5-(4-hydroxy-1-(4-(4-((7-methylpyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A219; 3-(5-(4-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A220; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-Attorney Docket No.260A003WO01 piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A221; 3-(5-(4-hydroxy-1-(4-(8-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.2.1]octan-3-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A222; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxy-4-methylquinazolin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A223; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxypyrido[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A224; 3-(5-(4-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A225; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A226; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A227; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A228; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A229; 3-(2-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A230; 3-(5-(4-fluoro-1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A231; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A232; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A233; 3-(5-(1-(4-(4-((3-methylbenzo[d]isoxazol-6-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A234; 3-(5-(4-hydroxy-1-(4-(4-((3-methylbenzo[d]isoxazol-6-yl)methyl)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A235;Attorney Docket No.260A003WO01 3-(5-(1-(4-(6-((1-methyl-1H-indazol-5-yl)oxy)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A236; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A237; 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A238; 3-(5-(1-(4-(3-(difluoro(1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A239; 3-(5-(1-(4-(1-((1-methyl-1H-indazol-5-yl)methyl)piperidin-4-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A240; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A241; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A242; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A243; 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A244; 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A245; 3-(5-(3-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A246; 3-(5-(3-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A247; 3-(5-(3-hydroxy-1-(4-(4-((1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A248; 3-(5-(3-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)oxy)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A249; 3-(5-(4-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A250; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1-Attorney Docket No.260A003WO01 yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A251; 3-(1-oxo-5-(1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A252; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A253; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A254; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A255; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)-4-fluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A256; 3-(5-(1-(4-(4-((3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A257; or 3-(5-(1-(4-(4-((3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A258; 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 yet another embodiment, provided herein is a compound of: 3-(5-(1-(4-((S)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A301; 3-(5-(1-(4-((R)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A302; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A303; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A304; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A305; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A306;Attorney Docket No.260A003WO01 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-2-methylbenzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A307; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-3-methylbenzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A308; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-2-methylbenzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A309; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-3-methylbenzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A310; 3-(5-(1-(4-((3S,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A311; 3-(5-(1-(4-((3R,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A312; 3-(5-(1-(4-((3S,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A313; 3-(5-(1-(4-((3R,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A314; 3-(5-(1-(4-((3S,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-hydroxypiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A315; or 3-(5-(1-(4-((3R,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-hydroxypiperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A316; 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.

[0205] In yet another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)-1,4-diazepan-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A401; 3-(5-(1-(4-(4-(5-isopropylpyrimidin-2-yl)-1,4-diazepan-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A402; 3-(1-oxo-5-(1-(4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A403; 3-(5-(1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-Attorney Docket No.260A003WO01 oxoisoindolin-2-yl)piperidine-2,6-dione A404; 3-(5-(4-fluoro-1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A405; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A406; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A407; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)-4-fluoro- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A408; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A409; 3-(5-(1-(4-(4-(5-isopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A410; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A411; 3-(5-(4-hydroxy-1-(4-(4-(2-isopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A412; 3-(5-(1-(4-(4-(2-cyclopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A413; 3-(5-(1-(4-(4-(2-isopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A414; 3-(5-(1-(4-(4-(2-cyclopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A415; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A416; 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A417; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A418; 3-(5-(1-(4-(4-(5-cyclopropylpyridin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A419;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyridin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A420; 3-(5-(1-(4-(4-(5-isopropylpyridin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A421; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A422; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin- 4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A423; or 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A424; 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 yet another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A501; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A502; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)oxy)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A503; 3-(5-(1-(4-(6-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A504; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A505; 3-(5-(1-(4-(6-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A506; 3-(5-(1-(4-(6-((5-chloropyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A507; 3-(1-oxo-5-(1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A508; 3-(5-(4-fluoro-1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3-yl)-Attorney Docket No.260A003WO01 benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A509; 3-(5-(4-hydroxy-1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)pyridin-3-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A510; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)-4-fluoro- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A511; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)-4- fluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A512; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A513; 3-(5-(1-(4-(6-((5-methylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A514; or 3-(5-(1-(4-(5-((5-methylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A515; 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 yet another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidine-1- carbonyl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A601; 3-(2-(1-((1-(4-((5-isopropylpyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A602; 3-(2-(4-hydroxy-1-((1-(4-((5-isopropylpyrimidin-2-yl)amino)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A603; 3-(2-(1-((2-((5-isopropylpyrimidin-2-yl)amino)quinolin-6-yl)methyl)piperidin-4- yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A604; 3-(2-(1-((3-((5-isopropylpyrimidin-2-yl)amino)isoquinolin-7-yl)methyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A605; 3-(2-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A606; or 3-(5-(4-hydroxy-1-((3-((5-isopropylpyrimidin-2-yl)amino)isoquinolin-7-yl)-Attorney Docket No.260A003WO01 methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A607; 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.

[0208] In yet another embodiment, provided herein is a compound of: 3-(5-(1-(4-(4-(6-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin- 2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B001; 3-(5-(1-(4-(4-(6-((4-(benzyloxy)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1- yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B002; 3-(5-(1-(4-(4-(6-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B003; 4-((2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)-3,5- dimethylbenzonitrile B004; 3-(2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzonitrile B005; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-morpholinopyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B006; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B007; 3-(5-(1-(4-(4-(6-((4-((cyclopropylmethyl)amino)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B008; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-phenylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B009; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B010; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3-Attorney Docket No.260A003WO01 yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B011; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-4-carbonitrile B012; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B013; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-isopropoxypyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B014; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-methylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B015; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-4-carboxamide B016; 3-(5-(1-(4-(4-(6-((4-(2-aminoethoxy)pyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B017; 3-(5-(4-hydroxy-1-(4-(4-(6-(pyrimidin-2-ylamino)pyridin-3-yl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B018; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile B019; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(hydroxymethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B020; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(hydroxymethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B021; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-methylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B022; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2- yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione B023; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-methoxypyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B024; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)amino)-Attorney Docket No.260A003WO01 pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B025; 3-(5-(1-(4-(4-(6-((5-chloropyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B026; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(piperazin-1-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B027; 3-(5-(1-(4-(4-(6-((5-(aminomethyl)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin- 1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B028; or 3-(5-(1-(4-(4-(6-((4-aminopyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B029; 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.

[0209] In still another embodiment, provided herein is a compound of: 3-(5-(4-hydroxy-1-(4-(4-(6-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-d]- pyrimidin-5-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B101; 3-(5-(1-(4-(4-(6-(((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro- pteridin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxo- isoindolin-2-yl)piperidine-2,6-dione B102; 3-(5-(4-hydroxy-1-(4-(4-(6-((7-methoxyquinazolin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B103; 3-(5-(4-hydroxy-1-(4-(4-(6-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B104; 3-(5-(4-hydroxy-1-(4-(4-(6-(quinazolin-2-ylamino)pyridin-3-yl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B105; 3-(5-(4-hydroxy-1-(4-(4-(6-((8-methoxyquinazolin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B106; 3-(5-(4-hydroxy-1-(4-(4-(6-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)- amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-Attorney Docket No.260A003WO01 dione B107; 3-(5-(1-(4-(4-(6-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]- oxazin-6-yl)amino)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B108; 3-(5-(1-(4-(4-(6-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B109; 3-(5-(4-Hydroxy-1-(4-(4-(6-(pyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B110; 3-(5-(1-(4-(4-(6-((7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin- 1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B111; or 3-(5-(1-(4-(4-(6-((7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B112; 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.

