Compounds and related methods useful for degradation of cyclin k and inhibition of cyclin dependent kinases

Abstract

The present disclosure features compounds and related compositions that, inter alia, modulate cyclin K (CCNK) and / or cyclin dependent kinase (CDK) activity, e.g., CDK12 or CDK13 activity, and methods of use thereof.

Description

[0001] COMPOUNDS AND RELATED METHODS USEFUL FOR DEGRADATION OF CYCLIN K AND INHIBITION OF CYCLIN DEPENDENT KINASES CLAIM OF PRIORITY

[0002] This application claims priority to U.S. Application No. 63 / 733,251, filed December 12, 2024; and U.S. Application No. 63 / 884,305, filed September 18, 2025. The disclosure of each of the foregoing applications is incorporated herein by reference in its entirety.

[0003] BACKGROUND

[0004] Cyclin dependent kinases (CDKs) along with their cofactor cyclins regulate a number of fundamental cellular processes, including cell cycle progression and gene transcription. Cell cycle progression and gene transcription are tightly regulated by CDKs to ensure that cells respond normally to a variety of internal and external stimuli. Aberrant function of CDKs and cyclins, such as inhibition of activity or overexpression of these proteins, has shown to be related to many disease states. Current therapeutic approaches to modulate CDK and cyclin activity are widespread; however, each of these modalities exhibit unique challenges as currently presented. As such, there is a need for new technologies to modulate CDK and cyclin activity.

[0005] SUMMARY

[0006] The present disclosure features compounds and related compositions that, inter alia, modulate the activity of cyclins (CCNs), e.g., cyclin K, and cyclin dependent kinases (CDKs), e.g., CDK12 or CDK13, and may be useful for stabilization of a protein of interest with an E3 ligase complex component, as well as methods of use thereof. In an embodiment, the compounds described herein are compounds of Formula (I) or (II) (e.g., a compound of Formulas (I), (T), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j)) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. The present disclosure additionally provides methods of using the compounds of the invention (e.g., compounds of Formulas (I), (I’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof), and compositions thereof, e.g., to target, and in embodiments bind or form a complex with, a nucleic acid or a protein (e.g., a cyclin, e.g., CCNK; a cyclin dependent kinase, e.g., CDK12 or CDK13). In some embodiments, the compounds of Formulas (I), (I’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof), and compositions thereof may be useful for stabilization of a protein of interest (e.g., CDK12 or CDK13) with an E3 ligase complex component, such as DNA damage-binding protein 1 (DDB1), e.g., for its degradation.

[0007] In another aspect, the compounds described herein may be used for the prevention and / or treatment of a disease, disorder, or condition, e.g., a disease, disorder or condition, e.g., associated with modulation of a cyclin or cyclin dependent kinase, e.g., a cancer. In some embodiments, the compounds described herein (e.g., compounds of Formulas (I), (F), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and / or treatment of a proliferative disease, disorder, or condition (e.g., a disease, disorder, or condition characterized by unwanted cell proliferation, e.g., a cancer or a benign neoplasm) in a subject. In some embodiments, the compounds described herein (e.g., compounds of Formulas (I), (F), (I”), (La), (Lb), (I-c), (I-d), (I-e), (Lf), (I-g), (I-h), (Li), (I-j), (I-k), (1-1), (I-m), (Ln), (Lo), (Lp), (Lq), (II), (ILa), (ILb), (ILc), (ILd), (ILe), (ILf), (ILg), (ILh), (ILi), or (ILj), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and / or treatment of a non-proliferative disease, disorder, or condition.

[0008] In one aspect, the present disclosure provides compounds of Formula (I):

[0009]

[0010] (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is heterocyclyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; Z1and Z2are each independently C(R2), N, NRZ1, or S; Z3is C(R4b), N, or NRZ3; wherein the bonds in the heteroaryl ring comprising Z1, Z2, and Z3are single bonds or double bonds as permitted by valency; RZ1, RZ2, and RZ3are each independently hydrogen, Ci-Cs-alkyl, C2-C6-alkenyl, Ci-C6-heteroalkyl, Ci-Cs-haloalkyl, cycloalkyl, or heterocyclyl; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1, R2, R4a, and R4bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkyleneheteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRDor-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Cs-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, or C1-C6 alkylene-heteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or-ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0011] In one aspect, the present disclosure provides compounds of Formula (I’):

[0012]

[0013] (I’), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl, aryl, heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1and R2is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRD, or-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aand R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6alkylene-aryl, C1-C6alkylene-heteroaryl, –C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0014] In another aspect, the present disclosure provides compounds of Formula (II):

[0015]

[0016] (11), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(O)-, - C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkyleneheteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRDor-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Cs-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or-S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, Ci-C6alkyl ene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0017] In another aspect, the present disclosure provides methods of down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (F), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), (ILa), (Il-b), (II-c), (Il-d), (Il-e), (ILf), (Il-g), (II-h), (Il-i), or (Il-j )) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides methods of up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (F), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), (ILa), (Il-b), (II-c), (Il-d), (Il-e), (ILf), (Il-g), (II-h), (ILi), or (II-j)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides methods of altering the isoform of a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (!’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), (ILa), (ILb), (ILc), (Il-d), (ILe), (ILf), (Il-g), (II-h), (Il-i), or (II-j)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. Another aspect of the disclosure relates to methods of inhibiting the activity of a target protein in a biological sample or subject. In some embodiments, administration of a compound of Formula (I) or Formula (II) to a biological sample, a cell, or a subject comprises inhibition of cell growth or induction of cell death.

[0018] In another aspect, the present disclosure provides compositions for use in preventing and / or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (F), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or related compositions. In some embodiments, the disease or disorder entails aberrant cyclin or cyclin dependent kinase splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases include cancer, a benign neoplasm, or angiogenesis. In other embodiments, the present disclosure provides methods for treating and / or preventing a non-proliferative disease, disorder, or condition. In still other embodiments, the present disclosure provides compositions for use in treating and / or preventing a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease.

[0019] In another aspect, the present disclosure provides compositions for use in

[0020] down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (I’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides compositions for use in up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (I’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (Il-h), (ILi), or (II-j)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides compositions for use in altering the isoform of a target protein with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (F), (I”), (I-a), (I-b), (Lc), (I-d), (I-e), (Lf), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (Ln), (Lo), (I-p), (Lq), (ILa), (ILb), (ILc), (ILd), (ILe), (11-f), (ILg), (11-h), (Il-i), or (11-j )) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. Another aspect of the disclosure relates to compositions for use in inhibiting the activity of a target protein in a biological sample or subject. In some embodiments, administration of a compound of Formula (I) or (II) to a biological sample, a cell, or a subject comprises inhibition of cell growth or induction of cell death.

[0021] In another aspect, the present disclosure features kits comprising a container with a compound of Formula (I) or (II) (e.g., a compound of Formulas (I), (I’), (I”), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (Lo), (Lp), (Lq), (II), (ILa), (ILb), (ILc), (ILd), (ILe), (ILf), (ILg), (ILh), (ILi), or (II-j)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits described herein further include instructions for administering the compound of Formula (I) or (II) or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or the pharmaceutical composition thereof.

[0022] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims.

[0023] DETAILED DESCRIPTION

[0024] Selected Chemical Definitions

[0025] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0026] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0027] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0028] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0029] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-Ce alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-C6alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tertbutyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-C6 alkyl.

[0030] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C2-C24 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C1-C10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-C6 alkenyl.

[0031] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon triple bonds (“C2-C24 alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-6 alkynyl.

[0032] As used herein, the term "haloalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. The halogen(s) F, Cl, Br, and I may be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CCI3, -CHF2, -CH2-CF3, -CH2-CCI3, -CH2-CBr3. -CH2-CI3, -CH2-CH2-CH(CF3)-CH3, -CH2-CH2-CH(Br)-CH3, and -CH2-CH=CH-CH2-CF3. Each instance of a haloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted haloalkyl”) or substituted (a “substituted haloalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -CH20, -NRCRD, or the like, it will be understood that the terms heteroalkyl and -CH2O or -NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH20, -NRCRD, or the like. Each instance of a heteroalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent

[0034] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10-membered aryl, wherein the term “membered” refers to the non -hydrogen ring atoms within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl.

[0035] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent

[0036] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

[0037] Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0038] As used herein, “cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), cubanyl (Cs), bicyclo[l.l.l]pentanyl (C5), bicyclo[2.2.2]octanyl (Cs), bicyclo[2.1.1]hexanyl (Ce), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl.

[0039] “Heterocyclyl” as used herein refers to a radical of a 3- to 16-membered non-aromatic ring system having ring carbon atoms and 1 to 8 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-16 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non- hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-16 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-16 membered heterocyclyl.

[0040] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

[0041] Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyri dinonyl (e.g., l-methylpyridin2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., l-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), di thianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (l,5)-8-azabicyclo[3.2.1]octanyl).

[0042] Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicy clo[3.3.1 ]nonanyl).

[0043] The terms "alkylene," “alkenylene,” “alkynylene,” “haloalkylene,” “heteroalkylene,” “cycloalkylene,” or “heterocyclylene,” alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described as, e.g., a Ci-Ce-membered alkylene, C2-C6-membered alkenylene, C2-Ce-membered alkynylene, Ci-Ce-membered haloalkylene, Ci-Ce-membered heteroalkylene, C3-C8-membered cycloalkylene, or C3-C8-membered heterocyclylene, wherein the term “membered” refers to the non-hydrogen atoms within the moiety. In the case of heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedi oxy, alkyleneamino, alkylenediamino, and the like). Still further, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2R’- may represent both -C(0)2R’- and -R’C(0)2-.

[0044] As used herein, the terms “cyano” or “-CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

[0045] As used herein, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine or iodine.

[0046] As used herein, the term “hydroxy” refers to -OH. As used herein, the term “nitro” refers to a substitutent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2.

[0047] As used herein, the term “nucleobase” as used herein, is a nitrogen-containing biological compounds found linked to a sugar within a nucleoside — the basic building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The primary, or naturally occurring, nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA) and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. Because A, G, C, and T appear in the DNA, these molecules are called DNA-bases; A, G, C, and U are called RNA-bases. Adenine and guanine belong to the double-ringed class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleobases that do not function as normal parts of the genetic code, are termed non-naturally occurring. In an embodiment, a nucleobase may be chemically modified, for example, with an alkyl (e.g., methyl), halo, -O-alkyl, or other modification.

[0048] As used herein, the term “nucleic acid” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. The term “nucleic acid” includes a gene, cDNA, pre-mRNA, or an mRNA. In one embodiment, the nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless specifically limited, the term encompasses nucleic acids containing analogues or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementarity sequences as well as the sequence explicitly indicated.

[0049] As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-.

[0050] The symbol “ as used herein in relation to a compound of Formula (I) or (II) refers to an attachment point to another moiety or functional group within the compound.

[0051] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0052] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ringforming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ringforming substituents are attached to non-adjacent members of the base structure.

[0053] The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans-forms; E- and Z-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and P-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0054] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In an embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et aL, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). This disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0055] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0056] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.

[0057] In some embodiments, a diastereomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereometerically pure exo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure exo compound. In certain embodiments, the diastereometerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising a diastereometerically pure endo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure endo compound. In certain embodiments, the diastereometerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound.

[0058] In some embodiments, an isomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an isomerically pure exo compound can comprise, for example, about 90% excipient and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising an isomerically pure endo compound can comprise, for example, about 90% excipient and about 10% isomerically pure endo compound. In certain embodiments, the isomerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound.

[0059] In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; N may be in any isotopic form, including14N and15N; F may be in any isotopic form, including18F,19F, and the like.

[0060] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.

[0061] In addition to salt forms, the present disclosure provides compounds in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0062] The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.

[0063] Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of Formula (I) or (II) may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both

[0064] solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0065] The term “hydrate” refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·x H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0066] The term “tautomer” refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0067] Other Definitions

[0068] The following definitions are more general terms used throughout the present disclosure. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “and / or” means either “and” or “or” unless indicated otherwise.

[0069] The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0070] “Acquire” or “acquiring” as used herein, refer to obtaining possession of a value, e.g., a numerical value, or image, or a physical entity (e.g., a sample), by “directly acquiring” or “indirectly acquiring” the value or physical entity. “Directly acquiring” means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. “Indirectly acquiring” refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Directly acquiring a value or physical entity includes performing a process that includes a physical change in a physical substance or the use of a machine or device. Examples of directly acquiring a value include obtaining a sample from a human subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g., mass spectrometer to acquire mass spectrometry data.

[0071] The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.

[0072] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

[0073] An “effective amount” of a compound of Formula (I) or (II) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of Formula (I) or (II) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor.

[0074] A “therapeutically effective amount” of a compound of Formula (1) or (11) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0075] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprised therein. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types.

[0076] “Prevention,” “prevent,” and “preventing” as used herein refers to a treatment that comprises administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I) or (II)) prior to the onset of a disease, disorder, or condition in order to preclude the physical manifestation of said disease, disorder, or condition. In some embodiments, “prevention,” “prevent,” and “preventing” require that signs or symptoms of the disease, disorder, or condition have not yet developed or have not yet been observed. In some embodiments, treatment comprises prevention and in other embodiments it does not. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non-human animal may be a transgenic animal.

[0077] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I) or (II)). In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not.

[0078] Compounds

[0079] In one aspect, the present disclosure provides compounds of Formula (I):

[0080]

[0081] (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; Z1and Z2are each independently C(R2), N, NRZ1, or S; Z3is C(R4b), N, or NRZ3; wherein the bonds in the heteroaryl ring comprising Z1, Z2, and Z3are single bonds or double bonds as permitted by valency; RZ1, RZ2, and RZ3are each independently hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1, R2, R4a, and R4bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkyleneheteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRDor-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or, two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Cs-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, or C1-C6 alkylene-heteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or-ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0082] As generally described herein for compounds of Formula (I), Z1and Z2are each independently C(R2), N, NRZ1, or S. In some embodiments, Z1and Z2are each independently C(R2), N, or S. In some embodiments, Z1and Z2are each independently C(R2) or S, wherein each R2is independently hydrogen, C1-C6-alkyl, Cs-Ce-alkenyl, C2-Cg-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or-S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, at least one of Z1and Z2is independently C(R2). In some embodiments, Z1is C(R2) and Z2is C(R2). In some embodiments, Z1is S and Z2is C(R2).

[0083] In some embodiments, Z1is C(R2), N, NRZ1, or S. In some embodiments, Z1is C(R2) or S. In some embodiments, Z1is C(R2). In some embodiments, Z1is N. In some embodiments, Z1is NRZ1. In some embodiments, Z1is S.

[0084] In some embodiments, Z2is C(R2), N, NRZ1, or S. In some embodiments, Z2is C(R2), N, orNRZ1. In some embodiments, Z2is C(R2) or NRZ1. In some embodiments, Z2is C(R2). In some embodiments, Z2is N. In some embodiments, Z2is NRZ1. In some embodiments, Z2is S.

[0085] As generally described herein for compounds of Formula (I), Z3is C(R4b), N, orNRZ3; wherein the bonds in the heteroaryl ring comprising Z1, Z2, and Z3are single bonds or double bonds as permitted by valency. In some embodiments, Z3is C(R4b), N, or NRZ3. In some embodiments, Z3is C(R4b) orNRZ3. In some embodiments, Z3is C(R4b). In some embodiments, Z3is N. In some embodiments, Z3is NRZ3.

[0086] As generally described herein for compounds of Formula (I), RZ1, RZ2, and RZ3are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, RZ1is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, RZ1is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, Ci-Ce-heteroalkyl, or Ci-Ce-haloalkyl. In some embodiments, RZ1is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, or Ci-Ce-haloalkyl. In some embodiments, RZ1is independently hydrogen, C1-C6-alkyl, or Ci-Ce-haloalkyl. In some embodiments, RZ1is independently hydrogen or C1-C6-alkyl. In some embodiments, RZ1is independently hydrogen or Ci-Cs-alkyl. In some embodiments, RZ1is independently hydrogen. In some embodiments, RZ1is independently Ci-Cs-alkyl. In some embodiments, RZ1is independently Ci-alkyl. In some embodiments, RZ1is independently CH3. In some embodiments, RZ2is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, RZ2is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, Ci-Ce-heteroalkyl, or Ci-C6-haloalkyl. In some embodiments, RZ2is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, or Ci-Ce-haloalkyl. In some embodiments, RZ2is independently hydrogen, C1-C6-alkyl, or Ci-Ce-haloalkyl. In some embodiments, RZ2is independently hydrogen or C1-C6-alkyl. In some embodiments, RZ2is independently hydrogen or Ci-Ca-alkyl. In some embodiments, RZ2is independently hydrogen. In some embodiments, RZ2is independently Ci-Cs-alkyl. In some embodiments, RZ2is independently Ci-alkyl. In some embodiments, RZ2is independently CH3.