[0210] In certain embodiments, a compound provided herein is not a CDK protein degrader. In certain embodiments, a compound provided herein is not a CDK4 protein degrader. In certain embodiments, a compound provided herein is not a CDK6 protein degrader. In certain embodiments, a compound provided herein is neither a CDK4 protein degrader nor a CDK6 protein degrader.

[0211] 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, and34S,35S, or36S for sulfur.Attorney Docket No.260A003WO01

[0212] 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 50, no less than about 100, no less than about 200, no less than 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 6,410 for deuterium and 90 for carbon-13.

[0213] 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. 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 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.

[0214] 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 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.Attorney Docket No.260A003WO01

[0215] 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 contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0216] 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 the compound that undergoes 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.

[0217] 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.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.

[0218] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein 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, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid,Attorney Docket No.260A003WO01 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-toluene- sulfonic acid, undecylenic acid, and valeric acid.

[0219] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl- amino)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.

[0220] A compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be 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.Attorney Docket No.260A003WO01 Pharmaceutical Compositions

[0221] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g., a compound of Formula (I) or (IV), 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.

[0222] The 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.

[0223] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration.

[0224] The 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 theAttorney Docket No.260A003WO01 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.

[0225] The 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. A. Oral Administration

[0226] The pharmaceutical composition provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

[0227] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limitedAttorney Docket No.260A003WO01 to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline celluloses, such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch. The amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.

[0228] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[0229] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross- linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; and algins. The amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible toAttorney Docket No.260A003WO01 those of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[0230] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL®200 and CAB-O-SIL®. The amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[0231] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes. A color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN®20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl- cellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxy- propyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueousAttorney Docket No.260A003WO01 liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0232] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0233] The pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[0234] The tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[0235] The pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient(s).Attorney Docket No.260A003WO01 The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s).

[0236] The pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0237] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further comprise one or more antioxidants, such asAttorney Docket No.260A003WO01 butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0238] The pharmaceutical composition provided herein for oral administration can also be provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No.6,350,458.

[0239] The pharmaceutical composition provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

[0240] Coloring and flavoring agents can be used in all of the dosage forms described herein.

[0241] The pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. B. Parenteral Administration

[0242] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0243] The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres,Attorney Docket No.260A003WO01 nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra.

[0244] The pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0245] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium- chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0246] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, suchAttorney Docket No.260A003WO01 as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ^- cyclodextrin, ^-cyclodextrin, hydroxypropyl-^-cyclodextrin, sulfobutylether-^-cyclodextrin, and sulfobutylether 7-^-cyclodextrin (CAPTISOL®).

[0247] When the pharmaceutical composition provided herein is formulated for multiple dosage administration, multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[0248] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0249] The pharmaceutical composition provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

[0250] The pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.Attorney Docket No.260A003WO01

[0251] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross- linked partially hydrolyzed polyvinyl acetate.

[0252] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. C. Topical Administration

[0253] The pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

[0254] The pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems.

[0255] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-Attorney Docket No.260A003WO01 aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0256] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ and BIOJECT™.

[0257] The pharmaceutical composition provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollient but generally require addition of antioxidants and preservatives.

[0258] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[0259] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;Attorney Docket No.260A003WO01 cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and / or stirring.

[0260] The pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

[0261] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient(s); and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0262] The pharmaceutical composition provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0263] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer,Attorney Docket No.260A003WO01 such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane. The pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

[0264] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0265] The pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0266] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical composition provided herein for inhaled / intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and / or sweeteners, such as saccharin and saccharin sodium.

[0267] The pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.Attorney Docket No.260A003WO01 D. Modified Release

[0268] The pharmaceutical composition provided herein can be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s). 1. Matrix Controlled Release Devices

[0269] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada et al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol.2.

[0270] In certain embodiments, the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0271] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl celluloseAttorney Docket No.260A003WO01 (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®); poly(2-hydroxyethyl- methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

[0272] In certain embodiments, the pharmaceutical composition provided herein is formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.

[0273] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and / or the active ingredient(s), the ratio of the active ingredient(s) versus theAttorney Docket No.260A003WO01 polymer, and other excipients or carriers in the compositions.

[0274] The pharmaceutical composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression. 2. Osmotic Controlled Release Devices

[0275] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).

[0276] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0277] The other class of osmotic agents is osmogens, which are capable of imbibingAttorney Docket No.260A003WO01 water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0278] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

[0279] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

[0280] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate,Attorney Docket No.260A003WO01 EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0281] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No.5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0282] The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.5,612,059 and 5,698,220.

[0283] The total amount of the active ingredient(s) released and the release rate can substantially be modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

[0284] The pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

[0285] The osmotic controlled-release 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; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27.Attorney Docket No.260A003WO01

[0286] In certain embodiments, the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Pat. No.5,612,059 and WO 2002 / 17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

[0287] In certain embodiments, the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices

[0288] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 µm to about 3 mm, about 50 µm to about 2.5 mm, or from about 100 µm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry- granulation, extrusion / spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

[0289] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet. 4. Targeted Delivery

[0290] The pharmaceutical composition provided herein can also be formulated to beAttorney Docket No.260A003WO01 targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos.6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. Methods of Use

[0291] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PAK4, CSTF2, or CSTF2T 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 (IV), 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.

[0292] In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a PAK4-mediated disorder, disease, or condition 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 (IV), 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.

[0293] In yet another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a CSTF2-mediated disorder, disease, or condition 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 (IV), 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.

[0294] In still another embodiment, provided herein is a method of treating, preventing,Attorney Docket No.260A003WO01 or ameliorating one or more symptoms of a CSTF2T-mediated disorder, disease, or condition 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 (IV), 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.

[0295] In certain embodiments, the PAK4-mediated disorder, disease, or condition is a proliferative disease. In certain embodiments, the CSTF2-mediated disorder, disease, or condition is a proliferative disease. In certain embodiments, the CSTF2T-mediated disorder, disease, or condition is a proliferative disease.

[0296] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease 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 (IV), 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.

[0297] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is refractory and / or relapsed. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable.

[0298] In certain embodiments, the cancer is drug-resistant. In certain embodiment, the cancer is multidrug-resistant. In certain embodiments, the cancer is resistant to a chemotherapy. In certain embodiments, the cancer is resistant to an immunotherapy. In certain embodiments, the cancer is resistant to a standard therapy for the cancer.

[0299] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0300] In certain embodiments, the therapeutically effective amount of a compoundAttorney Docket No.260A003WO01 provided herein is ranging from about 0.1 to about 100 mg / kg / day, from about 0.1 to about 50 mg / kg / day, from about 0.1 to about 25 mg / kg / day, from about 0.1 to about 20 mg / kg / day, from about 0.1 to about 15 mg / kg / day, from about 0.1 to about 10 mg / kg / day, or from about 0.1 to about 5 mg / kg / day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg / kg / day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg / kg / day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg / kg / day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg / kg / day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg / kg / day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg / kg / day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg / kg / day.

[0301] It is understood that the administered dose can also be expressed in units other than mg / kg / day. For example, doses for parenteral administration can be expressed as mg / m2 / day. One of ordinary skill in the art would readily know how to convert doses from mg / kg / day to mg / m2 / day to given either the height or weight of a subject or both. For example, a dose of 1 mg / m2 / day for a 65 kg human is approximately equal to 58 mg / kg / day.

[0302] Depending on the disorder, disease, or condition 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. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.

[0303] 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.260A003WO01 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.

[0304] A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets 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.

[0305] A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). In addition, the administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.

[0306] In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent 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 of the therapies, and / or improves the efficacy of the treatment.

[0307] A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of a condition, disorder, or disease described herein.

[0308] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g.,Attorney Docket No.260A003WO01 a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[0309] The route of administration of a compound provided herein is independent of the route of administration of a second therapy. In one ...

Claims

1. Attorney Docket No.260A003WO01 What is claimed is:

1. A compound of Formula (I):or an enantiomer, 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: A1is heterocyclylene; A2is C6-14 arylene or heteroarylene; A3is heterocyclylene, a bond, C3-10 cycloalkylene, C6-14 arylene, or heteroarylene; A4is a bond, C6-14arylene, or heteroarylene; L1is (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–; or (ii) C1-6 alkylene or C1-6 heteroalkylene; L2is (i) –NR1b–, a bond, –C(O)–, –O–, –S–, –S(O)–, or –S(O2)–; or (ii) C1-6alkylene or C1-6heteroalkylene; U is C(R3b) or N; V is C(R3c) or N; each R1is independently deuterium, cyano, halo, nitro, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or two R1are linked together to form C1-6 alkylene or C1-6 heteroalkylene; R9is heteroaryl, C3-10cycloalkyl, C6-14aryl, or heterocyclyl; R2aand R2bare each independently hydrogen, deuterium, or C1-6 alkyl; or R2aand R2btogether with the C atom to which they are attached form oxo, C3-10 cycloalkylene, or heterocyclylene; R3a, R3b, and R3care 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,Attorney Docket No.260A003WO01 –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; R5aand R5bare each independently hydrogen, deuterium, or C1-6 alkyl; or R5aand R5btogether with the C atom to which they are attached form oxo, C3-10cycloalkylene, or heterocyclylene; 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; and m is an integer of 0, 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, 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, –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, –P(O)(Ra)Rd, –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, C2-6alkenyl, 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; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro,Attorney Docket No.260A003WO01 imino, 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; 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, –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, –P(O)(Re)Rg, –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) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, wherein A4is a bond.

3. The compound of claim 1 or 2, wherein R9is heteroaryl or C6-14aryl, each optionally substituted with one or more substituents Q.

4. The compound of any one of claims 1 to 3, wherein R9is heteroaryl, optionally substituted with one or more substituents Q.

5. The compound of any one of claims 1 to 4, wherein R9is monocyclic heteroaryl, optionally substituted with one or more substituents Q.

6. The compound of any one of claims 1 to 5, wherein R9is 6-membered heteroaryl, optionally substituted with one or more substituents Q.

7. The compound of any one of claims 1 to 6, wherein R9is pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with one or more substituents Q.

8. The compound of any one of claims 1 to 4, wherein R9is bicyclic heteroaryl, optionally substituted with one or more substituents Q.

9. The compound of any one of claims 1 to 4 and 8, wherein R9is 5,5-, 5,6-, or 6,6- fused heteroaryl, each optionally substituted with one or more substituents Q.Attorney Docket No.260A003WO01 10. The compound of any one of claims 1 to 4, 8, and 9, wherein R9is 5,6-fused heteroaryl, each optionally substituted with one or more substituents Q.

11. The compound of any one of claims 1 to 4 and 8 to 10, wherein R9is benzo[d]- imidazolyl, benzo[d]isoxazolyl, indazolyl, furo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, or 6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, each optionally substituted with one or more substituents Q.

12. The compound of any one of claims 1 to 4, 8, and 9, wherein R9is 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q.

13. The compound of any one of claims 1 to 4, 8, 9, and 12, wherein R9is quinazolinyl, 5,6,7,8-tetrahydroquinazolinyl, pyrido[2,3-d]pyrimidinyl, 3,4-dihydro-2H-pyrano- [2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl, 6,7-dihydro-5H-pyrano[2,3-d]- pyrimidinyl, 5,6,7,8-tetrahydropteridinyl, or 3,4-dihydropyrido[3,2-b][1,4]oxazinyl, each optionally substituted with one or more substituents Q.

14. The compound of any one of claims 1 to 3, wherein R9is C6-14 aryl, optionally substituted with one or more substituents Q.

15. The compound of any one of claims 1 to 3, wherein R9is phenyl, pyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, benzo[d]imidazol-6-yl, benzo[d]isoxazol-6-yl, indazol-5-yl, indazol-6-yl, furo[2,3-d]pyrimidin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, pyrrolo[2,3-d]pyrimidin-2- yl, pyrazolo[3,4-d]pyrimidin-6-yl, pyrazolo[4,3-d]pyrimidin-5-yl, 6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl, quinazolin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, pyrido[2,3-d]pyrimidin-2- yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl, 6,7- dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl, 5,6,7,8-tetrahydropteridin-2-yl, or 3,4-dihydropyrido- [3,2-b][1,4]oxazin-6-yl, each optionally substituted with one or more substituents Q.

16. The compound of any one of claims 1 to 15, wherein: A1is heterocyclylene; A2is C6-14 arylene or heteroarylene; A3is C3-10 cycloalkylene, heteroarylene, or heterocyclylene;Attorney Docket No.260A003WO01 L1is a bond; and L2is (i) a bond, –C(O)–, –O–, –NR1b–, –S–, –S(O)–, or –S(O2)–; or (ii) C1-6 alkylene or C1-6heteroalkylene; wherein each alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

17. The compound of any one of claims 1 to 16, wherein: A1is monocyclic or bicyclic heterocyclylene; A2is phendiyl or monocyclic heteroarylene; A3is monocyclic or bicyclic C3-10cycloalkylene, monocyclic heteroarylene, or monocyclic or bicyclic heterocyclylene; L1is a bond; and L2is (i) a bond, –O–, –NR1b–, or –S–; or (ii) C1-6 alkylene or C1-6 heteroalkylene; wherein each alkylene, heteroalkylene, cycloalkylene, phendiyl, heteroarylene, or heterocyclylene is optionally substituted with one or more substituents Q.