[0087] In some embodiments, RZ3is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, RZ3is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, Ci-Ce-heteroalkyl, or Ci-Ce-haloalkyl. In some embodiments, RZ3is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, or Ci-Ce-haloalkyl. In some embodiments, RZ3is independently hydrogen, C1-C6-alkyl, or Ci-Ce-haloalkyl. In some embodiments, RZ3is independently hydrogen or C1-C6-alkyl. In some embodiments, RZ3is independently hydrogen or Ci-Cs-alkyl. In some embodiments, RZ3is independently hydrogen. In some embodiments, RZ3is independently Ci-Cs-alkyl In some embodiments, RZ3is independently Ci-alkyl. In some embodiments, RZ3is independently CH3. In some embodiments, Z1and Z2are each C(R2), and Z3is NRZ3. In some embodiments, Z1is S, Z2is C(R2), and Z3is C(R4b).

[0088] In some embodiments,

[0089]

[0090] embodiments,

[0091]

[0092] . In some embodiments,

[0093]

[0094] In some embodiments, the compound of Formula (I) is a compound of Formula (F):

[0095]

[0096] (I’), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1and R2is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRD, or-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aand R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or, two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6alkylene-aryl, C1-C6alkylene-heteroaryl, –C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0097] In some embodiments, the compound of Formula (I) is a compound of Formula (II):

[0098]

[0099] (11), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(O)-, - C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkyleneheteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRDor-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Cs-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or-S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, Ci-C6alkyl ene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0100] As generally described herein for Formulas (I) and (II) and subgenera therein, A is heterocyclyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5.

[0101] In some embodiments, A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 6-membered aryl optionally substituted with one or more R5. In some embodiments, A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is a 5-membered ring. In some embodiments, A is a 6-membered ring. In some embodiments, A is a heteroaryl, e.g., a nitrogen-containing heteroaryl, optionally substituted with one or more R5. In some embodiments, A is a nitrogen-containing 5-membered heteroaryl, optionally substituted with one or more R5. In some embodiments, A is a nitrogencontaining 6-membered heteroaryl optionally substituted with one or more R5. In some embodiments, A is 5-membered heterocyclyl, 5-membered heteroaryl, 6-membered aryl, or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 5-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 5-membered heteroaryl or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 6-membered nitrogencontaining heteroaryl, which is optionally substituted with one or more R5.

[0102] In some embodiments, A is selected from:

[0103]

[0104] (R5)0-2 N \ N'N

[0105] N

[0106]

[0107] (R5)O-2 wherein R5is as defined herein. In some

[0108] embodiments, A is selected from

[0109]

[0110]

[0111] wherein R5is as defined in herein. In some

[0112] embodiments, A

[0113]

[0114] is R5is as defined herein.

[0115] In some embodiments,

[0116]

[0117] A is In some embodiments, A

[0118]

[0119] is

[0120] wherein R5is as defined herein. In some embodiments, A is

[0121]

[0122] (R5)0-2 N

[0123] N

[0124] defined herein. In some embodiments, A is

[0125]

[0126] wherein R5is as defined herein. In

[0127] some embodiments,

[0128]

[0129] A is wherein R5is as defined herein. In some embodiments, A N'N

[0130] is

[0131]

[0132] (R5)O-2 wherein R5is as defined herein.

[0133]

[0134]

[0135] some embodiments, A

[0136]

[0137] is

[0138] embodiments, A is

[0139]

[0140] In some embodiments,

[0141]

[0142] A is. In some embodiments,

[0143]

[0144] As generally described herein for Formulas (I) and (II) and subgenera therein, B is aryl or heteroaryl, each of which is optionally substituted with one or more R5.

[0145] In some embodiments, B is aryl or heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, B is aryl (e.g., 6-membered aryl), optionally substituted with one or more R5. In some embodiments, B is heteroaryl (e.g., a 5-membered or 6-membered heteroaryl), optionally substituted with one or more R5. In some embodiments, B is a monocyclic heteroaryl, optionally substituted with one or more R5. In some embodiments, B is a bicyclic heteroaryl, optionally substituted with one or more R5. In some embodiments, B is a nitrogen-containing heteroaryl optionally substituted with one or more R5.

[0146] In some embodiments, B is 6-membered aryl, optionally substituted with one or more R5. In some embodiments, B is 5-membered heteroaryl or 6-membered aryl, optionally substituted with one or more R5. In some embodiments, B is 5-membered nitrogen-containing heteroaryl, optionally substituted with one or more R5.

[0147]

[0148]

[0149] as defined herein. In some embodiments, B is selected from

[0150]

[0151] (R5)0-2

[0152]

[0153] (R5)0-5, wherein R5is as defined herein. In some embodiments, B is selected from

[0154]

[0155] (R5)0-5, wherein R5is as defined herein. In some embodiments, B is

[0156]

[0157] . In some embodiments, B is

[0158]

[0159] In some embodiments, B is

[0160]

[0161] (R5)0-3in some embodiments, B is

[0162]

[0163] embodiments, B is

[0164]

[0165] . In some embodiments, B is

[0166]

[0167] some embodiments, B

[0168]

[0169] is some embodiments, B is

[0170]

[0171] (R5)0-3in some embodiments, B is

[0172]

[0173] . In some embodiments, B is

[0174]

[0175] In some embodiments, B is

[0176]

[0177] (R5)0-5in some

[0178] embodiments, B is

[0179]

[0180] In some embodiments, B is

[0181]

[0182] (R5)0-4in some

[0183] embodiments,

[0184]

[0185] B

[0186] In some embodiments, B is selected from:

[0187]

[0188]

[0189]

[0190]

[0191] V

[0192] In some embodiments, B is selected from:t N

[0193] OH OH

[0194]

[0195]

[0196]

[0197] In some embodiments, B is

[0198]

[0199] In some embodiments, B is

[0200]

[0201] . In some

[0202] Cl

[0203]

[0204] embodiments, B is

[0205]

[0206] In some embodiments, B is *. In some embodiments, B

[0207] N=\ i A

[0208]

[0209] . In some embodiments, B is. In some embodiments, B

[0210]

[0211] is *

[0212] In some embodiments,

[0213]

[0214] B is * In some embodiments,

[0215]

[0216] B is *HIn some

[0217] N

[0218] embodiments, B is

[0219]

[0220] . In some embodiments, B is *

[0221]

[0222] NBr

[0223] In some embodiments, OH

[0224] N=\

[0225]

[0226] B is *. In some embodiments,

[0227]

[0228] B is * In some embodiments,

[0229]

[0230] B is N=\ N=\ /

[0231] F 0

[0232] In some embodiments, B is *. In some embodiments, B is *. In some

[0233] embodiments,

[0234]

[0235] B is In some embodiments,

[0236]

[0237] B is In some embodiments,

[0238]

[0239] In some embodiments, B is

[0240] F

[0241]

[0242]

[0243] In some embodiments, B is. In some embodiments, B is ' In

[0244] some embodiments,

[0245]

[0246] B is. In some embodiments, B is

[0247]

[0248] . In some N N'N

[0249] ^N—

[0250] embodiments, B

[0251]

[0252] is*^'. In some embodiments, B is

[0253]

[0254] . In some embodiments, B

[0255]

[0256] . In some embodiments, B is In some embodiments, B

[0257]

[0258] is. In some embodiments, B is

[0259]

[0260] embodiments, B is

[0261]

[0262] In some embodiments,

[0263]

[0264] B is In some embodiments, B is

[0265]

[0266] In some embodiments, B is some embodiments,

[0267]

[0268] B is In some embodiments, B is

[0269]

[0270] . In some

[0271] O

[0272] embodiments, B is

[0273]

[0274] In some embodiments, B is

[0275]

[0276] . In some embodiments, B

[0277]

[0278] In some embodiments, B is

[0279]

[0280] In some embodiments, B is

[0281]

[0282] . In some

[0283] embodiments, B is

[0284]

[0285] In some embodiments,

[0286]

[0287] B is In some embodiments, B

[0288]

[0289] In an embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the rings described above. In an embodiment, A and B are each independently a stereoisomer of one of the rings described above.

[0290] In some embodiments, A-L-B is selected from:

[0291]

[0292]

[0293] is as defined herein. In some embodiments, A-L-B is selected from:

[0294]

[0295]

[0296] defined herein.

[0297] In some embodiments, A-L-B is selected from:

[0298]

[0299]

[0300]

[0301]

[0302] As generally described herein for Formulas (I) and (II), and subgenera therein, L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)X-, -NRBC(O)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6- heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5.

[0303] In some embodiments, L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)X-, -NRBC(O)-,-C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together. In some embodiments, L is absent, a bond, -O-, -NR8-, -C(O)-, or -S(O)X-wherein when L is absent, A and B are fused together.

[0304] In some embodiments, L is absent or a bond.

[0305] In some embodiments, L is absent, and A and B are fused together. In some embodiments, L is a bond. In some embodiments, L is -O-. In some embodiments, L is -NR8-. In some embodiments, L is -C(O)-. In some embodiments, L is -S(O)X-. In some embodiments, L is -NRBC(O)-. In some embodiments, L is -C(O)NRB-. In some embodiments, L is C1-C6-alkylene. In some embodiments, L is C1-C6-heteroalkylene.

[0306] In some embodiments, L is absent and A and B are fused together. In some embodiments, L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R5. In some embodiments, L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R5.

[0307]

[0308] wherein each R5is as defined herein. In some

[0309]

[0310] embodiments, L is absent and A and B are fused together to form

[0311]

[0312]

[0313] defined herein. In some embodiments, when A and B are fused together, A and B are selected

[0314]

[0315] defined herein. In some embodiments, L is absent and A and B are fused together to form

[0316]

[0317] herein. In some embodiments, A and B are fused together to form

[0318]

[0319]

[0320] wherein each R5is as defined herein. In some embodiments, A-L-B is selected from

[0321]

[0322]

[0323] In some embodiments, when A and B are fused together, A and B are

[0324]

[0325] selected from:

[0326]

[0327] In some embodiments, A

[0328]

[0329] -L-B

[0330]

[0331] . In some embodiments, A-L-B is In some embodiments, A-L-B is Cl

[0332]

[0333] embodiments,

[0334]

[0335] A-L-B is In some embodiments,

[0336]

[0337] A-L-B is

[0338] embodiments,

[0339]

[0340] A-L-B is In some embodiments,

[0341]

[0342] A-L-B is

[0343] some embodiments,

[0344]

[0345] A-L-B is In some embodiments, A-L-B is

[0346] . In some embodiments, A-L-B is. In some embodiments, A-L-

[0347]

[0348] As generally described herein for Formulas (I) and (II), and subgenera therein, each of R1and R2is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or -S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6.

[0349] In some embodiments, each R1is hydrogen, C1-C6-alkyl, haloalkyl, halo, cycloalkyl, or heteroaryl, and each of C1-C6-alkyl, haloalkyl, cycloalkyl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, R1is C1-C6-alkyl, haloalkyl, halo, or cycloalkyl wherein each of C1-C6-alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6. In some embodiments, each R1is cycloalkyl optionally substituted with one or more R6. In some embodiments, R2is hydrogen.

[0350] As generally described herein for Formulas (I) and (II), and subgenera therein, each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7.

[0351] In some embodiments, each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)xRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7.

[0352] In some embodiments, R3aand R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3aand R3bare independently selected from hydrogen, C1-C6-alkyl, or C1-C6-heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with one or more R7. In some embodiments, each of R3aand R3bis hydrogen. In some embodiments, R3ais hydrogen and R3bis C1-C6-alkyl, C1-C6-heteroalkyl, or aryl, wherein each alkyl, heteroalkyl, and aryl, is optionally substituted with one or more R7. In some embodiments, R3ais hydrogen and R3bis C1-C6-alkyl optionally substituted with one or more R7.

[0353] In some embodiments, one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom it is attached, forms a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom it is attached, forms a cycloalkyl or oxygen- or nitrogen-containing heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

[0354] In some embodiments,

[0355]

[0356]

[0357] As generally described herein for Formulas (I) and (II), and subgenera therein, each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, Cz-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or -S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, cycloalkyl, halo, and cyano, wherein each alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R6. In some embodiments, wherein R4ais hydrogen, C1-C6-alkyl, haloalkyl, halo, cycloalkyl, or heteroaryl, wherein each of alkyl, haloalkyl, cycloalkyl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, R4ais C1-C6-alkyl, haloalkyl, halo, or cycloalkyl, wherein each of alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6. In some embodiments, each R4ais cycloalkyl optionally substituted with one or more R6. In some embodiments, R4bis hydrogen.

[0358] As generally described herein for Formulas (I) and (II), and subgenera therein, each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6alkylene-heteroaryl, C2-C6alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or, two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8.

[0359] In some embodiments, each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, each R5is hydrogen. In some embodiments, R5is C1-C6-alkyl optionally substituted with one or more R6. In some embodiments, R5is C2-Ce-alkenyl optionally substituted with one or more R6. In some embodiments, R5is C2-Ce-alkynyl optionally substituted with one or more R6. In some embodiments, R5is Ci-Ce-heteroalkyl optionally substituted with one or more R6. In some embodiments, R5is Ci-Ce-haloalkyl optionally substituted with one or more R6. In some embodiments, R5is cycloalkyl optionally substituted with one or more R6. In some embodiments, R5is heterocyclyl optionally substituted with one or more R6. In some embodiments, R5is aryl optionally substituted with one or more R6. In some embodiments, R5is C1-C6 alkylene-aryl optionally substituted with one or more R6. In some embodiments, R5is C2-C6 alkenylene-aryl optionally substituted with one or more R6. In some embodiments, R5is halo. In some embodiments, R5is cyano. In some embodiments, R5is oxo. In some embodiments, R5is -ORA. In some embodiments, R5is -NRBRC. In some embodiments, R5is -NRBC(O)RD. In some embodiments, R5is -NO2. In some embodiments, R5is -C(O)NRBRC. In some embodiments, R5is -C(O)RD. In some embodiments, R5is -C(O)ORD. In some embodiments, R5is -S(O)XRD. In some embodiments, two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6.

[0360] As generally described herein for Formulas (I) and (II), and subgenera therein, each of R6, R7, and R8is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Cs-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9.

[0361] In some embodiments, each R6is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or-S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9. In some embodiments, each R6is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R9. In some embodiments, each R6is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R9. In some embodiments, each R6is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R9. In some embodiments, each R6is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, -ORA, -NRBRC, or -NRBC(O)RD, wherein each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R9. In some embodiments, R6is C1-C6-alkyl, optionally substituted with one or more R9. In some embodiments, R6is Ci-Ce-heteroalkyl, optionally substituted with one or more R9. In some embodiments, R6is Ci-Ce-haloalkyl, optionally substituted with one or more R9. In some embodiments, R6is halo. In some embodiments, R6is F. In some embodiments, R6is -ORA, -NRBRC, or -NRBC(O)RD. In some embodiments, R6is -ORA. In some embodiments, R6is -NRBRC. In some embodiments, R6is -NRBC(O)RD.

[0362] In some embodiments, R7is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9. In some embodiments, each R7is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA. In some embodiments, R7is C1-C6-alkyl. In some embodiments, R7is Ci-Ce-heteroalkyl. In some embodiments, R7is Ci-Ce-haloalkyl. In some embodiments, R7is cycloalkyl. In some embodiments, R7is heterocyclyl. In some embodiments, R7is aryl. In some embodiments, R7is heteroaryl. In some embodiments, R7is halo. In some embodiments, R7is cyano. In some embodiments, R7is oxo. In some embodiments, R7is -ORA. In some embodiments, R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9. In some embodiments, R8is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R9. In some embodiments, R8is independently C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R9. In some embodiments, each R8is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or-ORA. In some embodiments, R8is hydrogen or C1-C6-alkyl. In some embodiments, R8is hydrogen or Ci-C4-alkyl. In some embodiments, R8is hydrogen or Ci-Cs-alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C6-alkyl. In some embodiments, R8is Ci-C4-alkyl. In some embodiments, R8is Ci-Cs-alkyl. In some embodiments, R8is hydrogen or Ci-C2-alkyl. In some embodiments, R8is CH3.

[0363] As generally described herein for Formulas (I) and (II), and subgenera therein, each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkyleneheteroaryl, -C(O)RU, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10.

[0364] In some embodiments, each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkyl ene-heteroaryl, -C(O)RD, or-S(O)xRDIn some embodiments, RAis hydrogen. In some embodiments, RAis C1-C6-alkyl. In some embodiments, RAis C2-Ce-alkenyl. In some embodiments, RAis C2-Ce-alkynyl. In some embodiments, RAis Ci-Ce-heteroalkyl. In some embodiments, RAis Ci-Ce-haloalkyl. In some embodiments, RAis cycloalkyl. In some embodiments, RAis heterocyclyl. In some embodiments, RAis heterocyclyl. In some embodiments, RAis heterocyclyl. In some embodiments, RAis aryl. In some embodiments, RAis aryl. In some embodiments, RAis heteroaryl. In some embodiments, RAis C1-C6 alkylene-aryl. In some embodiments, RAis C1-C6 alkylene-heteroaryl. In some embodiments, RAis -C(O)RD. In some embodiments, RAis -S(O)XRD.

[0365] As generally described herein for Formulas (1) and (11), and subgenera therein, each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or –ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11.

[0366] In some embodiments, each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or –ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11. In some embodiments, RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11.

[0367] In some embodiments, RBis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or –ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11. In some embodiments, Rcis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or -ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11.

[0368] In some embodiments, each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, or –ORA; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11.

[0369] In some embodiments, RBis hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, or –ORA. In some embodiments, RBis hydrogen. In some embodiments, RBis C1-C6-alkyl. In some embodiments, RBis C2-Ce-alkenyl. In some embodiments, RBis C2-C6-alkynyl. In some embodiments, RBis Ci-Ce-heteroalkyl. In some embodiments, RBis Ci-Ce-haloalkyl. In some embodiments, RBis cycloalkyl. In some embodiments, RBis heterocyclyl. In some embodiments, RBis -ORA.

[0370] In some embodiments, RCis hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, or –ORA. In some embodiments, RCis hydrogen. In some embodiments, RCis C1-C6-alkyl. In some embodiments, RCis C2-Ce-alkenyl. In some embodiments, RCis C2-C6-alkynyl. In some embodiments, RCis Ci-Ce-heteroalkyl. In some embodiments, RCis Ci-Ce-haloalkyl. In some embodiments, RCis cycloalkyl. In some embodiments, RCis heterocyclyl. In some embodiments, RCis –ORA.

[0371] As generally described herein for Formulas (I) and (II), and subgenera therein, each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl.

[0372] In some embodiments, each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl. In some embodiments, RDis hydrogen. In some embodiments, RDis C1-C6 alkyl. In some embodiments, RDis C2-C6 alkenyl. In some embodiments, RDis C2-C6 alkynyl. In some embodiments, RDis Ci-Ce heteroalkyl. In some embodiments, RDis Ci-Ce heteroalkyl. In some embodiments, RDis Ci-Ce heteroalkyl. In some embodiments, RDis Ci-Ce haloalkyl. In some embodiments, RDis cycloalkyl. In some embodiments, RDis heterocyclyl. In some embodiments, RDis aryl. In some embodiments, RDis heteroaryl. In some embodiments, Ruis C1-C6 alkylene-aryl. In some embodiments, RDis C1-C6 alkylene-heteroaryl.

[0373] As generally described herein for Formulas (I) and (II), and subgenera therein, each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12. In some embodiments, R9is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12.

[0374] In some embodiments, R10is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12.

[0375] As generally described herein for Formulas (I) and (II), and subgenera therein, R11is hydrogen or C1-C6-alkyl. In some embodiments, R11is hydrogen or Ci-C4-alkyl. In some embodiments, R11is hydrogen or Ci-C2-alkyl. In some embodiments, R11is H or CH3. In some embodiments, R11is hydrogen. In some embodiments, R11is C1-C6-alkyl. In some embodiments, R11is Ci-C4-alkyl. In some embodiments, R11is Ci-C2-alkyl. In some embodiments, R11is CH3.

[0376] As generally described herein for Formulas (I) and (II), and subgenera therein, R12is C1-C6-alkyl or -ORA1. In some embodiments, R12is Ci-C4-alkyl or -ORA1. In some embodiments, R12is Ci-C2-alkyl or -ORA1. In some embodiments, R12is CH3 or -ORA1. In some embodiments, R12is C1-C6-alkyl. In some embodiments, R12is Ci-C4-alkyl. In some embodiments, R12is Ci-C2-alkyl. In some embodiments, R12is CH3. In some embodiments, R12is -ORA1.

[0377] As generally described herein for Formulas (I) and (II), and subgenera therein, RA1is hydrogen or C1-C6-alkyl. In some embodiments, RA1is hydrogen or Ci-C4-alkyl. In some embodiments, RA1is hydrogen or Ci-C2-alkyl. In some embodiments, RA1is hydrogen or CH3. In some embodiments, RA1is hydrogen. In some embodiments, RA1is C1-C6-alkyl. In some embodiments, RA1is Ci-C4-alkyl. In some embodiments, RA1is Ci-C2-alkyl. In some embodiments, RA1is CH3.

[0378] As generally described herein for Formulas (I) and (II), and subgenera therein, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0379] As generally described herein, each of x and y is independently 0, 1, or 2.

[0380] In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0, 1, or 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0381] In some embodiments, x and y are both 0.

[0382] In some embodiments, the compound of Formula (I) is a compound of Formula (I”):

[0383]

[0384] (I”), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1and R2is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-C6-heteroalkyl, Ci-C6-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or, two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, C1-C6 alkyl ene-heteroaryl, -C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyleneheteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0385] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):

[0386] B U

[0387] H

[0388]

[0389] (1-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: each of R1, R2, R3a, R3b, A, and B is as defined herein.

[0390] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):

[0391]

[0392] RR(I-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, each of R1, R2, R3a, R3b, R5, and B is as defined herein.

[0393] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):

[0394] (R5)O-5

[0395] N

[0396]

[0397] (I-c), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, each of R1, R2, R3a, R3b, and R5are as defined herein.

[0398] In some embodiments, the compound of Formula (I) is a compound of Formula (I-d):

[0399] HN -^1 B

[0400] O A V- N

[0401] H 3b

[0402]

[0403] (I-d), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, and B is as defined herein.

[0404] In some embodiments, the compound of Formula (I) is a compound of Formula (I-e):

[0405] (R5)O-5

[0406] (R5)O-3

[0407] N

[0408] N

[0409] 2 H

[0410]

[0411] (I-e), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R2and R5is as defined herein.

[0412] In some embodiments, the compound of Formula (I) is a compound of Formula (I-f):

[0413]

[0414] (I-f), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, and R5is as defined herein, and wherein X is N or CR5.

[0415] In some embodiments, X is N or CR5. In some embodiments, X is N. In some embodiments, X is CR5. In some embodiments, X is CH. In some embodiments, X is N or CH.

[0416] In some embodiments, the compound of Formula (I) is a compound of Formula (I-g):

[0417] N O

[0418] ^NF

[0419] H

[0420]

[0421] (I-g), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, and R5is as defined herein.

[0422] In some embodiments, the compound of Formula (I) is a compound of Formula (I-h):

[0423] N O

[0424] H „

[0425]

[0426] (I-h), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, and R5is as defined herein.

[0427] In some embodiments, the compound of Formula (I) is a compound of Formula (I-i):

[0428] N

[0429]

[0430] (I-i), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, and R5is as defined herein; and X is N or CR5. In some embodiments, X is N or CR5. In some embodiments, X is N. In some embodiments, X is CR5. In some embodiments, X is CH. In some embodiments, X is N or CH.

[0431] In some embodiments, the compound of Formula (I) is a compound of Formula (I-j):

[0432]

[0433] (I-j), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, and R5is as defined herein.

[0434] In some embodiments, the compound of Formula (I) is a compound of Formula (I-k):

[0435]

[0436] (I-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is a 6-membered aryl or heteroaryl, optionally substituted with one or more R5; A” is a 6-membered cycloalkyl or heterocyclyl, optionally substituted with one or more R7; and wherein B, L, R1, R2, R3b, and subvariables therein are as defined herein.

[0437] In some embodiments, the compound of Formula (I) is a compound of Formula (1-1):

[0438]

[0439] (1-1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is a 6-membered aryl or heteroaryl, optionally substituted with one or more R5; A” is a 5-membered cycloalkyl or heterocyclyl, optionally substituted with one or more R7; and wherein B, L, R1, R2, R3b, and subvariables therein are as defined herein.

[0440] In some embodiments, the compound of Formula (I) is a compound of Formula (I-m):

[0441]

[0442] (r7)°-6(I-m),or apharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y2and Y3are independently CR5or N; Y4and Y5are independently C(R7)2, O, or NR7a; R7ais hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R9; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined herein. In some embodiments, R7ais hydrogen, C1-C6-alkyl, Ci-Ce-haloalkyl, or cycloalkyl, wherein each alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R9. In some embodiments, R7ais hydrogen or C1-C6-alkyl, wherein each alkyl is optionally substituted with one or more R9. In some embodiments, R7ais hydrogen. In some embodiments, R7ais C1-C6-alkyl, optionally substituted with one or more R9. In some embodiments, R7ais hydrogen or CH3.

[0443] In some embodiments, the compound of Formula (I) is a compound of Formula (I-n):

[0444]

[0445] (R)°-6(I-n), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y2and Y3are independently CR5or N; Y4and Y5are independently C(R7)2, O, NR7a; R7ais hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R9; and wherein R1, R2, R3b, R5, R7, and subvariables therein are as defined herein. In some embodiments, R7ais hydrogen, C1-C6-alkyl, Ci-Ce-haloalkyl, or cycloalkyl, wherein each alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R9. In some embodiments, R7ais hydrogen or C1-C6-alkyl, wherein each alkyl is optionally substituted with one or more R9. In some embodiments, R7ais hydrogen. In some embodiments, R7ais C1-C6-alkyl, optionally substituted with one or more R9. In some embodiments, R7ais hydrogen or CH3. In some embodiments, the compound of Formula (I) is a compound of Formula (I-o):

[0446]

[0447] (I-o), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y1is CR5or N; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined herein.

[0448] In some embodiments, the compound of Formula (I) is a compound of Formula (I-p):

[0449]

[0450] (R7)0-4(I-p), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y1is CR5or N; and wherein R1, R2, R3b, R5, R7, and subvariables therein are as defined herein.

[0451] In some embodiments, the compound of Formula (I) is a compound of Formula (I-q):

[0452] HN-N

[0453] N

[0454] R2H R3aR3b(R5)O-3

[0455]

[0456] (I-q), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X3and X4are each independently CR5or N; and wherein B, L, R1, R2, R3a, R3b, R5, and subvariables therein are as defined herein.

[0457] In some embodiments, the compound of Formula (I’) is selected from a compound in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0458] Table 1: Exemplary compounds of Formula (F)

[0459] Cmpd Cmpd

[0460] Structure Structure

[0461] No. No.

[0462] HN-N 0

[0463] 100 HN~N 0

[0464] 101

[0465]

[0466] H

[0467]

[0468] H = Cmpd

[0469] Structure

[0470] No.

[0471] HN-N 0

[0472] 102 h

[0473] z i

[0474] \ Ho= 1

[0475] / III" N=\

[0476] 103 HN-N o XYN^F

[0477] M

[0478] zz- Y

[0479] 104

[0480] 105

[0481] H £

[0482] 106

[0483] H z

[0484] 107

[0485] X^JcOr0

[0486] H

[0487] 108

[0488] H N XXX

[0489] 109 HN-N O e

[0490] l> — Y jL X k JJ

[0491] H

[0492] N jQ

[0493] 110 HN-N 0

[0494] r> — < L ji X L J

[0495]

[0496] H

[0497]

[0498]

[0499] Cmpd Cmpd

[0500] Structure Structure No. No.

[0501] F

[0502] 143 HN-N 0 iff 136 X JL

[0503] HN-N o Ai 'A

[0504] H H

[0505] F

[0506] 144 HN-N O iff 4> —

[0507] H

[0508] 137 F. HN-NQ / K / XA'F

[0509] HAAJJFN 145

[0510] F Y. A

[0511] H

[0512] 138 F. HN-No X J.

[0513] 146 HN-N o

[0514] A Ji JJ L 1]FH H F Li

[0515] A z^ \ /

[0516] 1 f l 147 / 'z /

[0517] H- 39 \ / I

[0518] HN-N OFA A IZ I HANV J H IZ

[0519] H r° \o=

[0520] z — < 148 / Illi"N\

[0521] 140 HN-N O NA / )

[0522] -A jl A / z=

[0523] HN-N O AA / Z= H 149

[0524] N=\

[0525] HN-N O NA #

[0526] 141

[0527] — A A A- / N\

[0528] H

[0529] 150

[0530] N=\

[0531] _ N A— F

[0532] 142 N-NH o Ay

[0533]

[0534] H

[0535] 151 HN-N o AV^ FA JI N A Y AJ

[0536]

[0537] H i Cmpd

[0538] Structure

[0539] No.

[0540] M M

[0541] 152 / / 1 I

[0542] IZ zz

[0543] \ \°O==. CA

[0544] H / in' £

[0545] Y z

[0546] V / / / / _

[0547] 153

[0548] N-NH o ZZ-

[0549] A A " Y Y

[0550] F J T

[0551] 154 N-NHO

[0552] H

[0553] N=\

[0554] FN z / ~F155 F— ( A’-NH O AA / JU

[0555] H |

[0556] 156

[0557] 157

[0558] 158

[0559] N^=\

[0560] N~NH o

[0561] 159

[0562] a^^.NA J^^i

[0563]

[0564]

[0565] H |

[0566]

[0567] Cmpd Cmpd

[0568] Structure Structure

[0569] No. No.

[0570] z\,

[0571] 189

[0572] 181 Jlz / A T? rV

[0573] IZ l / ' xX / 'y'N 'yo H |

[0574] 190 N'NH O rfN H / / z\ r> — < J ji Jl

[0575] 182 z —.

[0576] X / N'NH o L U / J H

[0577] o i

[0578] H I N'NH 0 rr M 191 -N\ / / r>— < Jl JI J>~ N H

[0579] 183 HN~N o Ar'O i I> AXNAJJ

[0580] H N A A /

[0581] 192 2^ / / N'NH o ff 'Y

[0582] H

[0583] 184 N-\ F 193. _ / N-NH o ^yN^ F IMANAX N HN-N o H

[0584] 185

[0585] H z

[0586] 194 N'NH 0 # 186 N'NH 0 rr-\ - r> — \ A H Jl y-N

[0587] ^^N^i^NFAH1

[0588] H I N-\

[0589] 195 y,"-NH o

[0590] 187

[0591] > J^H? JL W - H

[0592] H £

[0593] N'NH 0

[0594] 196

[0595] 188 _rNH 0

[0596]

[0597] H |

[0598] 1 / X^'N-'^Y^N

[0599]

[0600] H I

[0601]

[0602] Cmpd Cmpd

[0603] Structure Structure

[0604] No. No.

[0605] Al Az / F\

[0606] \ / X A

[0607] 213 Iz / TZ

[0608] N-NHTZ IZ 0 ||NYN'^ 223. HN~NO

[0609] \O=

[0610] X^A^A \ x° 1 Ji Ji

[0611] °=AA^ J

[0612] H H

[0613] z

[0614] 214 <z / / \X ' / /

[0615] M 224 HN-N 0

[0616] Br— 4 Ji 5 JI J

[0617] O o O\\

[0618] 215 H

[0619] 225 HN-N O r^V1^ 216 z

[0620] II H

[0621] z z- 217

[0622] y ZT z z LX

[0623] 22F-< HN-N0YO~6

[0624] Ynu o-A JI JL JL J

[0625] N

[0626] 218 u\AO°=J H

[0627] TZ ZT ZI ZT F f=\^ F \\zZ== FX X°H / N~N 0 ^^N'N / / y \ 1 \ / 227

[0628] z °-UKW111XH ( z\

[0629] \ / / < NX / oN, N.. N^A ~° 219 ^^ N~NHo [f X z —.

[0630] 1A 228 A H

[0631] 220

[0632] N =( V 229

[0633] H. HN-NO

[0634] 221

[0635] €-AANAJJ

[0636] H \H,N-N 0 rT-\ / ) - 230

[0637] N^\ F VA X I Ji AN i \ _ /

[0638] H. HN~NO ANX / F

[0639]

[0640] 222

[0641] (ZAAJVV

[0642] H

[0643]

[0644] . Xx Cmpd Cmpd

[0645] Structure Structure

[0646] No. No.