18. The compound of any one of claims 1 to 4, having the structure of Formula (X): or an morediastereomers, a a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R9a, R9b, and R9care 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, each optionally substituted with one or more substituents Q; 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,Attorney Docket No.260A003WO01 –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; or R9aand R9btogether with the carbon atoms to which they are attached form C3-10cycloalkyl, C6-14aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

19. The compound of any one of claims 1 to 18, wherein A1is monocyclic or bicyclic heterocyclylene, each optionally substituted with one or more substituents Q.

20. The compound of any one of claims 1 to 19, wherein A1is azetidindiyl, pyrrolidindiyl, piperidindiyl, piperazindiyl, azepandiyl, 8-azabicyclo[3.2.1]octandiyl, octahydro- cyclopenta[c]pyrroldiyl, or 2-azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q.

21. The compound of any one of claims 1 to 20, wherein A1is azetidindiyl or piperidindiyl, each optionally substituted with one or more substituents Q.

22. The compound of claim 18 or 19, having the structure of Formula (X): or ana a or more or an thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; 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,Attorney Docket No.260A003WO01 –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; or two R4are linked together to form a bond, C1-6alkylene, or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; R4ais hydrogen or R4; or R4aand R3bare linked together to form C1-6 alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; and p and q are each independently an integer of 0, 1, 2, or 3.

23. The compound of any one of claims 1 to 22, wherein A2is C6-14arylene, optionally substituted with one or more substituents Q.

24. The compound of any one of claims 1 to 23, wherein A2is phendiyl, optionally substituted with one or more substituents Q.

25. The compound of any one of claims 1 to 24, wherein A2is phen-1,3-diyl or phen- 1,4-diyl, each optionally substituted with one or more substituents Q 26. The compound of any one of claims 1 to 22, wherein A2is heteroarylene, optionally substituted with one or more substituents Q.

27. The compound of any one of claims 1 to 22 and 26, wherein A2is monocyclic heteroarylene, optionally substituted with one or more substituents Q.

28. The compound of any one of claims 1 to 22, 26, and 27, wherein A2is pyridindiyl, pyrimidindiyl, or pyrazindiyl, each optionally substituted with one or more substituents Q.

29. The compound of any one of claims 1 to 22 and 26 to 28, wherein A2is pyridin- 2,5-diyl, optionally substituted with one or more substituents Q.

30. The compound of any one of claims 1 to 29, wherein A3is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q.Attorney Docket No.260A003WO01 31. The compound of any one of claims 1 to 30, wherein A3is C3-10 cycloalkylene, optionally substituted with one or more substituents Q.

32. The compound of any one of claims 1 to 31, wherein A3is bicyclic C4-10cycloalkylene, optionally substituted with one or more substituents Q.

33. The compound of any one of claims 1 to 32, wherein A3is bridged C5-10 cycloalkylene, optionally substituted with one or more substituents Q.

34. The compound of any one of claims 1 to 30, wherein A3is heteroarylene, optionally substituted with one or more substituents Q.

35. The compound of any one of claims 1 to 30 and 34, wherein A3is monocyclic heteroarylene, optionally substituted with one or more substituents Q.

36. The compound of any one of claims 1 to 30, 34, and 35, wherein A3is 6- membered heteroarylene, optionally substituted with one or more substituents Q.

37. The compound of any one of claims 1 to 30, wherein A3is heterocyclylene, optionally substituted with one or more substituents Q.

38. The compound of any one of claims 1 to 30 and 37, wherein A3is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.

39. The compound of any one of claims 1 to 30, 37, and 38, wherein A3is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q.

40. The compound of any one of claims 1 to 30 and 37 to 39, wherein A3is 4- or 6- membered heterocyclylene, each optionally substituted with one or more substituents Q.

41. The compound of any one of claims 1 to 30, wherein A3is cyclopentanediyl, cyclohexanediyl, cyclohexanediyl, bicyclo[1.1.1]pentanediyl, phendiyl, pyridindiyl, azetidindiyl, pyrrolidindiyl, piperidindiyl, piperidindiyl, piperazindiyl, 8-azabicyclo[3.2.1]octandiyl, octahydrocyclopenta[c]pyrroldiyl, or 2-azaspiro[3.3]heptandiyl, each optionally substituted with one or more substituents Q.Attorney Docket No.260A003WO01 42. The compound of any one of claims 1 to 30 and 41, wherein A3is cyclopentane- 1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, bicyclo[1.1.1]pentan-1,3-diyl, phen-1,3- diyl, phen-1,4-diyl, pyridin-2,5-diyl, azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-dyl, piperidin-1,4-dyl, piperazin-1,4-diyl, 8-azabicyclo[3.2.1]octan-3,8-diyl, octahydrocyclopenta[c]- pyrrol-2,5-diyl, or 2-azaspiro[3.3]heptan-2,6-diyl, each optionally substituted with one or more substituents Q, each optionally substituted with one or more substituents Q.

43. The compound of any one of claims 1, 3 to 15, and 18 to 42, wherein A4is heteroarylene, optionally substituted with one or more substituents Q.

44. The compound of any one of claims 1, 3 to 15, and 18 to 43, wherein A4is monocyclic heteroarylene, optionally substituted with one or more substituents Q.

45. The compound of any one of claims 1, 3 to 15, and 18 to 44, wherein A4is 6- membered heteroarylene, optionally substituted with one or more substituents Q.

46. The compound of any one of claims 1, 3 to 15, and 18 to 45, wherein A4is pyridindiyl, pyrimidindiyl, or pyrazindiyl, each optionally substituted with one or more substituents Q.

47. The compound of any one of claims 1, 3 to 15, and 18 to 46, wherein A4is pyridin-2,5-diyl, optionally substituted with one or more substituents Q.

48. The compound of any one of claims 1 to 15 and 16 to 47, wherein L1is bond.

49. The compound of any one of claims 1 to 48, wherein L2is (i) a bond, –O–, or –NR1b–; or (ii) C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q.

50. The compound of any one of claims 1 to 49, wherein L2is –NR1b–.

51. The compound of any one of claims 1 to 50, wherein L2is –N(H)-or –N(CH3)–.

52. The compound of any one of claims 1 to 49, wherein L2is a bond, –O–, –N(H)–, –N(CH3)–, methanediyl, or difluoromethanediyl.Attorney Docket No.260A003WO01 53. The compound of any one of claims 1 to 52, wherein U is C(R3b).

54. The compound of claim 53, wherein R3bis hydrogen.

55. The compound of claim 53, wherein R3bis fluoro.

56. The compound of any one of claims 1 to 52, wherein U is N.

57. The compound of any one of claims 1 to 56, wherein V is C(R3c).

58. The compound of claim 57, wherein R3cis hydrogen.

59. The compound of claim 57, wherein R3cis fluoro.

60. The compound of any one of claims 1 to 56, wherein V is N.

61. The compound of any one of claims 1 to 60, wherein R2ais hydrogen.

62. The compound of any one of claims 1 to 60, wherein R2ais C1-6alkyl, optionally substituted with one or more substituents Q.