[0647] XxE

[0648] z N^\ F F \ /

[0649] \ z= ■

[0650] Hi K

[0651] NI ZI N.. N -. i \ 231 HN~N IZ 0 AMF240 \, -N 0 < N 'FX — X X IZ A A JJ y-4 jf J\ z=f II J

[0652] \ \°=°= ^ ZX H2A 1

[0653] H / I 1m- 11

[0654] z

[0655] / /

[0656] 232 241 \ HN-N O

[0657] zz z-z- /

[0658] H

[0659] p=\ F r===\ OH 2. HN~N OX A.

[0660] 33 N-NH o

[0661] z \— < K II II XX A A N11242 TN'N< ZANA

[0662] H H

[0663] A\F

[0664] 234 HN~N 0 AN'NF 243 HN'N o ^XNAXJBr^\ ji n inH H

[0665] 235 FAFHN-N o XVN^

[0666] H,N~N 0 >> AANAA II 244 oA X U II Z> N H PX

[0667] >H

[0668] 2 F— J \ M

[0669] 36H, NN~. N. 0 i / fNxzNX

[0670] oAA 1 1 J

[0671] H 245

[0672] F ^A / F

[0673] 237 FXH,N~N 0 XVN^ F r=\ F H 246 HN-N 0 AzN'N N=\ IHXXU

[0674] XH HN-N o

[0675] 238

[0676] \— 4 ji I JI J

[0677] / \ / '\N / \AXX

[0678] H 247

[0679] xNx n rCX H

[0680] 239

[0681]

[0682] 248h / n'n? rNCi0A x A A AN —

[0683]

[0684] FA ^ z 1

[0685] Cmpd Cmpd iL Structure Structure No. No. \z^

[0686] 249 257 ZIk °

[0687] H

[0688] N=\ V 250 Y °U"

[0689] 258

[0690] H

[0691] 251 HN-N o

[0692] 259

[0693] H H

[0694] N^\ F

[0695] LJKI ~ N x. N \

[0696] 252 260

[0697] H i H

[0698] I AIl

[0699] zZ Zz z < \ \ / /

[0700] 253Z ZTZ / /

[0701] IZZ I

[0702] 261

[0703] H

[0704] N^\ F c

[0705] z z: c Xzz^ 254 z—. tuuor *'

[0706] H 262 L L MAA k T

[0707] 255

[0708] -vty.. Cr"?nFH 263 N-NH 0

[0709] / =\FZ'U / A N 256 HN~N 0 / rNx# — ( H

[0710] ji I JL F

[0711] F i - 3-

[0712]

[0713] H264 HN-N 0

[0714] £> AKN^U

[0715]

[0716] H LL A

[0717] Cmpd Cmpd

[0718] Structure Structure \z= No. No.

[0719] 274 ( o=

[0720] 265 ZI

[0721] / X

[0722] N=\ Y\F1

[0723] 275 A N-NH 0

[0724] 266 H ZN~N ij o || YY HN'N F

[0725] FH

[0726] 276 267

[0727] Zz z Z- C C ^ —zH277 o JNYN^ z z A '

[0728] \=z \=z \z=Z Z- - 268 \=z

[0729] tAA’.jua> z Z '■

[0730] H _ A #

[0731] ° \ — 278

[0732] (

[0733] ZY Zo=Y ° °= a

[0734] I zxI\ ° / X

[0735] 269 / / / I ZI X X zx XZ

[0736] / X \O H=

[0737] $\ z=

[0738] \ 1

[0739] zvZ zz

[0740] 11X

[0741] 279

[0742] F HN'N 0 rNr )~ 270 zz- H V N

[0743] OxA N'NH 0

[0744] 271 280

[0745] H i

[0746] 272

[0747] 281

[0748] H

[0749] Y\FA HN~N O

[0750] 273 A HN~N0 YvN'N ^F A vS. s V:r 282

[0751] M A^AX I

[0752]

[0753]

[0754] fa Z Z- Cmpd Cmpdz\=

[0755] Structure Structure No. No.

[0756] i n X ki N= | Z \ Tl Z X7 / X

[0757] A H \N / Z Z s.-N

[0758] 28 Ipz\ \z= / O

[0759] 291 HN~N O 3 \

[0760] io=

[0761] — JL zx

[0762] Ziz / IZ iz X / X A

[0763] \ \ XZ

[0764] \ooO=== H

[0765] \o= x N=\ 284 4 ( z Z\. 292

[0766] \ / / / /

[0767] z\ A U X k M z z—, — z.— H

[0768] ^l I' ''zz

[0769] o

[0770] 293

[0771] 285

[0772] 294

[0773] z v — -z

[0774] 286 N^\

[0775] \z=

[0776] 295 A N~NH 0

[0777] LL \ ^ ZZ

[0778] \o=&

[0779] ZI / I xz TZ 287 \ z= N~NH \ 0 \°=°= NA / ) — =

[0780] \ / 296

[0781] / Z Z BrX X.

[0782] N X X. / N^NI1H

[0783] o

[0784] 300

[0785] 7'z 288 o \

[0786] N-NH o N= AZ 301

[0787] H \ _ /

[0788] 289

[0789] ■A A N-NH 0

[0790] H 302 H A

[0791] N N A

[0792] Hr Vu Ly ^

[0793] N=Z 290 >- h 303 N-NH 0

[0794] \z A N X y / 4 f

[0795]

[0796] H L_y

[0797]

[0798]

[0799] Cmpd Cmpd

[0800] Structure Structure

[0801] No. No.

[0802] Az

[0803] A7 Z / z.

[0804] \ < 1

[0805] Z /

[0806] 320 F h N^ / HI / Z z Z 328

[0807] Z z I Z o

[0808] \O -n=

[0809] ) \oO==

[0810] Q OzM

[0811] 3 _ / N-NH 0 < N £>- YZ >= 29

[0812] z^

[0813] 321 I

[0814] F— 4. N-NH 0

[0815] H

[0816] 330

[0817] 322

[0818] A Z Z- 331

[0819] £5

[0820] 323, N'NH 0£X|| '0

[0821] ^ / Z

[0822] ( H o= 6 / TN==:\— Z T

[0823] / N-N^„1 / Z Z Z z I zz I I z o jfY^~F332 \ \°°O^ -n==

[0824] \ / o= < m —

[0825] 324 H F F

[0826] 2MzMZ z=N=Nzzz z zz- 333 z \--N NHU N z / = Z Z

[0827] 325 H 'FY V Y H

[0828] 334

[0829] 326

[0830] N=\ M N FA -Z ~ ^ Y'NH 0 Y YF335 327

[0831]

[0832] HA

[0833]

[0834] Cmpd o Cmpd

[0835] O Structure Structure No. No.

[0836] I h Li 345

[0837] 336 Zz T z / \ / X Z PZo \ / o= Z ZE ( o p—Q / N=\ N"N

[0838] N p z H AHJ0-.. 7 / ^>=\

[0839] 346

[0840] NH 0NA 337 QzZ \Z- H LAn

[0841] ZZ-HA N V==\ 3

[0842] l “F F 47

[0843] / x. HN~

[0844] 338 / \ _ ZNn 0 || PY II 'N^ F

[0845] F

[0846] H

[0847] 348 N-NH O / ^P < J l| / VN. X 339hp /

[0848] 349

[0849] . HN-NO XVO p p o

[0850] P / I

[0851] 340 / / X I < OO^N^ K p / I zz xz / xz I IZ

[0852] yz i° p= H °

[0853] 350 l v

[0854] 341 AZiYzs / s

[0855] ZZZZ Z / Z TfzJJ X XzZ mN==\ F Tj y x v 351 "n T1 342 PPp H OAf

[0856] X? NA, N— NH 9

[0857] 343 V - ^NX XNP 352 XTI o (\ p^ FAFN J l|, II J

[0858] HHV I TI ^

[0859] N'NH 0Z-=\ -NA

[0860]

[0861] 344 ^ /

[0862]

[0863] H■ LXW Cmpd Cmpd

[0864] Structure Structure No. No.

[0865] Z\ZA z z _ _.

[0866] ''z zz z / N

[0867] 353 Z zz Z 361

[0868] N JI J \ JIoO== JI J

[0869] 'N N' Y Y

[0870] H HI J H

[0871] d ' ' z Z — —

[0872] / / N NSS / / ,N~NH o # —N362

[0873] 354

[0874] 4^ H

[0875] 363

[0876] H

[0877] 355

[0878] 364 UXHNAO> H

[0879] <d _ N~NHO

[0880] \ N i A N 365

[0881] 356 4 7i 0 i| HHN. 1 JI, JI J

[0882] r^ / '-NH o <Ny^f3H HI J 366 N'JXA\A-0 / ?H

[0883] <1 NA

[0884] 357 An 9 f

[0885] Nxi

[0886] JI JI JI J 367

[0887] NxNzyx- / r^'NH? £

[0888] H HI J H F F HN^N o rN^ —

[0889] 359 368

[0890] H

[0891] N

[0892] 369

[0893] c< uJ 360 HN~N o |TNVA—H

[0894] / N

[0895] FH

[0896] FtF370

[0897]

[0898] :, -7X5 A

[0899]

[0900] H Cmpd Cmpd

[0901] Structure Structure No. No.

[0902] ' iz <7 \ N i =\ X 371 \ _ „

[0903] iz 486 v ii o fi ^ 4^ ^O= < 1 Ji A J H N H ^ HT "r r

[0904] yN1HQ <zf < J N=\ 480 \ i X z—.

[0905] 3' z^ 487Nv, ~i IlI J 9I I III J

[0906] N H H 1

[0907] n^NH< J \ N I =\ A

[0908] n

[0909] / 9 \ N 8 i / i =\ 4 1 Nv / IlI J H Y A I JI \

[0910] 488 v Xl 0 fl ^ jXn; 1 ji I JH Hu> H H 1 <5 N-z X ^AX "

[0911] \ Z Z 1 ^\ \

[0912] < A7 N i =\ 482 k o rYN^ A < A A Ju J 489

[0913] Nnn 9 li n ti Qr N / jl \XNzJIy JkI A J °

[0914] ZT H H 1 ZT

[0915] <? NA \^N\

[0916] ZT 1C

[0917] Z. ZT <7 N=\ 483 K / z'

[0918] X A nr Y

[0919] AAV 490 r~n 0 f| rUH HI J N 1 ji A J

[0920] H HM

[0921] 484

[0922] 491 A NX A o X rX^TH HM

[0923] 485 492 N-NH 9 / PYAf^

[0924] XAxf yN

[0925]

[0926] 493 / AT i AYA^

[0927]

[0928] H \ _ /

[0929]

[0930]

[0931] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a):

[0932]

[0933] (II-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5; B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; each R3aand R3bis independently hydrogen, Ci-Ce- alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, - ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, - NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5is independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylenearyl, C1-C6 alkylene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12; R11is hydrogen or C1-C6-alkyl; R12is C1-C6-alkyl or -ORA1; RA1is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.

[0934] In some embodiments of Formula (II), A is aryl or heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments of Formula (II), A is 5-membered heteroaryl, 6-membered heteroaryl, or 6-membered aryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 6-membered heteroaryl, or 6-membered aryl, each of which is optionally substituted with one or more R5. In some embodiments, A is 5-membered heteroaryl or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, A is nitrogen-containing 5-membered heteroaryl or nitrogencontaining 6-membered heteroaryl, each of which is optionally substituted with one or more R5.

[0935] (R5)CM JU, / UN / ^(R5)O.3

[0936] In some embodiments of Formula (I

[0937]

[0938] I), A is, or X (R )o-3, wherein R5is as defined herein. In some embodiments of Formula (II), A is. (R5)O-4 XT (R' )o-3 or / ’ r', wherein R5is as defined herein. In some embodiments of

[0939] F

[0940]

[0941] ormula (II), A is (R)°-3, wherein R5is as defined herein.

[0942]

[0943] embodiments of Formula (

[0944]

[0945] II), A is In some embodiments of Formula (II), B is 6-membered aryl optionally substituted with one or more R5. In some embodiments of Formula (II), B is 5-membered heteroaryl or 6-membered aryl, each of which is optionally substituted with one or more R5. In some embodiments, B is 5-membered nitrogen-containing heteroaryl or 6-membered nitrogencontaining heteroaryl, each of which is optionally substituted with one or more R5.

[0946] In some embodiments of Formula (II), B is selected from

[0947]

[0948]

[0949] is selected from

[0950]

[0951] wherein R5is as defined herein.

[0952] O N=\

[0953] In some embodiments of Formula (II), B is selected from:

[0954]

[0955] z 1

[0956]

[0957] embodiments of Formula (II), B is selected from

[0958]

[0959]

[0960] In some embodiments of Formula (II), A-L-B is selected from:

[0961]

[0962]

[0963]

[0964] , wherein each R5is as defined herein. In some embodiments, A-L-B is

[0965] wherein each R5is as defined herein.

[0966]

[0967] In some embodiments, L is absent. In some embodiments, L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. In some embodiments, L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5.

[0968] In some embodiments of Formula (II), A and B are fused together to form

[0969]

[0970] wherein each R5is as defined herein.

[0971] In some embodiments of Formula (II), A and B are fused together to form

[0972]

[0973] Formula (II), A and B are fused together to form

[0974]

[0975]

[0976] In some embodiments of Formula (II), each of R4aand R4bis independently hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, halo, cyano, -ORA, or -NRBRC, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6. In some embodiments, each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, cycloalkyl, halo, and cyano, wherein each alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R6. In some embodiments, wherein R4ais hydrogen, C1-C6-alkyl, haloalkyl, halo, cycloalkyl, or heteroaryl, wherein each of alkyl, haloalkyl, cycloalkyl, and heteroaryl is optionally substituted with one or more R6. In some embodiments, R4ais C1-C6-alkyl, haloalkyl, halo, or cycloalkyl, wherein each of alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6. In some embodiments, each R4ais cycloalkyl optionally substituted with one or more R6. In some embodiments, R4bis hydrogen.

[0977] In some embodiments, R3aand R3bare independently selected from hydrogen, C1-C6-alkyl, or Ci-Ce-heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with one or more R7. In some embodiments, each of R3aand R3bis hydrogen. In some embodiments, R3ais hydrogen and R3bis C1-C6-alkyl, Ci-Ce-heteroalkyl, or aryl, wherein each alkyl, heteroalkyl, and aryl, is optionally substituted with one or more R7. In some embodiments, R3ais hydrogen and R3bis Ci-C6-alkyl optionally substituted with one or more R7.

[0978] In some embodiments, R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom that it is attached, forms a 5-to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7. In some embodiments, R3atogether with the atom that it is attached, forms a cycloalkyl or oxygen- or nitrogen-containing heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7. (R5)0-3 In some embodiments of Formula (I

[0979]

[0980] I),

[0981]

[0982] In some embodiments of Formula (1

[0983]

[0984] 1),

[0985]

[0986] embodiments,

[0987]

[0988] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-b):

[0989]

[0990] (Il-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, B, and subvariables therein are as defined herein.

[0991] In some embodiments, the compound of Formula (II) is a compound of Formula (II-c):

[0992]

[0993] (II-c), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, A, and subvariables therein are as defined herein.

[0994] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-d):

[0995]

[0996] (Il-d), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, A, and subvariables therein are as defined herein.

[0997] In some embodiments, the compound of Formula (II) is a compound of Formula (II-e):

[0998]

[0999] (Il-e) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined herein.

[1000] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-f):

[1001]

[1002] (Il-f), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R4b, R5, and subvariables therein are as defined herein.

[1003] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-g):

[1004]

[1005] (Il-g) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, A, B, and subvariables therein are as defined herein.

[1006] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-h): R4b(R5)CM

[1007] R4a

[1008] H

[1009]

[1010] (II-h), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined herein; and X is N or CR5.

[1011] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-i):

[1012]

[1013] (Il-i), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R5, and subvariables therein are as defined herein.

[1014] In some embodiments, the compound of Formula (II) is a compound of Formula (Il-j):

[1015] / ^(R5)0-5

[1016] H £7

[1017]

[1018] R a R(Il-j), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R5, and subvariables therein are as defined herein.

[1019] In some embodiments, the compound of Formula (II) is selected from a compound in Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[1020] Table 2: Exemplary compounds of Formula (II)

[1021] Cmpd No. Structure Cmpd No. Structure

[1022] 372 373

[1023] o A XT

[1024]

[1025] H

[1026]

[1027] H z z- 0 A Cmpd No. Structure Cmpd No. Structure z \z=

[1028] 374 384

[1029] z ZIz\(o o==

[1030] H?<\ z^=

[1031] 375 385

[1032] Y V H N=\ 376 386 f^Tn? Hr

[1033] H H 1

[1034] F

[1035] 377 jAN387

[1036] IX \X^ ^\X^N

[1037] H £ r^xTn? f^lFH

[1038] 378 r^Tii H 388

[1039] H I A N I =\ A F 379 f XN 0 0 ■ > \zz= _ /

[1040] >— < 1 I 1 J zz

[1041] 389 ZZ

[1042] r^-xTn z T Z z

[1043] ) SoO H

[1044] y==°=FH °^ /

[1045] H

[1046] 380 H rYN^ C ozMf

[1047] Z z z H 390 —, V 0CkzOx381 N

[1048] H | 391

[1049] H I

[1050] 382

[1051] l^ y\A N A^N

[1052] H I 392

[1053] 383 r x^-TIf If D

[1054] s\N

[1055] Hw

[1056]

[1057] £ 393

[1058]

[1059] Cmpd No. Structure Cmpd No. Structure

[1060] N=\

[1061] N hk YF

[1062] 394 403

[1063] A / C /

[1064] >zH

[1065] I z F N=\ ^o= N hk YF404

[1066] 395 Kv / T

[1067] A IzM

[1068] H zz- N==\ 405

[1069] N hk Y / / F

[1070] 396 AUyCr

[1071] N=\

[1072] N hk YF406

[1073] 397 HXklA A W H

[1074] H - - N=\ N=\ NF407

[1075] 398 »A

[1076] A A to U J

[1077] / C /

[1078] H

[1079] >z>zI z x zN=\ Y°°^ /

[1080] 408

[1081] 399 W. UTFkkvy:><' H

[1082] H w W r^=\ F zz- 409

[1083] 40 M W V 0 '"' ■n H " H T|F-w ur

[1084] H

[1085] N=\

[1086] N ISk / 7 " F 410

[1087] 401 okkkcA K-UUJ

[1088] H H N=\

[1089] 411

[1090] 402 cWNW

[1091]

[1092] H

[1093]

[1094] Cmpd No. Structure Cmpd No. Structure

[1095] 412

[1096] F421

[1097] H

[1098] 413 422

[1099] H H £

[1100] 414 423

[1101] H I H

[1102] N^\ / 415 424

[1103] H F KW H R

[1104] / 416

[1105] 425

[1106] >-O j? jrN^~ / V rW1

[1107] H H 1

[1108] N=\ N 417 426

[1109] H S N

[1110] H£

[1111] N

[1112] 418

[1113] H 427

[1114] 419

[1115] / =\FH 428

[1116] H

[1117] 420

[1118]

[1119] 429

[1120]

[1121] H Cmpd No. Structure Cmpd No. Structure

[1122] N

[1123] 430

[1124] H 439 _ / ) —

[1125] N vT« 1 f w H =

[1126] 431

[1127] HA H 440 O fCjT / XS^N'AY / <N H i

[1128] 432

[1129] >-GL 1 rC?

[1130] HF 441

[1131] 433 H K V. <0

[1132] H

[1133] 442

[1134] H

[1135] 434

[1136] HV / K

[1137] 443

[1138] 435 H-SY”

[1139] H =

[1140] 444

[1141] 436 HM / H N

[1142] 445

[1143] 437 cAl AJLW KW H H

[1144] H /

[1145] 446 0 n-N )> — 438 F-< Ji K A

[1146]

[1147] H

[1148]

[1149]

[1150]

[1151] Pharmaceutical Compositions, Kits, and Administration

[1152] The present invention provides pharmaceutical compositions comprising a compound of Formula (I) or (II) e.g., a compound of Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, as described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[1153] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of Formula (I) or (II) (the “active ingredient”) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[1154] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[1155] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

[1156] The term “pharmaceutically acceptable excipient” refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention are any of those that are well known in the art of pharmaceutical formulation and include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[1157] Compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and / or orally.

[1158] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained / delayed release. In some embodiments, the

[1159] composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro-encapsulated form.

[1160] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[1161] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions or in an ointment such as petrolatum.

[1162] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[1163] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. Compounds provided herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[1164] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[1165] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[1166] In certain embodiments, the compounds of Formula (I) or (II) may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[1167] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[1168] It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[1169] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents.

[1170] Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[1171] Exemplary additional pharmaceutical agents include, but are not limited to,

[1172] anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[1173] Also encompassed by the invention are kits (e.g., pharmaceutical packs). The inventive kits may be useful for preventing and / or treating a proliferative disease or a non-proliferative disease, e.g., as described herein. The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one-unit dosage form.

[1174] Thus, in one aspect, provided are kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit of the disclosure includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful in preventing and / or treating a disease, disorder, or condition described herein in a subject (e.g., a proliferative disease or a non-proliferative disease). In certain embodiments, the kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject to prevent and / or treat a proliferative disease or a non-proliferative disease.

[1175] Methods of Use Described herein are compounds useful for modulating cyclin dependent kinase (CDK) activity (e.g., CDK12 activity) and / or cyclin protein expression (e.g., Cyclin K). In some embodiments, a compound of Formula (I) or (II) modulates the activity of a CDK and / or cyclin. The compounds and compositions described herein may also be useful for treating a disease, disorder, or condition described herein (e.g., cancer).

[1176] Cyclin K Degradation

[1177] Cyclins are a family of genes that regulate the enzymatic activity of cyclin dependent kinases (CDKs). Every CDK must be complexed with a partner cyclin to be catalytically active. Cyclin K plays a role as an important regulator of gene transcription by activating the cyclin dependent kinases CDK12 and CDK13. In the absence of Cyclin K, both CDK12 and CDK13 are functionally inactive. Cyclin K therefore plays a pivotal role in regulating cellular processes downstream of CDK12 and CDK13 activity, including gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation.

[1178] It has been demonstrated that Cyclin K protein levels can be modulated by small molecule compounds, such as molecular glue degraders (molecular glues). Molecular glues result in proteasome mediated degradation of Cyclin K by inducing ternary complex formation between CDK12 (or CDK13) and the ubiquitin ligase scaffolding protein DDB1. DDB1 positions the CDK12 / Cyclin K (or CDK13 / Cyclin K) complex in the proximity of an E2 ubiquitin ligase for efficient ubiquitination of Cyclin K, which results in the degradation of Cyclin K by the proteasome.

[1179] In an embodiment, the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof is capable of modulating an activity of Cyclin K. The compound of Formula (I) or (II) may inhibit the activity of Cyclin K. In an embodiment, the compound of Formula (I) or (II) inhibits the activity of Cyclin K, e.g., by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard. In an embodiment, the compound of Formula (I) or (II) inhibits the activity of Cyclin K between about 1% and 50%.

[1180] In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 15%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 20%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 25%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 75%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 95%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) or (II) slows the activity of Cyclin K by more than 99%.

[1181] In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K, e.g., in a cell or sample. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of Cyclin K by more than 99%.

[1182] In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of increasing the rate of Cyclin K degradation by more than 99%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 0.1% (e.g., by about 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 0.5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 1%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 2%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 10%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 15%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 20%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 25%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 50%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 75%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 90%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by about 95%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to Cyclin K by more than about 95%.

[1183] In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 0.1% (e.g., by about 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 0.5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 1%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 2%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 10%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 15%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 20%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 25%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 50%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 75%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 90%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by about 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for Cyclin K by more than about 95%.

[1184] CDK12 / 13 Inhibition

[1185] The cell cycle is a highly regulated process governing cell division and is controlled by several cyclins and cyclin-dependent kinases (CDKs), a group of serine / threonine protein kinases. Cyclins phosphorylate CDKs, forming complexes that play crucial roles in cell cycle regulation and gene transcription (see, e.g., Ding, L. et al. International Journal of Molecular Sciences. (2020) 21:65-78). While cyclins activate CDKs, there are other regulatory molecules that can inhibit their function. Under normal conditions, the activation and inhibition of CDK complexes controls the behavior of the cell at many important cell cycle checkpoints to regulate healthy division. However, this process can become dysregulated and promote uncontrolled division of cells, leading to cancer. In fact, in many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. Inhibiting CDKs can promote cell cycle arrest and attenuate cell proliferation (Malumbres, M., et al. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer (2009) 9:153–166).

[1186] CDKs are divided into two subfamilies, including cell cycle-associated CDKs and transcription-associated CDKs. Cell cycle-associated CDKs mainly contain CDK1, CDK2, CDK4 and CDK6, which directly regulate the cell cycle progression. The transcription-associated CDKs, consisting of CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13, control gene transcription. Cyclin-dependent kinase 12 (CDK12) is known to regulate gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation. CDK12 complexes with cyclin K to regulate gene transcription elongation via phosphorylating RNA polymerase II (RNAP II) and additionally regulates translation. CDK12 is mainly composed of three domains: a central Cdc2 -related protein kinase domain (KD), an N-terminal “arm”, about 700 amino acids, and a C-terminal “arm”, about 500 amino acids. The central KD is composed of 300 amino acids, and its main function is to mediate phosphorylation of the C-terminal domain of RNAP II. The RS domain, which is enriched arginine and serine, is a prominent feature of CDK12. There are 21 RS motifs in the first 400 amino acids of CDK12, and one RS motif in the rest of the approximately 1000 amino acids. In CDK12, the RS domain mainly functions to target CDK12 to the nuclear speckles. The central KD and the RS domain give CDK12 the capacity to directly link transcription with splicing machinery. Proline-rich motifs (PRM) are located between the RS domain and the central KD and are also found in the C-terminal region. The PRM contains the consensus binding sites for Src homology 3 (SH3) and tryptophan (WW) regions, which mediate protein-protein interactions by binding proline-rich modules in ligands. The presence of the RS domain and PRM domain indicates that CDK12 can take part in numerous protein-protein interactions. When CDK12 is bound to cyclin K, the complex functions as an RNA polymerase II (RNAP II) C-terminal domain kinase. Inhibition of CDK12 reduces RNAP II processivity and is correlated with defective transcription elongation (Chirackal Manavalan A. P., et al. EMBO Rep. (2019) 20:e47592). Additionally, CDK12 phosphorylates 4E-BP1 (the mRNA 5’ cap-binding repressor) at Ser65 and Thr70 and is known to suppress intronic polyadenylation (KrajewskaM., et al. Nat. Commun. (2019) 10:1757).

[1187] The closest human homologue of CDK12 is CDK13. While their KD sequences are highly homologous (sharing 43% sequence identity), their C- and N-terminal regions differ. CDK12 / 13 phosphorylate Ser5 and Ser2 of the RNAP II C-terminal domain when complexed with cyclin K. CDK13 has been shown to be involved in alternative splicing (R. Berro, et al. J. Virol., (2008) 82:7155-7166), and also capable of direct phosphorylation of two key components of the protein translation machinery, e.g., 4E-BP1 at Thr6 and eIF4B at Ser422.

[1188] In some embodiments, CDK12 comprises the amino acid sequence of SEQ ID NO 1: MPNSERHGGKKDGSGGASGTLQPS SGGGS SNSRERHRLVSKHKRHKSKHSKDMGLVTP EAASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHR RSRDLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRS SKLHKEKTRKERELKSGHKDRSK SHRKRETPK S YKTVD SPKRRSRSPHRK WSD S SKQD DSPSGASYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPY SRRQRSVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRS RSP A YSRHS S SHSKKKRS S SRSRHS SISP VRLPLNS SLGAEL SRKKKERAAAAAAAKMDG KESKGSPVFLPRKENSSVEAKDSGLESKKLPRSVKLEKSAPDTELVNVTHLNTEVKNSSD TGK VKLDEN SEKHL VKDLKAQGTRD SKP1ALKEE1 VTPKETETSEKETPPPLPT1ASPPPPL PTTTPPPQTPPLPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQANSQP P VQ VS VKTQ VS VTAAIPHLKT STLPPLPLPPLLPGDDDMD SPKETLP SKP VKKEKEQRTR HLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKKRPKICCPRYGERRQTESDWGKRCV DKFDIIGIIGEGTYGQVYKAKDKDTGELVALKKVRLDNEKEGFPITAIREIKILRQLIHRSV VNMKEIVTDKQDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFMKQL MEGLEYCHKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLWYRP PELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISRLCGSPCPAVWPDVI KLP YFNTMKPKKQ YRRRLREEF SFIP S AALDLLDHMLTLDP SKRCTAEQTLQ SDFLKD V ELSKMAPPDLPHWQDCHELWSKKRRRQRQSGVVVEEPPPSKTSRKETTSGTSTEPVKNS SPAPPQPAPGKVESGAGDAIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNIHS NPEMQQQLEALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEASSTP ADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACPPHILPP EKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAALLQLLSQPEAEPPGHLPHEHQAL RPMEYSTRPRPNRTYGNTDGPETGFSAIDTDERNSGPALTESLVQTLVKNRTFSGSLSHL GESSSYQGTGSVQFPGDQDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNYGE LGPGTTGASSSGAGLHWGGPTQSSAYGKLYRGPTRVPPRGGRGRGVPY. In some embodiments, CDK12 comprises an amino acid sequence having at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or greater) sequence identity to SEQ ID NO: 1.

[1189] In some embodiments, CDK13 comprises the amino acid sequence of SEQ ID NO 2: MP S S SDTALGGGGGL S WAEKKLEERRKRRRFLSPQQPPLLLPLLQPQLLQPPPPPPPLLFL AAPGTAAAAAAAAAASSSCFSPGPPLEVKRLARGKRRAGGRQKRRRGPRAGQEAEKRR VF SLPQPQQDGGGGAS SGGGVTPL VEYED VS SQ SEQGLLLGGAS AAT AAT AAGGTGGS GGSP ASS SGTQRRGEGSERRPRRDRRS S SGRSKERHREHRRRDGQRGGSEASKSRSRHS HSGEERAEVAKSGS S SS SGGRRKS AS ATS S SS S SRKDRDSKAHRSRTKS SKEPPS AYKEPP KAYREDKTEPKAYRRRRSLSPLGGRDDSPVSHRASQSLRSRKSPSPAGGGSSPYSRRLPR SPSPYSRRRSPSYSRHSSYERGGDVSPSPYSSSSWRRSRSPYSPVLRRSGKSRSRSPYSSRH SRSRSRHRLSRSRSRHSSISPSTLTLKSSLAAELNKNKKARAAEAARAAEAAKAAEATKA AEAAAKAAKASNTSTPTKGNTETSASASQTNHVKDVKK1K1EHAPSPSSGGTLKNDKAK TKPPLQVTKVENNLIVDKATKKAVIVGKESKSAATKEESVSLKEKTKPLTPSIGAKEKEQ HVALVTSTLPPLPLPPMLPEDKEADSLRGNISVKAVKKEVEKKLRCLLADLPLPPELPGG DDLSKSPEEKKTATQLHSKRRPKICGPRYGETKEKDIDWGKRCVDKFDIIGIIGEGTYGQ VYKARDKDTGEMVALKKVRLDNEKEGFPITAIREIKILRQLTHQSIINMKEIVTDKEDAL DFKKDKGAFYLVFEYMDHDLMGLLESGLVHFNENHIKSFMRQLMEGLDYCHKKNFLH RDIKCSNILLNNRGQIKLADFGLARLYSSEESRPYTNKVITLWYRPPELLLGEERYTPAID VWSCGCILGELFTKKPIFQANQELAQLELISRICGSPCPAVWPDVIKLPYFNTMKPKKQY RRKLREEFVFIPAAALDLFDYMLALDPSKRCTAEQALQCEFLRDVEPSKMPPPDLPLWQ DCHELWSKKRRRQKQMGMTDDVSTIKAPRKDLSLGLDDSRTNTPQGVLPSSQLKSQGS SNVAPVKTGPGQHLNHSELAILLNLLQSKTSVNMADFVQVLNIKVNSETQQQLNKINLP AGILATGEKQTDPSTPQQESSKPLGGIQPSSQTIQPKVETDAAQAAVQSAFAVLLTQLIKA QQSKQKDVLLEERENGSGHEASLQLRPPPEPSTPVSGQDDLIQHQDMRILELTPEPDRPRI LPPDQRPPEPPEPPPVTEEDLDYRTENQHVPTTSSSLTDPHAGVKAALLQLLAQHQPQDD PKREGGIDYQAGDTYVSTSDYKDNFGSSSFSSAPYVSNDGLGSSSAPPLERRSFIGNSDIQ SLDNYST AS SHSGGPPQP S AF SESFP S S VAGYGDIYLNAGPMLF SGDKDHRFEYSHGPIA VLANSSDPSTGPESTHPLPAKMHNYNYGGNLQENPSGPSLMHGQTWTSPAQGPGYSQG YRGHISTSTGRGRGRGLPY.