63. The compound of any one of claims 1 to 60 and 62, wherein R2ais methyl, optionally substituted with one or more substituents Q.

64. The compound of any one of claims 1 to 63, wherein R2bis hydrogen.

65. The compound of any one of claims 1 to 63, wherein R2bis C1-6 alkyl, optionally substituted with one or more substituents Q.

66. The compound of any one of claims 1 to 63 and 65, wherein R2bis methyl, optionally substituted with one or more substituents Q.

67. The compound of any one of claims 1 to 66, wherein R3ais hydrogen.

68. The compound of any one of claims 1 to 66, wherein R3ais fluoro.

69. The compound of any one of claims 22 to 68, wherein R4ais (i) hydrogen, deuterium, or halo; or (ii) –OR1a.Attorney Docket No.260A003WO01 70. The compound of any one of claims 22 to 69, wherein R4ais hydrogen, fluoro, or hydroxyl.

71. The compound of any one of claims 22 to 70, wherein R4ais hydrogen.

72. The compound of any one of claims 22 to 70, wherein R4ais hydroxyl.

73. The compound of any one of claims 1 to 72, wherein R5ais hydrogen.

74. The compound of any one of claims 1 to 72, wherein R5ais C1-6alkyl, optionally substituted with one or more substituents Q.

75. The compound of any one of claims 1 to 72 and 74, wherein R5ais methyl, optionally substituted with one or more substituents Q.

76. The compound of any one of claims 1 to 75, wherein R5bis hydrogen.

77. The compound of any one of claims 1 to 75, wherein R5bis C1-6 alkyl, optionally substituted with one or more substituents Q.

78. The compound of any one of claims 1 to 75 and 77, wherein R5bis methyl, optionally substituted with one or more substituents Q.

79. The compound of any one of claims 18 to 78, wherein R9ais (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c.

80. The compound of any one of claims 18 to 79, wherein R9ais hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoromethyl, 1- methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3- yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxyethyl)- amino, aminocarbonyl, dimethylphosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)amino.

81. The compound of any one of claims 18 to 80, wherein R9ais hydrogen, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydro-Attorney Docket No.260A003WO01 pyran-4-yl, or methoxy.

82. The compound of any one of claims 18 to 81, wherein R9bis (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c.

83. The compound of any one of claims 18 to 82, wherein R9bis hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoro- methyl, 1-methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3-yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxy- ethyl)amino, aminocarbonyl, dimethylphosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)- amino.

84. The compound of any one of claims 18 to 83, wherein R9bis hydrogen, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydro- pyran-4-yl, or methoxy.

85. The compound of any one of claims 18 to 84, wherein R9cis (i) hydrogen, deuterium, cyano, or halo; (ii) C1-6alkyl, C1-6heteroalkyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)NR1bR1c, –OR1a, or –NR1bR1c.

86. The compound of any one of claims 18 to 85, wherein R9cis hydrogen, deuterium, cyano, fluoro, chloro, methyl, isopropyl, hydroxymethyl, aminomethyl, trifluoro-methyl, 1- methylcyclopropyl, phenyl, 3-cyanophenyl, 4-cyano-2,6-dimethylbenzyl, pyridin-3-yl, oxeten-3- yl, morpholino, isopropoxy, benzyloxy, (1-methylpiperidin-4-yl)methoxy, (2-hydroxyethyl)- amino, aminocarbonyl, dimethylphosphorylphenyl, or (2-(isopropylsulfonyl)phenyl)amino.

87. The compound of any one of claims 18 to 86, wherein R9cis hydrogen, chloro, methyl, isopropyl, trifluoromethyl, cyclopropyl, 1-methylimidazol-2-yl, oxetan-3-yl, tetrahydro- pyran-4-yl, or methoxy.

88. The compound of any one of claims 1 to 87, wherein m is an integer of 0.Attorney Docket No.260A003WO01 89. The compound of any one of claims 22 to 88, wherein n is an integer of 0, 1, or 2.