[1190] In an embodiment, the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof is capable of modulating an activity of a CDK, e.g., CDK12 and / or CDK13. The compound of Formula (I) or (II) may inhibit the activity of a CDK, e.g., CDK12 and / or CDK13. In an embodiment, the compound of Formula (I) or (II) inhibits the activity of a CDK, e.g., CDK12 and / or CDK13 by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard. In an embodiment, the compound of Formula (I) or (II) inhibits the activity of a CDK, e.g., CDK12 and / or CDK13 between about 1% and 50%. In an embodiment, the compound of Formula (I) or (II) does not substantially inhibit the activity of CDK13.

[1191] In some embodiments, the compound of Formula (I) or (II) slows the activity of a CDK, e.g., CDK12 and / or CDK13. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 15%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 20%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 25%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 50%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 75%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 90%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 95%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK12 by at least 99%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK 12 by more than 99%.

[1192] In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 15%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 20%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 25%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 50%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 75%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 90%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 95%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by at least 99%. In some embodiments, the compound of Formula (I) or (II) slows the activity of CDK13 by more than 99%.

[1193] In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by more than 99%.

[1194] In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by more than 99%.

[1195] In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by more than 99%.

[1196] In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 5%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 10%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 30%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 50%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 95%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 99%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%.

[1197] In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 10% (e.g., about 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 25%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 50%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 75%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 90%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 95%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 99%. In some embodiments, the compound of Formula (I) or (II) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%.

[1198] In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 0.1% (e.g., by about 0.5%.

[1199] 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 10%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 15%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 75%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 90%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK12 to RNAP II by more than about 95%.

[1200] In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 0.1% (e.g., by about 0.5%.

[1201] 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 10%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 15%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 75%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 90%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) or (II) is capable of modulating the binding of CDK13 to RNAP II by more than about 95%.

[1202] In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 0.1% (e.g., by about 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 1%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 2%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 25%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 50%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by about 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK12 for RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 0.1% (e.g., by about 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 1%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 2%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 25%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 50%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by about 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of CDK13 for RNAP II by more than about 95%.

[1203] In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 0.1% (e.g., 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 0.5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 1%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 2%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 10%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 15%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 20%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 25%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 50%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 75%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 90%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by at least 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK12 by more than 95%.

[1204] In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 0.1% (e.g., 0.5%. 1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 0.5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 1%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 2%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 5%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 10%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 15%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 20%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 25%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 50%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 75%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 90%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by at least 95%. In some embodiments, the compound of Formula (I) or (II) reduces the binding affinity of RNAP II for CDK13 by more than 95%.

[1205] Methods of Treatment

[1206] The present disclosure also provides methods for the treatment or prevention of a disease, disorder, or condition. In an embodiment, the disease, disorder or condition is related to (e.g., caused by) modulation of a phosphorylation event, such as an unwanted, aberrant, or alternative phosphorylation event. In an embodiment, the disease, disorder or condition comprises a proliferative disease (e.g., cancer, benign neoplasm, or inflammatory disease) or nonproliferative disease. Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods described herein include administering to a subject an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[1207] In certain embodiments, the disease or disorder to be treated or prevented using the compounds of Formula (I) or (II) is cancer. As used herein, the term “cancer” refers to a malignant neoplasm (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the disclosure. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), e.g., adenoid cystic carcinoma (ACC)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (eg., Paget’s disease of the vulva). In some embodiments, the cancer is bladder cancer, blood cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, ovarian cancer, prostate cancer, salivary cancer, skin cancer, or uterine cancer. In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. For example, in some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a melanoma. In some embodiments, the cancer is a mesothelioma. In some embodiments, the cancer is a multiple myeloma. In some embodiments, the cancer is a seminoma.

[1208] In some embodiments, the disease or disorder is associated with a benign neoplasm. For example, a benign neoplasm may include adenoma, fibroma, hemangioma, tuberous sclerosis, and lipoma. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1209] In some embodiments, the disease or disorder is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1210] In some embodiments, a compound of Formula (I) or (II) may slow progression of tumor growth, reduce tumor size, slow and / or prevent cell division, accelerate cell death, prevent metastasis, enhance immune recognition of the tumor, and / or reduce inflammation. For example, in some embodiments, a compound of Formula (I) or (II) slows progression of tumor growth. In some embodiments, a compound of Formula (I) or (II) reduces tumor size. In some embodiments, a compound of Formula (I) or (II) slows and / or prevents cell division. In some embodiments, a compound of Formula (I) or (II) accelerates cell death. In some embodiments, a compound of Formula (I) or (II) slows and / or prevents metastasis. In some embodiments, a compound of Formula (I) or (II) enhances immune recognition of the tumor. In some embodiments, a compound of Formula (I) or (II) reduces inflammation.

[1211] In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) or (II) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%.

[1212] In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) or (II) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%.

[1213] In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) or (II) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%. In some embodiments, the compound of Formula (I) or (II) results in the death of a cancer cell.

[1214] A compound of Formula (I) or (II) may be used to treat a subject having or diagnosed having a cancer. In some embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a neurological disease, autoimmune disorder, immunodeficiency disorder, lysosomal storage disease, cardiovascular condition, metabolic disorder, respiratory condition, inflammatory disease, renal disease, or infectious disease.

[1215] In certain embodiments, the disease is a neurological disease. In certain embodiments, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a neurological disease, disorder, or condition. A neurological disease, disorder, or condition may include a neurodegenerative disease, a psychiatric condition, or a musculoskeletal disease. Exemplary neurological diseases, disorders, and conditions include Alzheimer’s disease, Huntington’s chorea, a prion disease (e.g., Creutzfeldt-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), a mental retardation disorder (e.g., a disorder caused by a SETD5 gene mutation, e.g., intellectual disability-facial dysmorphism syndrome, autism spectrum disorder), Lewy Body disease, diffuse Lewy body disease (DLBD), dementia, progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick’s disease, primary progressive aphasia, corticobasal dementia, Parkinson’s disease, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, a demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), autism, Machado- Joseph disease, or a combination thereof. In some embodiments, the neurological disease comprises Friedrich’s ataxia or Sturge Weber syndrome. In some embodiments, the neurological disease comprises Huntington’s disease. In some embodiments, the neurological disease comprises spinal muscular atrophy. All types of neurological diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1216] In certain embodiments, the disease is an autoimmune disorder or an immunodeficiency disorder. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat an autoimmune disease, disorder, or condition, or an immunodeficiency disease, disorder, or condition. Exemplary autoimmune and immunodeficiency diseases, disorders, and conditions include arthritis (e.g., rheumatoid arthritis, osteoarthritis, gout), Chagas disease, chronic obstructive pulmonary disease (COPD), dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s disease, Hidradenitis suppurativa, Kawasaki disease, ankylosing spondylitis, IgA nephropathy, idiopathic thrombocytopenic purpura, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, infective colitis, indeterminate colitis, interstitial cystitis, lupus (e.g., systemic lupus erythematosus, discoid lupus, drug-induced lupus, neonatal lupus), mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, scleroderma, Sjogren’s syndrome, Stiff person syndrome, vasculitis, vitiligo, a disorder caused by a GATA2 mutation (e.g., GATA2 deficiency; GATA2 haploinsufficiency; Emberger syndrome; monocytopenia and mycobacterium avium complex / dendritic cell, monocyte, B and NK lymphocyte deficiency; familial myelodysplastic syndrome; acute myeloid leukemia; chronic myelomonocytic leukemia), neutropenia, aplastic anemia, and Wegener’s granulomatosis. In some embodiments, the autoimmune or immunodeficiency disorder comprises chronic mucocutaneous candidiasis. All types of autoimmune disorders and immunodeficiency disorders disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1217] In certain embodiments, the disease is a cardiovascular condition. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a cardiovascular disease, disorder, or condition. A cardiovascular disease, disorder, or condition may include a condition relating to the heart or vascular system, such as the arteries, veins, or blood. Exemplary cardiovascular diseases, disorders, or conditions include angina, arrhythmias (atrial or ventricular or both), heart failure, arteriosclerosis, atheroma, atherosclerosis, cardiac hypertrophy, cardiac or vascular aneurysm, cardiac myocyte dysfunction, carotid obstructive disease, endothelial damage after PTCA (percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), myocardial infarction, myocardial ischemia, peripheral obstructive arteriopathy of a limb, an organ, or a tissue; peripheral artery occlusive disease (PAOD), reperfusion injury following ischemia of the brain, heart or other organ or tissue, restenosis, stroke, thrombosis, transient ischemic attack (TIA), vascular occlusion, vasculitis, and vasoconstriction. All types of cardiovascular diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1218] In certain embodiments, the disease is a metabolic disorder. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a metabolic disease, disorder, or condition. A metabolic disease, disorder, or condition may include a disorder or condition that is characterized by abnormal metabolism, such as those disorders relating to the consumption of food and water, digestion, nutrient processing, and waste removal. A metabolic disease, disorder, or condition may include an acid-base imbalance, a mitochondrial disease, a wasting syndrome, a malabsorption disorder, an iron metabolism disorder, a calcium metabolism disorder, a DNA repair deficiency disorder, a glucose metabolism disorder, hyperlactatemia, a disorder of the gut microbiota. Exemplary metabolic conditions include obesity, diabetes (Type I or Type II), insulin resistance, glucose intolerance, lactose intolerance, eczema, hypertension, Hunter syndrome, Krabbe disease, sickle cell anemia, maple syrup urine disease, Pompe disease, and metachromatic leukodystrophy. All types of metabolic diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1219] In certain embodiments, the disease is a respiratory condition. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a respiratory disease, disorder, or condition. A respiratory disease, disorder, or condition can include a disorder or condition relating to any part of the respiratory system, such as the lungs, alveoli, trachea, bronchi, nasal passages, or nose. Exemplary respiratory diseases, disorders, or conditions include asthma, allergies, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), lung cancer, oxygen toxicity, emphysema, chronic bronchitis, and acute respiratory distress syndrome. All types of respiratory diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1220] In certain embodiments, the disease is a renal disease. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a renal disease, disorder, or condition. A renal disease, disorder, or condition can include a disease, disorder, or condition relating to any part of the waste production, storage, and removal system, including the kidneys, ureter, bladder, urethra, adrenal gland, and pelvis. Exemplary renal diseases include acute kidney failure, amyloidosis, Alport syndrome, adenovirus nephritis, acute lobar nephronia, tubular necrosis, glomerulonephritis, kidney stones, urinary tract infections, chronic kidney disease, polycystic kidney disease, and focal segmental glomerulosclerosis (FSGS). In some embodiments, the renal disease, disorder, or condition comprises HIV-associated nephropathy or hypertensive nephropathy. All types of renal diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is an infectious disease. In certain embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat an infectious disease, disorder, or condition. An infectious disease may be caused by a pathogen such as a virus or bacteria. Exemplary infectious diseases include human immunodeficiency syndrome (HIV), acquired immunodeficiency syndrome (AIDS), meningitis, African sleeping sickness, actinomycosis, pneumonia, botulism, chlamydia, Chagas disease, Colorado tick fever, cholera, typhus, giardiasis, food poisoning, ebola hemorrhagic fever, diphtheria, Dengue fever, gonorrhea, streptococcal infection (e.g., Group A or Group B), hepatitis A, hepatitis B, hepatitis C, herpes simplex, hookworm infection, influenza, Epstein-Barr infection, Kawasaki disease, kuru, leprosy, leishmaniasis, measles, mumps, norovirus, meningococcal disease, malaria, Lyme disease, listeriosis, rabies, rhinovirus, rubella, tetanus, shingles, scarlet fever, scabies, Zika fever, yellow fever, tuberculosis, toxoplasmosis, or tularemia. In some embodiments, the infectious disease comprises cytomegalovirus. All types of infectious diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[1221] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[1222] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has improved cell permeability over a reference compound, e.g., in a standard assay for measuring cell permeability. Cell permeability may be investigated, for example, using a standard assay run in either Madin-Darby Canine Kidney (MDCK) cells expressing Breast Cancer Resistance Protein (BCRP), CaCo-2 colorectal adenocarcinoma cells, or subclone MDCKII cells expressing Multidrug Resistance Protein 1 (MDR1); see, e.g., Drug Metabolism and Disposition 36. 268-275 (2008) and Journal of Pharmaceutical Sciences 107:2225-2235 (2018). In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, is evaluated using a cell permeability measurement (Papp), where the cell permeability measurement (Papp) may be either in the A to B direction or the B to A direction. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell permeability measurement (Papp) of < 2X10'6cm s'1. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell permeability measurement (Papp) of between 2-6X10'6cm s'1. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell permeability measurement (Papp) of Papp greater than 6x 10'6cm s'1. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell permeability greater than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%, 95%, 99% or more, e.g., compared with a reference compound.

[1223] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, exhibits decreased cell efflux, e.g., over a reference compound, e.g., in a standard assay for measuring cell efflux. Cell efflux may be investigated, for example, using a standard assay run in either Madin-Darby Canine Kidney (MDCK) cells expressing Breast Cancer Resistance Protein (BCRP) or subclone MDCKII cells expressing Multidrug Resistance Protein 1 (MDR1); see, e.g., Drug Metabolism and Disposition 36, 268-275 (2008) and Journal of Pharmaceutical Sciences 107:2225-2235 (2018). In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell efflux ratio of less than 1.5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell efflux ratio of between 1.5 and 5. In an embodiment, a compound of F Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell efflux ratio greater than 5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a cell efflux ratio less than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%, 95%, 99% or more, e.g., compared with a reference compound.

[1224] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, modulates the expression of a target protein (e.g., HTT or MYB) in a reference cell or sample. In an embodiment, a compound of Formula (1) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, increases the expression of a target protein (e.g., HTT or MYB) in a reference cell or sample. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, decreases the expression of a target protein (e.g., HTT or MYB) in a reference cell or sample. The effect of an exemplary compound of Formula (I) or (II) on protein abundance may be measured using a standard assay for measuring protein abundance, such as the HiBit-assay system (Promega). In this assay, percent response for each respective cell line may be as calculated at each compound concentration as follows: % response = 100 * (S - PC) / (NC - PC). For the normalized response at each concentration, a four-parameter logistical regression may be fit to the data and the response may be interpolated at the 50% value to determine a concentration for protein abundance at 50% (IC50) an untreated control. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a protein abundance response less than 100 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a protein abundance response between 100-1000 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a protein abundance response greater than 1000 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a protein abundance response greater than 10 uM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, modulates the protein abundance of a target protein by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%, 95%, 99% or more, e.g., compared with a reference compound. In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, modulates the viability of a target cell in a subject or sample. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, increases the viability of a target cell in a subject or sample. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, decreases the viability of a target cell in a subject or sample. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, does not impact the viability of a cell (e.g., is non-toxic) in a subject or sample. The effect an exemplary compound of Formula (I) or (II) on cell viability may be measured using a standard assay for measuring cell toxicity, such as the Cell Titer Gio 2.0 assay in either K562 (human chronic myelogenous leukemia) or SH-SY5Y (human neuroblastoma) cells. The concentration at which cell viability is measured may be based on the particular assay used. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, is tolerated by a target cell at a concentration of less than 100 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, is tolerated by a target cell at a concentration of between 100-1000 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, is tolerated by a target cell at a concentration of greater than 1000 nM. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, is tolerated by a target cell at a concentration of greater than 10 uM.

[1225] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has improved brain permeability over a reference compound, e.g., in a standard assay for measuring brain permeability. Brain permeability may be measured, for example, by determining the unbound partition coefficient (Kpuu), brain. In such an assay, the unbound brain partition coefficient (Kp,Uu, brain) may be defined as the ratio of unbound brain-free compound concentration to unbound plasma

[1226] rs f.. x C,

[1227] / > X (7 concentration. It is calculated using the following equation:

[1228]

[1229] Cbrain and Cplasmarepresent the total concentrations in brain and plasma, respectively. In this assay, the fu, brain and fu, plasma may be the unbound fraction of the compound in brain and plasma, respectively. Both fu, brain and fu,plasma may be determined in vitro via equilibrium dialysis. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kp value of greater than 5. In an embodiment, a compound of Formula (1) or (11), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kp value between 1 and 5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kp value between 0.2-1. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has aKp value of less than 0.2. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kpuu value of greater than 2.5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kpuu value between 0.5-2.5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kpuu value between 0.1-0.5. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a Kpuu value of less than 0.1. In an embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., as described herein, has a brain permeability greater than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%, 95%, 99% or more, e.g., compared with a reference compound.

[1230] In certain embodiments, the methods described herein comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of Formula (I) or (II), a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Such additional pharmaceutical agents include, but are not limited to, anti -proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. The additional pharmaceutical agent(s) may synergistically augment the modulation of CDK activity induced by the inventive compounds or compositions of this disclosure in the biological sample or subject. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating, for example, a cancer or other disease, disorder, or condition resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[1231] ENUMERATED EMBODIMENTS

[1232] 1. A compound of F ormula (I):

[1233]

[1234] (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

[1235] A is heterocyclyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;

[1236] B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; Z1and Z2are each independently C(R2), N, NRZ1, or S;

[1237] Z3is C(R4b), N, or NRZ3; wherein the bonds in the heteroaryl ring comprising Z1, Z2, and Z3are single bonds or double bonds as permitted by valency;

[1238] RZ1, RZ2, and RZ3are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, or heterocyclyl;

[1239] L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(0)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5;

[1240] each of R1, R2, R4a, and R4bis independently hydrogen, C1-C6-alkyl, Cs-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylenearyl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RU, -NO2, -C(O)NRBRC, -C(O)RD, -C(0)0Ru, - P(O)yRD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, - S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or

[1241] R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or

[1242] one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;

[1243] each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,

[1244] two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;

[1245] each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;

[1246] each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, Ci-C(, alkylene-heteroaryl, -C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;

[1247] each of RBand RCis independently hydrogen, Ci-Cg-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or

[1248] RBand RCtogether with the atom to which they are attached form a 3 -7-membered heterocyclyl ring optionally substituted with one or more R11;

[1249] each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-het eroaryl;

[1250] each of R9and R10is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;

[1251] R11is hydrogen or C1-C6-alkyl;

[1252] R12is C1-C6-alkyl or -ORA1;

[1253] RA1is hydrogen or C1-C6-alkyl;

[1254] n is 0, 1, 2, or 3; and

[1255] each of x and y is independently 0, 1, or 2.

[1256] 2. The compound of any one of the preceding embodiments, wherein

[1257]

[1258] R4b

[1259]

[1260] The compound of any one of the preceding embodiments, wherein

[1261]

[1262]

[1263] The compound of any one of the preceding embodiments, wherein

[1264]

[1265] R4b

[1266]

[1267] 5. The compound of any one of embodiments 1-3, wherein the compound of Formula (I) is a compound of Formula (I’):

[1268]

[1269] (I’), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

[1270] A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;

[1271] B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5;

[1272] each of R1and R2is independently hydrogen, Ci-Cs-alkyl, Cs-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkyl ene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or-S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;

[1273] each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or

[1274] R3aand R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or

[1275] one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;

[1276] each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,

[1277] two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;

[1278] each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;

[1279] each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;

[1280] each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or

[1281] RBand RCtogether with the atom to which they are attached form a 3 -7-membered heterocyclyl ring optionally substituted with one or more R11;

[1282] each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-het eroaryl;

[1283] each of R9and R10is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;

[1284] R11is hydrogen or C1-C6-alkyl;

[1285] R12is C1-C6-alkyl or -ORA1;

[1286] RA1is hydrogen or C1-C6-alkyl;

[1287] n is 0, 1, 2, or 3; and

[1288] each of x and y is independently 0, 1, or 2.

[1289] 6. The compound of embodiment 5, wherein A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5.

[1290] 7. The compound of any one of the preceding embodiments, wherein A is 5-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl, each of which is optionally substituted with one or more R5.

[1291] 8. The compound of any one of the preceding embodiments, wherein A is 5-membered heteroaryl or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. 9. The compound of any one of the preceding embodiments, wherein A is 6-membered nitrogen-containing heteroaryl, which is optionally substituted with one or more R5.

[1292] The compound of any one of the preceding embodiments, wherein A is

[1293]

[1294]

[1295] 11. The compound of any one of the preceding embodiments, wherein A

[1296]

[1297] is Xr" )°-3, wherein R5is as defined in embodiment 5.

[1298]

[1299] 13. The compound of any one of the preceding embodiments, wherein A is

[1300]

[1301] 14. The compound of any one of the preceding embodiments, wherein L is absent or a bond.

[1302] 15. The compound of any one of the preceding embodiments, wherein L is a bond. 16. The compound of any one of the preceding embodiments, wherein B is aryl or heteroaryl, optionally substituted with one or more R5.

[1303] 17. The compound of any one of the preceding embodiments, wherein B is 5-membered heteroaryl or 6-membered aryl, optionally substituted with one or more R5.

[1304] 18. The compound of any one of the preceding embodiments, wherein B is 6-membered aryl optionally substituted with one or more R5.

[1305] 19. The compound of any one of the preceding embodiments, wherein B is 5-membered nitrogen-containing heteroaryl, optionally substituted with one or more R5.

[1306] 20. The compound of any one of the preceding embodiments, wherein B is selected from

[1307]

[1308] 21. The compound of any one of the preceding embodiments, wherein B is selected from

[1309]

[1310] (R5)O-5, wherein R5is as defined in embodiment

[1311] 22. The compound of any one of the preceding embodiments, wherein B is selected from:

[1312]

[1313]

[1314] 23. The compound of any one of the preceding embodiments, wherein B is selected from

[1315]

[1316] 24. The compound of any one of the preceding embodiments, wherein A-L-B is selected

[1317]

[1318] 25. The compound of any one of the preceding embodiments, wherein A-L-B is selected

[1319]

[1320]

[1321] 26. The compound of any one of embodiments 1-11, wherein L is absent.

[1322] 27. The compound of any one of the preceding embodiments, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R5.

[1323] 28. The compound of any one of embodiments 26-27, wherein L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R5.

[1324] 29. The compound of any one of embodiments 26-28, wherein when A and B are fused

[1325]

[1326] embodiment 5.

[1327] 30. The compound of any one of embodiments 26-29, wherein when A and B are fused together, A and B are selected from:

[1328]

[1329] is as defined in embodiment 5.

[1330] 31. The compound of any one of embodiments 26-30, wherein when A and B are fused

[1331]

[1332] 32. The compound of any one of embodiments 26-31, wherein when A and B are fused

[1333] together, A and B are selected from:

[1334]

[1335]

[1336] 33. The compound of any one of the preceding embodiments, wherein R2is hydrogen.

[1337] 34. The compound of any one of the preceding embodiments, wherein each R1is hydrogen, C1-C6-alkyl, haloalkyl, halo, cycloalkyl, or heteroaryl, and each of C1-C6-alkyl, haloalkyl, cycloalkyl, and heteroaryl is optionally substituted with one or more R6.

[1338] 35. The compound of any one of the preceding embodiments, wherein R1is C1-C6-alkyl, haloalkyl, halo, or cycloalkyl wherein each of C1-C6-alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6.

[1339] 36. The compound of any one of the preceding embodiments, wherein each R1is cycloalkyl optionally substituted with one or more R6.

[1340] 37. The compound of any one of the preceding embodiments, wherein R3aand R3bare independently selected from hydrogen, C1-C6-alkyl, or C1-C6-heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with one or more R7.

[1341] 38. The compound of any one of the preceding embodiments, wherein each of R3aand R3bis hydrogen.

[1342] 39. The compound of any one of the preceding embodiments, wherein R3ais hydrogen and R3bis C1-C6-alkyl, C1-C6-heteroalkyl, or aryl, wherein each alkyl, heteroalkyl, and aryl, is optionally substituted with one or more R7. 40. The compound of any one of the preceding embodiments, wherein R3ais hydrogen and R3bis C1-C6-alkyl optionally substituted with one or more R7.

[1343] 41. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

[1344] 42. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7.

[1345] 43. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or oxygen- or nitrogen-containing heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

[1346]

[1347]

[1348] 46. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-a):

[1349] HN-N o

[1350] R

[1351]

[1352] RRaR (I-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, B, and subvariables therein are as defined in embodiment 5.

[1353] 47. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-b):

[1354]

[1355] (I-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, B, and subvariables therein are as defined in embodiment 5.

[1356] 48. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-c):

[1357] (R5)O-5

[1358] (R®)O-3

[1359] N O

[1360] k AJJ

[1361] N H A „u

[1362]

[1363] (1-c) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, and subvariables therein are as defined in embodiment 5.

[1364] 49. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-d):

[1365] HN~N O B

[1366] 1-\\ 'I 11

[1367] A H

[1368]

[1369] (I-d) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, B, and subvariables therein are as defined in embodiment 5.

[1370] 50. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-e): (R5)O-5

[1371] (R5

[1372]

[1373] (I-e), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R2, R5, and subvariables therein are as defined in embodiment 5.

[1374] 51. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-f):

[1375] N

[1376] H

[1377]

[1378] (I-f), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, R5, and subvariables therein are as defined in embodiment 5, and wherein X is N or CR5.

[1379] 52. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-g):

[1380] N

[1381]

[1382] (I-g), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, R5, and subvariables therein are as defined in embodiment 5.

[1383] 53. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-h):N^(R5)0-4

[1384]

[1385] (I-h), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, B, and subvariables therein are as defined in embodiment 5.

[1386] 54. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-i):

[1387] N

[1388]

[1389] (I-i), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, R5, and subvariables therein are as defined in embodiment 5; and X is N or CR5.

[1390] 55. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-j):

[1391] H,N-N 0 N

[1392] i-<\ '1 11 II

[1393] N

[1394] ,2 H i p5

[1395]

[1396] (I-j), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, R5, and subvariables therein are as defined in embodiment 5.

[1397] 56. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-k): HN-N

[1398] R1^

[1399]

[1400] (I-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is a 6-membered aryl or heteroaryl, optionally substituted with one or more R5; A” is a 6-membered cycloalkyl or heterocyclyl, optionally substituted with one or more R7; and wherein B, L, R1, R2, R3b, and subvariables therein are as defined in embodiment 5.

[1401] 57. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (1-1):

[1402]

[1403] (1-1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is a 6-membered aryl or heteroaryl, optionally substituted with one or more R5; A” is a 5-membered cycloalkyl or heterocyclyl, optionally substituted with one or more R7; and wherein B, L, R1, R2, R3b, and subvariables therein are as defined in embodiment 5.

[1404] 58. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-m):

[1405]

[1406] (I-m), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y2and Y3are independently CR5or N; Y4and Y5are independently C(R7)2, O, or NR7a; R7ais hydrogen, Ci-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R9; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined in embodiment 5.

[1407] 59. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-n):

[1408] NR3l>

[1409] ■3

[1410]

[1411] (R7)O-B (I-n), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y2and Y3are independently CR5or N; Y4and Y5are independently C(R7)2, O, or NR7a; R7ais hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R9; and wherein R1, R2, R3b, R5, R7, and subvariables therein are as defined in embodiment 5.

[1412] 60. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-o):

[1413] (R5)O-2

[1414] J-V1

[1415] x II B

[1416] R2 H

[1417]

[1418] (I-o), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y1is CR5or N; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined in embodiment 5.

[1419] 61. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-p):

[1420]

[1421] (R7)0-4(I-p), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y1is CR5or N; and wherein R1, R2, R3b, R5, R7, and subvariables therein are as defined in embodiment 5.

[1422] 62. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-q):

[1423]

[1424] (I-q), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X3and X4are each independently CR5or N; and wherein R1, R2, R3a, R3b, R5, and subvariables therein are as defined in embodiment 5.

[1425] 63. The compound of any one of the preceding embodiments, wherein the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[1426] 64. The compound of any one of embodiments 1-4, wherein the compound is a compound of Formula (II):

[1427]

[1428] (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

[1429] A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;

[1430] B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(O)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5;

[1431] each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or

[1432] R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or

[1433] one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;

[1434] each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, -P(0)yRD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;

[1435] each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,

[1436] two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;

[1437] each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;

[1438] each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or

[1439] RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11;

[1440] each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl;

[1441] each of R9and R10is independently C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;

[1442] R11is hydrogen or C1-C6-alkyl;

[1443] R12is C1-C6-alkyl or –ORA1;

[1444] RA1is hydrogen or C1-C6-alkyl;

[1445] n is 0, 1, 2, or 3; and

[1446] each of x and y is independently 0, 1, or 2. 65. The compound of embodiment 64, wherein A is aryl or heteroaryl, each of which is optionally substituted with one or more R5.

[1447] 66. The compound of any one of the preceding embodiments, wherein A is 5-membered heteroaryl, 6-membered heteroaryl, or 6-membered aryl, each of which is optionally substituted with one or more R5.

[1448] 67. The compound of any one of the preceding embodiments, wherein A is 6-membered heteroaryl, or 6-membered aryl, each of which is optionally substituted with one or more R5.

[1449] 68. The compound of any one of the preceding embodiments, wherein A is 5-membered heteroaryl or 6-membered heteroaryl, each of which is optionally substituted with one or more R5.

[1450] 69. The compound of any one of the preceding embodiments, wherein A is nitrogencontaining 5-membered heteroaryl or nitrogen-containing 6-membered heteroaryl, each of which is optionally substituted with one or more R5.

[1451] 5 / r'~(R5)o-3 70. The compound of any one of the preceding embodiments, wherein A is

[1452]

[1453] ’

[1454] o

[1455]

[1456] r XT (R" )°-3, wherein R5is as defined in embodiment 64.

[1457] 71. The compound of any one of the preceding embodiments, wherein A

[1458]

[1459] is Xr (R" )°-3, wherein R5is as defined in embodiment 64. 72. The compound of any one of the preceding embodiments, wherein A

[1460]

[1461] is Xr (R' )°-3, wherein R5is as defined in embodiment 64.

[1462] 73. The compound of any one of the preceding embodiments, wherein A is J

[1463] 74. The compound of any one of the preceding embodiments, wherein A is T 75. The compound of any one of the preceding embodiments, wherein L is absent or a bond.

[1464] 76. The compound of any one of the preceding embodiments, wherein L is a bond.

[1465] 77. The compound of any one of the preceding embodiments, wherein B is 6-membered aryl optionally substituted with one or more R5.

[1466] 78. The compound of any one of the preceding embodiments, wherein B is 5-membered heteroaryl or 6-membered aryl, each of which is optionally substituted with one or more R5.

[1467] 79. The compound of any one of the preceding embodiments, wherein B is 5-membered nitrogen-containing heteroaryl or 6-membered nitrogen-containing heteroaryl, each of which is optionally substituted with one or more R5. The compound of any one of the preceding embodiments, wherein B is selected from

[1468]

[1469] wherein R5is as defined in embodiment 64.

[1470] The compound of any one of the preceding embodiments, wherein B is selected from

[1471]

[1472] wherein R5is as defined in embodiment 64.

[1473] The compound of any one of the preceding embodiments, wherein B is selected from:

[1474] F

[1475]

[1476] The compound of any one of the preceding embodiments, wherein B is selected from

[1477]

[1478] The compound of any one of the preceding embodiments, wherein A-L-B is selected

[1479] efined in embodiment 64.

[1480]

[1481] 85. The compound of any one of the preceding embodiments, wherein A-L-B is selected

[1482]

[1483] embodiment 64.

[1484] 86. The compound of any one of the preceding embodiments, wherein A-L-B is selected

[1485]

[1486] 87. The compound of any one of the preceding embodiments, wherein L is absent.

[1487] 88. The compound of any one of the preceding embodiments, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5.

[1488] 89. The compound of any one of the preceding embodiments, wherein L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. 90. The compound of any one of the preceding embodiments, wherein when A and B are

[1489] (R5)O-5

[1490] fused together, A and B are selected from:

[1491]

[1492]

[1493] in embodiment 64.

[1494] 91. The compound of any one of the preceding embodiments, wherein when A and B are

[1495] fused together, A and B are selected from:

[1496]

[1497] wherein each R5is as defined in embodiment 64.

[1498] 92. The compound of any one of the preceding embodiments, wherein when A and B are

[1499]

[1500] 93. The compound of any one of the preceding embodiments, wherein when A and B are

[1501] fused together, A and B are selected from:

[1502]

[1503] 94. The compound of any one of the preceding embodiments, wherein each of R4aand R4bis independently hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, halo, cyano, -ORA, or -NRBRC, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6.