90. The compound of claim 89, wherein each R4is independently fluoro or hydroxyl.

91. The compound of any one of claims 22 to 90, wherein p is an integer of 0.

92. The compound of any one of claims 22 to 90, wherein p is an integer of 1.

93. The compound of any one of claims 22 to 92, wherein q is an integer of 0.

94. The compound of any one of claims 22 to 92, wherein q is an integer of 1.

95. A compound of: 3-(5-(1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A001; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A002; 3-(2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidin-4-yl)benzonitrile A003; 3-(5-(4-hydroxy-1-(4-(4-((4-phenylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A004; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A005; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A006; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropoxypyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A007; 3-(5-(1-(4-(4-((4-(benzyloxy)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A008; 3-(5-(4-hydroxy-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A009; 3-(5-(4-hydroxy-1-(4-(4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A010;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-((4-((2-hydroxyethyl)amino)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A011; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carbonitrile A012; 3-(5-(1-(4-(4-((4-(2-(dimethylphosphoryl)phenyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A013; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile A014; 4-((2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidin-4-yl)methyl)-3,5-dimethyl- benzonitrile A015; 3-(5-(4-hydroxy-1-(4-(4-((5-(hydroxymethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A016; 3-(5-(4-hydroxy-1-(4-(4-((4-morpholinopyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A017; 3-(5-(4-hydroxy-1-(4-(4-((5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)- amino)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A018; 3-(5-(4-hydroxy-1-(4-(4-((4-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A019; 3-(5-(4-hydroxy-1-(4-(4-((4-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A020; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A021; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide A022; 3-(5-(4-hydroxy-1-(4-(4-(pyrimidin-2-ylamino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A023; 3-(5-(4-hydroxy-1-(4-(4-((4-(hydroxymethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A024; 3-(5-(1-(4-(4-((5-(aminomethyl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-Attorney Docket No.260A003WO01 hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A025; 3-(5-(4-hydroxy-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A026; 3-(5-(4-hydroxy-1-(4-(4-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A027; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A028; 3-(5-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A029; 3-(2-(1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A030; 3-(2-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]- pentan-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione A031; 3-(5-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A032; 3-(2-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A033; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A034; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A035; 3-(2-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A036; 3-(2-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A037; 3-(5-(1-((6-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-3-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A038; 3-(5-(1-((5-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A039;Attorney Docket No.260A003WO01 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperazin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A040; 3-(5-(1-(4-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A041; 3-(5-(1-(4-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A042; 3-(5-(1-(4-(4-(difluoro(5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A043; 3-(2-((3aR,5r,6aS)-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)piperidine-2,6-dione A044; 3-(5-((S)-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A045; 3-(5-((R)-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A046; 3-(5-(3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A047; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A048; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A049; 3-(6-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A050; 3-(5-(4-hydroxy-1-((1-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)-1H- pyrazol-4-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A051; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A052; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A053; 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A054;Attorney Docket No.260A003WO01 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A055; 3-(5-(4-hydroxy-1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A056; 3-(5-(1-(4-(4-((4-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A057; 3-(5-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A058; 3-(5-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A059; 3-(5-(1-(4-((1R,5S)-3-((5-(oxetan-3-yl)pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]- octan-8-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A060; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A061; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A062; 3-(5-(1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A063; 3-(5-(1-(4-(3-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A064; 3-(5-(1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A065; 3-(5-(1-(4-(4-(4-(1-methyl-1H-imidazol-2-yl)phenoxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A066; 3-(1-oxo-5-(1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A067; 3-(5-(4-hydroxy-1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A068; 3-(1-oxo-5-(1-(4-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A069; 3-(5-(4-hydroxy-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-Attorney Docket No.260A003WO01 benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A070; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A071; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2- yl)methyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A072; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A073; 3-(5-(1-((5-(4-((5-cyclopropylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)- methyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A074; 3-(5-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)azetidin-3-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A075; 3-(5-(1-(4-(3-((5-isopropylpyridin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)benzyl)- azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A076; 3-(5-(1-((5-(4-((5-cyclopropylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-2-yl)- methyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A077; 3-(5-(1-(4-(3-((5-cyclopropylpyridin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A078; 3-(2-(1-(4-(4-((5-isopropylpyridin-2-yl)oxy)piperidin-1-yl)benzyl)azetidin-3-yl)- 5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A079; 3-(5-(1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A080; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A081; 3-(2-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- azetidin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A082; 3-(5-(1-((5-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2- yl)methyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A083; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A084; 3-(5-(1-((5-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)pyridin-2-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A085;Attorney Docket No.260A003WO01 3-(5-((R)-1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-3,3- difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A086; 3-(5-((S)-1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-3,3- difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A087; 3-(5-((R)-1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- 3,3-difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A088; 3-(5-((S)-1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- 3,3-difluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A089; 5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione A090; 5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione A091; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A092; (S)-3-((R)-5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A093; (S)-3-((R)-5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A094; (S)-3-((R)-5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A095; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A096; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A097; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A098; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A099; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A100; 3-(5-(4-hydroxy-1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)-2-azaspiro[3.3]-heptan-2-Attorney Docket No.260A003WO01 yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A101; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyridin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A102; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A103; (S)-3-((S)-5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A104; 3-(5-(4-hydroxy-1-(4-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- methyl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A105; 3-(2-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A106; 3-(5-(4-fluoro-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A107; 3-(5-(4-hydroxy-1-((6-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A108; 3-(5-(4-hydroxy-1-((5-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A109; 3-(2-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A110; 3-(5-(4-hydroxy-1-(3-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A111; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methylcyclopropyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A112; 3-(5-(4-hydroxy-1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A113; 3-(5-(4-hydroxy-1-(4-((R)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A114; 3-(5-(4-hydroxy-1-(4-((S)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A115; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)azetidin-1-yl)-Attorney Docket No.260A003WO01 benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A116; (S)-3-((R)-2-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A117; 3-(5-(4-hydroxy-1-(4-(((5-isopropylpyrimidin-2-yl)amino)methyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A119; 3-(5-(4-hydroxy-1-(4-(5-((5-isopropylpyrimidin-2-yl)amino)hexahydrocyclo- penta[c]pyrrol-2(1H)-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A120; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]- octan-8-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A121; 3-(5-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidine-1-carbonyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A122; 3-(5-(1-(4-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)methyl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A124; 3-(5-(1-(4-(((5-isopropylpyrimidin-2-yl)amino)methyl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A125; (S)-3-((R)-2-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl) 4-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione A126; 3-(5-(4-hydroxy-1-(4-(4-((3-isopropylbicyclo[1.1.1]pentan-1-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A127; 3-(5-(4-hydroxy-1-(4-(4-((4-isopropylphenyl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A128; 3-(5-(4-hydroxy-1-(4-(4-((6-isopropylpyridin-3-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A129; 3-(5-(1-(4-(4-(difluoro(5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- 4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A130; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A131; 3-(5-(4-hydroxy-1-(4-(1-((5-isopropylpyrimidin-2-yl)methyl)piperidin-4-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A132;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)methyl)piperazin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A133; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)(methyl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A134; 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)piperazin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A135; 3-(5-(4-hydroxy-1-((6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)methyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A136; 3-(5-(4-hydroxy-1-(2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- phenyl)propan-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A137; 3-(6-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A138; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A139; 3-(5-(4-hydroxy-1-(4-(4-((2-isopropylpyrimidin-5-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A140; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A141; 3-(5-(4-hydroxy-1-(3-((S)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A142; 3-(5-(4-hydroxy-1-(3-((R)-3-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A143; 3-(5-(4-hydroxy-1-(4-((S)-3-((5-isopropylpyrimidin-2-yl)amino)pyrrolidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A144; 3-(5-(4-hydroxy-1-(4-((R)-3-((5-isopropylpyrimidin-2-yl)amino)pyrrolidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A145; 3-(5-(4-hydroxy-1-(4-(((1s,4s)-4-((5-isopropylpyrimidin-2-yl)methyl)cyclo- hexyl)oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A146; 3-(5-(4-hydroxy-1-(4-(((1s,4s)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A147;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(((1r,4r)-4-((5-isopropylpyrimidin-2-yl)methyl)cyclo- hexyl)oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A148; 3-(5-(4-hydroxy-1-(4-(((1r,4r)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- oxy)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A149; 3-(5-(4-hydroxy-1-(4-((1s,4s)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A150; 3-(5-(4-hydroxy-1-(4-((1r,4r)-4-((5-isopropylpyrimidin-2-yl)amino)cyclohexyl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A151; 3-(5-(4-hydroxy-1-(4-(3-((5-isopropylpyrimidin-2-yl)amino)bicyclo[1.1.1]- pentan-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A152; 3-(5-(4-hydroxy-1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A153; 3-(5-(1-(4-(2-((5-isopropylpyrimidin-2-yl)amino)ethoxy)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A154; 3-(5-((3aR,5s,6aS)-5-hydroxy-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A155; 3-(5-((3aR,5r,6aS)-5-hydroxy-2-(4-(4-((5-isopropylpyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)octahydrocyclopenta[c]pyrrol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A156; 3-(5-((S)-3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A157; 3-(5-((R)-3-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A158; 3-(6-(1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione A159; 3-(5-(1-(4-(4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- (difluoromethyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A160; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-(difluoro- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A161; 3-(5-(4-(difluoromethyl)-1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-Attorney Docket No.260A003WO01 piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A162; 3-(5-(4-(difluoromethyl)-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A163; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A164; 3-(5-(1-(4-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A165; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A166; 3-(5-(4-fluoro-1-(4-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A167; 3-(5-(1-(4-(4-((4-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A168; 3-(5-(4-fluoro-1-((5-(4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A169; 3-(5-(1-(4-(4-((4-chloropyridin-2-yl)oxy)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A170; 3-(5-(1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A171; 3-(5-(4-fluoro-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A172; 3-(5-(4-fluoro-1-(4-(4-((5-methylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A173; 3-(5-(1-(4-(4-((5-methylpyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A174; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A175; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A176; 3-(5-(4-hydroxy-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A177;Attorney Docket No.260A003WO01 3-(5-(4-fluoro-1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A178; 3-(5-(1-(4-(4-((5-(1-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A179; 3-(5-(1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A180; 3-(5-(4-fluoro-1-(4-(4-((5-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A181; 3-(1-oxo-5-(1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A182; 3-(5-(4-fluoro-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A183; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)- methyl)phenyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile A184; 3-(5-(1-(4-(4-((5-methoxypyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A185; 3-(5-(1-(4-(4-((4-methoxypyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A186; 3-(5-(1-(4-(4-((4-methylpyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A187; 2-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)- methyl)phenyl)piperidin-4-yl)amino)pyrimidine-4-carbonitrile A188; 3-(1-oxo-5-(1-(4-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A189; 3-(1-oxo-5-(1-((5-(4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)- pyridin-2-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A190; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A191; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A192; (S)-3-((R)-3-methyl-5-(1-(4-(4-((5-methylpyrimidin-2-yl)amino)piperidin-1-Attorney Docket No.260A003WO01 yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A193; (S)-3-((R)-5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)- piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A194; 3-(2-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A195; (S)-3-((R)-5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A196; (S)-3-((R)-5-(4-hydroxy-1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione A197; (S)-3-((R)-3-methyl-1-oxo-5-(1-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A198; 3-(5-(1-(4-((S)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A199; 3-(5-(1-(4-((R)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A200; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A201; 3-(5-(4-hydroxy-1-(4-(4-(quinazolin-2-ylamino)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A202; 3-(5-(4-hydroxy-1-(4-(4-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-d]- pyrimidin-5-yl)amino)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A203; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxyquinazolin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A204; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A205; 3-(5-(4-hydroxy-1-(4-(4-((8-methoxyquinazolin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A206; 3-(5-(1-(4-(4-((1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)piperidin-1-yl)benzyl)- 4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A207; 3-(5-(4-hydroxy-1-(4-(4-(pyrido[2,3-d]pyrimidin-2-ylamino)piperidin-1-yl)-Attorney Docket No.260A003WO01 benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A208; 3-(5-(4-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A209; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A210; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A211; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)amino)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A212; 3-(2-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A213; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)oxy)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A214; 3-(5-(1-(4-(4-((5,8-dimethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)- amino)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione A215; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxy-5-methylquinazolin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A216; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A217; 3-(5-(4-hydroxy-1-(4-(4-((5-methylfuro[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A218; 3-(5-(4-hydroxy-1-(4-(4-((7-methylpyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A219; 3-(5-(4-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A220; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A221; 3-(5-(4-hydroxy-1-(4-(8-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.2.1]octan-3-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A222;Attorney Docket No.260A003WO01 3-(5-(4-hydroxy-1-(4-(4-((7-methoxy-4-methylquinazolin-2-yl)amino)piperidin- 1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A223; 3-(5-(4-hydroxy-1-(4-(4-((7-methoxypyrido[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A224; 3-(5-(4-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A225; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A226; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A227; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A228; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A229; 3-(2-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)- benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A230; 3-(5-(4-fluoro-1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A231; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A232; 3-(5-(1-(4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A233; 3-(5-(1-(4-(4-((3-methylbenzo[d]isoxazol-6-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A234; 3-(5-(4-hydroxy-1-(4-(4-((3-methylbenzo[d]isoxazol-6-yl)methyl)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A235; 3-(5-(1-(4-(6-((1-methyl-1H-indazol-5-yl)oxy)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A236; 3-(5-(4-hydroxy-1-(4-(4-((1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A237;Attorney Docket No.260A003WO01 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A238; 3-(5-(1-(4-(3-(difluoro(1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A239; 3-(5-(1-(4-(1-((1-methyl-1H-indazol-5-yl)methyl)piperidin-4-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A240; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A241; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)methyl)piperidin-1-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A242; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A243; 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A244; 3-(5-(1-(4-(3-((1-methyl-1H-indazol-5-yl)amino)bicyclo[1.1.1]pentan-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A245; 3-(5-(3-hydroxy-1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A246; 3-(5-(3-hydroxy-1-(4-(4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- piperidin-1-yl)benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A247; 3-(5-(3-hydroxy-1-(4-(4-((1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A248; 3-(5-(3-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)oxy)piperidin-1-yl)- benzyl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A249; 3-(5-(4-hydroxy-1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)oxy)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A250; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A251; 3-(1-oxo-5-(1-(4-(4-((5,6,7,8-tetrahydroquinazolin-2-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A252; 3-(5-(1-(4-(4-((1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl)piperidin-1-Attorney Docket No.260A003WO01 yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A253; 3-(5-(1-(4-(4-((1-methyl-1H-indazol-5-yl)amino)piperidin-1-yl)benzyl)piperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A254; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A255; 3-(5-(1-(4-(4-((6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)benzyl)-4-fluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A256; 3-(5-(1-(4-(4-((3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A257; 3-(5-(1-(4-(4-((3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)amino)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A258; 3-(5-(1-(4-((S)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A301; 3-(5-(1-(4-((R)-4-((5-chloropyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A302; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A303; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A304; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A305; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)benzyl)piperidin-4- yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A306; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-2-methylbenzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A307; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-3-methylbenzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A308; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-2-methylbenzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A309; 3-(5-(1-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-3-methylbenzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A310;Attorney Docket No.260A003WO01 3-(5-(1-(4-((3S,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A311; 3-(5-(1-(4-((3R,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A312; 3-(5-(1-(4-((3S,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A313; 3-(5-(1-(4-((3R,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A314; 3-(5-(1-(4-((3S,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-hydroxypiperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A315; 3-(5-(1-(4-((3R,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-hydroxypiperidin-1- yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A316; 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)-1,4-diazepan-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A401; 3-(5-(1-(4-(4-(5-isopropylpyrimidin-2-yl)-1,4-diazepan-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A402; 3-(1-oxo-5-(1-(4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A403; 3-(5-(1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A404; 3-(5-(4-fluoro-1-(4-(4-(6-isopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A405; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A406; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A407; 3-(5-(1-(4-(4-(6-cyclopropylpyridin-3-yl)piperidin-1-yl)benzyl)-4-fluoro- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A408; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A409; 3-(5-(1-(4-(4-(5-isopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-Attorney Docket No.260A003WO01 oxoisoindolin-2-yl)piperidine-2,6-dione A410; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A411; 3-(5-(4-hydroxy-1-(4-(4-(2-isopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A412; 3-(5-(1-(4-(4-(2-cyclopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A413; 3-(5-(1-(4-(4-(2-isopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A414; 3-(5-(1-(4-(4-(2-cyclopropylpyrimidin-5-yl)piperidin-1-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A415; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A416; 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A417; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A418; 3-(5-(1-(4-(4-(5-cyclopropylpyridin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A419; 3-(5-(4-hydroxy-1-(4-(4-(5-isopropylpyridin-2-yl)piperidin-1-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A420; 3-(5-(1-(4-(4-(5-isopropylpyridin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione A421; 3-(5-(1-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxy- piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A422; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin- 4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A423; 3-(5-(1-(4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A424; 3-(5-(4-hydroxy-1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A501;Attorney Docket No.260A003WO01 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A502; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)oxy)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A503; 3-(5-(1-(4-(6-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A504; 3-(5-(1-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)azetidin-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A505; 3-(5-(1-(4-(6-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)azetidin- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A506; 3-(5-(1-(4-(6-((5-chloropyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione A507; 3-(1-oxo-5-(1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3-yl)- benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione A508; 3-(5-(4-fluoro-1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A509; 3-(5-(4-hydroxy-1-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)pyridin-3-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A510; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)oxy)pyridin-2-yl)benzyl)-4-fluoro- piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A511; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)-4- fluoropiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A512; 3-(5-(1-(4-(5-((5-cyclopropylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A513; 3-(5-(1-(4-(6-((5-methylpyrimidin-2-yl)amino)pyridin-3-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A514; 3-(5-(1-(4-(5-((5-methylpyrimidin-2-yl)amino)pyridin-2-yl)benzyl)piperidin-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A515; 3-(5-(4-hydroxy-1-(4-(4-((5-isopropylpyrimidin-2-yl)amino)piperidine-1- carbonyl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A601; 3-(2-(1-((1-(4-((5-isopropylpyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)-Attorney Docket No.260A003WO01 piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A602; 3-(2-(4-hydroxy-1-((1-(4-((5-isopropylpyrimidin-2-yl)amino)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A603; 3-(2-(1-((2-((5-isopropylpyrimidin-2-yl)amino)quinolin-6-yl)methyl)piperidin-4- yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A604; 3-(2-(1-((3-((5-isopropylpyrimidin-2-yl)amino)isoquinolin-7-yl)methyl)piperidin- 4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A605; 3-(2-(1-(4-(4-((5-(oxetan-3-yl)pyrimidin-2-yl)methyl)piperidin-1-yl)benzyl)- piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione A606; or 3-(5-(4-hydroxy-1-((3-((5-isopropylpyrimidin-2-yl)amino)isoquinolin-7-yl)- methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A607; 3-(5-(1-(4-(4-(6-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin- 2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B001; 3-(5-(1-(4-(4-(6-((4-(benzyloxy)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1- yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B002; 3-(5-(1-(4-(4-(6-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B003; 4-((2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)-3,5- dimethylbenzonitrile B004; 3-(2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzonitrile B005; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-morpholinopyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B006; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B007; 3-(5-(1-(4-(4-(6-((4-((cyclopropylmethyl)amino)pyrimidin-2-yl)amino)pyridin-3-Attorney Docket No.260A003WO01 yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B008; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-phenylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B009; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-isopropylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B010; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B011; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-4-carbonitrile B012; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B013; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-isopropoxypyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B014; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-methylpyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B015; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-4-carboxamide B016; 3-(5-(1-(4-(4-(6-((4-(2-aminoethoxy)pyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B017; 3-(5-(4-hydroxy-1-(4-(4-(6-(pyrimidin-2-ylamino)pyridin-3-yl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B018; 2-((5-(1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxy- piperidin-1-yl)methyl)phenyl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile B019; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(hydroxymethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B020; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(hydroxymethyl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B021; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-methylpyrimidin-2-yl)amino)pyridin-3-yl)-Attorney Docket No.260A003WO01 piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B022; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2- yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione B023; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-methoxypyrimidin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B024; 3-(5-(4-hydroxy-1-(4-(4-(6-((5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)amino)- pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B025; 3-(5-(1-(4-(4-(6-((5-chloropyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B026; 3-(5-(4-hydroxy-1-(4-(4-(6-((4-(piperazin-1-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B027; 3-(5-(1-(4-(4-(6-((5-(aminomethyl)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin- 1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B028; 3-(5-(1-(4-(4-(6-((4-aminopyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)- benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B029; 3-(5-(4-hydroxy-1-(4-(4-(6-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-d]- pyrimidin-5-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)- piperidine-2,6-dione B101; 3-(5-(1-(4-(4-(6-(((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro- pteridin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxo- isoindolin-2-yl)piperidine-2,6-dione B102; 3-(5-(4-hydroxy-1-(4-(4-(6-((7-methoxyquinazolin-2-yl)amino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B103; 3-(5-(4-hydroxy-1-(4-(4-(6-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B104; 3-(5-(4-hydroxy-1-(4-(4-(6-(quinazolin-2-ylamino)pyridin-3-yl)piperidin-1-yl)- benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B105; 3-(5-(4-hydroxy-1-(4-(4-(6-((8-methoxyquinazolin-2-yl)amino)pyridin-3-yl)-Attorney Docket No.260A003WO01 piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B106; 3-(5-(4-hydroxy-1-(4-(4-(6-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)- amino)pyridin-3-yl)piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione B107; 3-(5-(1-(4-(4-(6-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]- oxazin-6-yl)amino)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)benzyl)-4- hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B108; 3-(5-(1-(4-(4-(6-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B109; 3-(5-(4-Hydroxy-1-(4-(4-(6-(pyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)- piperidin-1-yl)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B110; 3-(5-(1-(4-(4-(6-((7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin- 1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B111; or 3-(5-(1-(4-(4-(6-((7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-1-yl)benzyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione B112; 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.

96. A pharmaceutical composition comprising the compound of any one of claims 1 to 95, 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, or hydrate thereof; and a pharmaceutically acceptable excipient.

97. The pharmaceutical composition of claim 96, wherein the composition is in single dosage form.

98. The pharmaceutical composition of claim 96 or 97, wherein the composition is in an oral, parenteral, or intravenous dosage form.Attorney Docket No.260A003WO01 99. The pharmaceutical composition of claim 98, wherein the composition is formulated in an oral dosage form.

100. The pharmaceutical composition of claim 99, wherein the oral dosage form is a tablet or capsule.

101. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PAK4, CSTF2, or CSTF2T in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of a compound of any one of claims 1 to 95 or a pharmaceutical composition of any one of claims 96 to 100.

102. The method of claim 101, wherein the disorder, disease, or condition is a proliferative disease.

103. A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 95 or a pharmaceutical composition of any one of claims 96 to 100.

104. The method of claim 102 or 103, wherein the proliferative disease is cancer.

105. The method of claim 104, wherein the cancer is relapsed or refractory.

106. The method of claim 104 or 105, wherein the cancer is metastatic.

107. The method of any one of claims 104 to 106, wherein the cancer is drug-resistant.

108. The method of any one of claims 101 to 107, wherein the subject is a human.

109. A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 95 or a pharmaceutical composition of any one of claims 96 to 100.

110. The method of claim 109, wherein the cell is a cancerous cell.Attorney Docket No.260A003WO01 111. A method of inducing degradation of a PAK4, CSTF2, or CSTF2T protein, comprising contacting the protein with an effective amount of a compound of any one of claims 1 to 95 or a pharmaceutical composition of any one of claims 96 to 100.

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