[1504] 95. The compound of any one of the preceding embodiments, wherein each of R4aand R4bis independently hydrogen, C1-C6-alkyl, Ci-Ce-haloalkyl, cycloalkyl, halo, and cyano, wherein each alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R6.

[1505] 96. The compound of any one of the preceding embodiments, wherein R4ais hydrogen, C1-C6-alkyl, haloalkyl, halo, cycloalkyl, or heteroaryl, wherein each of alkyl, haloalkyl, cycloalkyl, and heteroaryl is optionally substituted with one or more R6.

[1506] 97. The compound of any one of the preceding embodiments, wherein R4ais C1-C6-alkyl, haloalkyl, halo, or cycloalkyl, wherein each of alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6.

[1507] 98. The compound of any one of the preceding embodiments, wherein each R4ais cycloalkyl optionally substituted with one or more R6.

[1508] 99. The compound of any one of the preceding embodiments, wherein R4bis hydrogen. 100. The compound of any one of the preceding embodiments, wherein R3aand R3bare independently selected from hydrogen, C1-C6-alkyl, or C1-C6-heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with one or more R7.

[1509] 101. The compound of any one of the preceding embodiments, wherein each of R3aand R3bis hydrogen.

[1510] 102. The compound of any one of the preceding embodiments, wherein R3ais hydrogen and R3bis C1-C6-alkyl, C1-C6-heteroalkyl, or aryl, wherein each alkyl, heteroalkyl, and aryl, is optionally substituted with one or more R7.

[1511] 103. The compound of any one of the preceding embodiments, wherein R3ais hydrogen and R3bis C1-C6-alkyl optionally substituted with one or more R7.

[1512] 104. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

[1513] 105. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7.

[1514] 106. The compound of any one of the preceding embodiments, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or oxygen- or nitrogen-containing heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

[1515]

[1516] R4b109. The compound of any one of the preceding embodiments, wherein

[1517]

[1518] is selected from:

[1519]

[1520] 110. The compound of any one of the preceding embodiments, wherein

[1521]

[1522]

[1523] 111. The compound of any one of the preceding embodiments, wherein

[1524]

[1525] is selected

[1526]

[1527] 112. The compound of any one of the preceding embodiments, wherein

[1528]

[1529] is selected

[1530]

[1531] 113. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II-a):

[1532]

[1533] (II-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, A, B, and subvariables therein are as defined in embodiment 64. 114. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-b):

[1534] R4b(R5)0-3 B

[1535] N

[1536]

[1537] (Il-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, B, and subvariables therein are as defined in embodiment 64.

[1538] 115. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II-c):

[1539] R4bN

[1540] / r-N O

[1541] i4a\ JL A

[1542]

[1543] (II-c), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, A, and subvariables therein are as defined in embodiment 64.

[1544] 116. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-d):

[1545] R4b

[1546] #NO

[1547] '4a-< / II II

[1548]

[1549] (Il-d), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, A, B, and subvariables therein are as defined in embodiment 64.

[1550] 117. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II-e):

[1551]

[1552] (Il-e) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined in embodiment 64.

[1553] 118. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II-F):

[1554]

[1555] (Il-f), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R4b, R5, and subvariables therein are as defined in embodiment 64.

[1556] 119. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-g):

[1557]

[1558] (Il-g) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, A, B, and subvariables therein are as defined in embodiment 64.

[1559] 120. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-h): N O (7-NV / ?

[1560] ^3a p3b

[1561]

[1562] (II-h), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined in embodiment 64; and X is N or CR5.

[1563] 121. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-i):

[1564] N

[1565] H

[1566]

[1567] (Il-i), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R5, and subvariables therein are as defined in embodiment 64.

[1568] 122. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (Il-j):

[1569] N

[1570] H

[1571]

[1572] (Il-j ), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R5, and subvariables therein are as defined in embodiment 64.

[1573] 123. The compound of any one of the preceding embodiments, wherein the compound is selected from a compound listed in Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 124. A pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[1574] 125. A method of modulating the rate of degradation of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) or (II) as described in any one of embodiments 1-123.

[1575] 126. The method of embodiment 125, wherein the compound increases the rate of degradation of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

[1576] 127. A method of modulating the level of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) or (II) as described in any one of embodiments 1-123.

[1577] 128. The method of embodiment 127, wherein the compound reduces the level of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

[1578] 129. A method of modulating the activity of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) or (II) as described in any one of embodiments 1-123.

[1579] 130. The method of embodiment 129, wherein the compound inhibits the activity of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 131. A method of modulating the rate of degradation of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) or (II) as described in any one of embodiments 1-123.

[1580] 132. The method of embodiment 131, wherein the compound increases the rate of degradation of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

[1581] 133. A method of reducing the level of a cyclin dependent kinase (e.g., CDK12 or CDK13) comprising contacting the cyclin dependent kinase (e.g., CDK12 or CDK13) with a compound of Formula (I) or (II) as described in any one of embodiments 1-123.

[1582] 134. The method of embodiment 133, wherein the compound reduces the level of a cyclin dependent

[1583] kinase (e.g., CDK12 or CDK13) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

[1584] 135. A method for treating a disease or disorder in a subject comprising administering to the subject a compound of Formula (I) or (II) according to any one of embodiments 1-123 or the pharmaceutical composition of embodiment 124.

[1585] 136. The method of embodiment 135, wherein the disease or disorder comprises a proliferative disease (e.g., cancer, a benign neoplasm, or angiogenesis).

[1586] 137. The method of any one of embodiments 135-136, wherein the disease or disorder comprises cancer. 138. The method of embodiment 137, wherein the cancer is selected from bladder cancer, blood cancer, breast cancer, colorectal cancer, gastro-esophageal cancer, lung cancer, ovarian cancer, prostate cancer, salivary cancer, skin cancer, or uterine cancer.

[1587] 139. The method of embodiment 135, wherein the disease or disorder comprises a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease.

[1588] 140. A composition for use in treating a disease or disorder in a subject comprising a compound of Formula (I) or (II) according to any one of embodiments 1-123 or the pharmaceutical composition of embodiment 124.

[1589] EXAMPLES

[1590] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[1591] The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (z.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[1592] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. Reactions can be purified or analyzed according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g.,1H or13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[1593] Proton NMR:1H NMR spectra were recorded in CDCl3solution in 5-mm o.d. tubes (Wildmad) at 24 °C and were collected on a BRUKER AVANCE NEO 400 at 400 MHz for ’H. The chemical shifts (δ) are reported relative to tetramethylsilane (TMS = 0.00 ppm) and expressed in ppm.

[1594] LC / MS: Liquid chromatography-mass spectrometry (LC / MS) was performed on Shimadzu-2020EV using column: Shim-pack XR-ODS (Cl 8, 04.6 x 50 mm, 3 pm, 120 A, 40 °C) operating in ESI(+) ionization mode; flow rate = 1.2 mL / min. Mobile phase = 0.05% TFA in water or CH3CN; or on Shimadzu-2020EV using column: Poroshell HPH-C18 (Cl 8, 04.6 x 50 mm, 3 pm, 120 A, 40 °C) operating in ESI(+) ionization mode; flow rate = 1.2 mL / min. Mobile phase A: Water / 5mMNH4HCO3, Mobile phase B: CH3CN).

[1595] Analytical chiral HPLC: Analytical chiral HPLC was performed on a Agilent 1260 using column: CHIRALPAK IG-3, CHIRALPAK IC-3 or CHIRALPAK OJ-3, with flow rate = 1.2 mL / min. Mobile phase = MTBE(DEA): EtOH=50:50).

[1596] Preparative HPLC: prep-HPLC was performed using one of the following conditions: Condition 1: Column: XBride Prep OBD Column 19x150mm 8um; Mobile Phase A: water (0.1%NH3 H2O); Mobile Phase B: MeCN; Flow rate: 12 mL / min; Gradient 1: 25% B to 50% B in 8 min; Gradient 2: Flow rate: 10 mL / min, 25% B to 50% B in 8 min; Gradient 3: Flow rate: 15 mL / min, 25% B to 50% B in 12 min; Gradient 4: Flow rate: 20 mL / min, 40% B to 70% B in 8 min; Gradient 5: Flow rate: 80 mL / min, 35% B to 60% B in 15 min; Gradient 6: 20% B to 45% B in 8 min; Gradient 7: 30% B to 60% B in 8 min; Gradient 8: 30% B to 65% B in 12 min; Gradient 9: Flow rate: 90 mL / min, 40% B to 70% B in 20 min; Gradient 10: 30% B to 80% B in 8 min; Gradient 11: 15% B to 50% B in 8 min; Gradient 12: 30% B to 80% B in 12 min; Gradient 13: 20% B to 60% B in 12 min;

[1597] Condition 2: Column, C18 silica gel, XBridge, 19x150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: MeCN; Gradient 1: 10% B to 30% B in 10 min.

[1598] Condition 3: Column: Ultimate-XB-C18 Column, 50*250 mm, 10pm; Mobile Phase A: Water (lOmmol / L NH4HCO3); Mobile Phase B: ACN; Flow rate: 90 mL / min; Gradient 1: Mobile Phase A: Water(10mmol / L NH4HCO3+0.1%NH3 H2O), 30% B to 45% B in 20 min.

[1599] Condition 4: Column: XBridePrep OBD Column 19x150mm, 8um; Mobile Phase A: water (0.05% NH3. H2O), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient 1: 40% B to 70% B in 8 min; Gradient 2: 30% B to 60% B in 8 min; Gradient 3: 30% B to 70% B in 8 min; Gradient 4: 10% B to 50% B in 8 min; Gradient 5: 5...

Claims

1. CLAIMS1. A compound of F ormula (I):

4.

5. (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:6.A is heterocyclyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;7.B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; Z1and Z2are each independently C(R2), N, NRZ1, or S;8.Z3is C(R4b), N, or NRZ3; wherein the bonds in the heteroaryl ring comprising Z1, Z2, and Z3are single bonds or double bonds as permitted by valency;9.RZ1, RZ2, and RZ3are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, or heterocyclyl;10.L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5;11.each of R1, R2, R4a, and R4bis independently hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylenearyl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, - P(O)yRD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or12.one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;13.each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, ORA, NRBRC, NRBC(O)RD, NO2, C(O)NRBRC, C(O)RD, C(O)ORD, or S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,14.two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;15.each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;16.each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, Ci-Cr, alkylene-heteroaryl, -C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;17.each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or18.RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11; each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyl ene-heteroaryl;19.each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;20.R11is hydrogen or C1-C6-alkyl;21.R12is C1-C6-alkyl or -ORA1;22.RA1is hydrogen or C1-C6-alkyl;23.n is 0, 1, 2, or 3; and24.each of x and y is independently 0, 1, or 2.

2. The compound of claim 1, wherein26.

3. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I’):

30.

31. (I'), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:32.A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;33.B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R1and R2is independently hydrogen, Ci-Cs-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkyl ene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, -P(O)yRD, or-S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;34.each R3aand R3bis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or35.R3aand R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or36.one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;37.each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NBC(O)RD, -NO2, -C(O)NRBRC, -C(O)RD, -C(O)ORD, or-S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,38.two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;39.each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each RAis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;40.each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or41.RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11;42.each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl;43.each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;44.R11is hydrogen or C1-C6-alkyl;45.R12is C1-C6-alkyl or –ORA1;46.RA1is hydrogen or C1-C6-alkyl;47.n is 0, 1, 2, or 3; and48.each of x and y is independently 0, 1, or 2.

4. The compound of claim 3, wherein A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R5.

5. The compound of claim 3, wherein A is 5-membered heteroaryl or 6-membered heteroaryl, each of which is optionally substituted with one or more R5.The compound of claim 3, wherein A51.

52. is54.

8. The compound of claim 3, wherein L is absent or a bond.

9. The compound of claim 3, wherein B is aryl or heteroaryl, optionally substituted with one or more R5.

10. The compound of claim 3, wherein B is 5-membered heteroaryl or 6-membered aryl, optionally substituted with one or more R5.59.The compound of claim 3, wherein B is selected from60.

63.

65. 67.409 as defined in claim 3.

69.

71.

15. The compound of claim 3, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R5.

16. The compound of claim 3, wherein when A and B are fused together, A and B are76.

77. and79.

17. The compound of claim 3, wherein when A and B are fused together, A and B are83.

18. The compound of claim 3, wherein R1is C1-C6-alkyl, haloalkyl, halo, or cycloalkyl wherein each of C1-C6-alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6.

19. The compound of claim 3, wherein R3ais hydrogen and R3bis C1-C6-alkyl, C1-C6-heteroalkyl, or aryl, wherein each alkyl, heteroalkyl, and aryl, is optionally substituted with one or more R7.

20. The compound of claim 3, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

21. The compound of claim 3, wherein R3atogether with the atom that it is attached, forms a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7.

89.

23. The compound of claim 3, wherein92.

94.

24. The compound of claim 3, wherein the compound is a compound of Formula (I-a):97.R198.R R3aR3b100.

101. (I-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, B, and subvariables therein are as defined in claim 3.

25. The compound of claim 3, wherein the compound is a compound of Formula (I-b):103.R1105.

106. (I-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, B, and subvariables therein are as defined in claim 3.

26. The compound of claim 3, wherein the compound is a compound of Formula (I-d):

109.

110. (I-d) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, B, and subvariables therein are as defined in claim 3.

27. The compound of claim 3, wherein the compound is a compound of Formula (I-f):111.R2 H113.

114. (I-f), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, A, R5, and subvariables therein are as defined in claim 3, and wherein X is N or CR5.

28. The compound of claim 3, wherein the compound is a compound of Formula (I-i):116.N118.

119. (I-i), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R1, R2, R3a, R3b, R5, and subvariables therein are as defined in claim 3; and X is N or CR5.

29. The compound of claim 3, wherein the compound is a compound of Formula (I-m):121.N-N O B122.R3b123.J £_£ ii124.R2 H126.

127. (I-m), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y2and Y3are independently CR5or N; Y4and Y5are independently C(R7)2, O, or NR7a; R7ais hydrogen, C1-C6-alkyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R9; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined in claim 3.

30. The compound of claim 3, wherein the compound is a compound of Formula (I-o):

129.

130. (I-o), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y1is CR5or N; and wherein B, L, R1, R2, R3b, R5, R7, and subvariables therein are as defined in claim 3.

31. The compound of claim 3, wherein the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

32. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (II):

134.

135. (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:136.A is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R5;137.B is aryl or heteroaryl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NRB-, -C(O)-, -S(O)X-, -NRBC(0)-, -C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, A and B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5;138.each R3aandR3bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-C6-heteroalkyl, Ci-C6-haloalkyl, halo, cyano, oxo, -ORA, -NRBRC, -C(O)RD, -C(O)ORD, -S(O)XRD, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; or R3aor R3b, together with the atom that they are attached, form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7; or139.one of R3aor R3b, together with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R7;140.each of R4aand R4bis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, ORA, NRBRC, NRBC(O)RD, -NO2, C(O)NRBRC, C(O)RD, C(O)ORD, -P(O)yRD, or -S(O)XRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;141.each R5is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8; or,142.two R5groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;143.each of R6, R7, and R8is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA, -NRBRC, -NRBC(O)RD, -NO2, -C(0)NRBRC, -C(O)RD, -C(O)ORD, or -S(O)XRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;144.each RAis independently hydrogen, C1-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10; each of RBand RCis independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-heteroalkyl, Ci-Ce-haloalkyl, cycloalkyl, heterocyclyl, S(O)XRD, or-ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R11; or145.RBand RCtogether with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R11;146.each RDis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkyl ene-heteroaryl;147.each of R9and R10is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;148.R11is hydrogen or C1-C6-alkyl;149.R12is C1-C6-alkyl or -ORA1;150.RA1is hydrogen or C1-C6-alkyl;151.n is 0, 1, 2, or 3; and152.each of x and y is independently 0, 1, or 2.

33. The compound of claim 32, wherein A is aryl or heteroaryl, each of which is optionally substituted with one or more R5.

34. The compound of claim 32, wherein A is 6-membered heteroaryl, or 6-membered aryl, each of which is optionally substituted with one or more R5.

35.

35. The compound of claim 32, wherein A is HEIGHT="60" WIDTH="277" SRC="imgf000419_0001.tif" / > is as defined in claim 32.

36. The compound of claim 32, wherein A is HEIGHT="54" WIDTH="74" SRC="imgf000420_0001.tif" / >37. The compound of claim 32, wherein L is absent or a bond.

38. The compound of claim 32, wherein B is 5-membered heteroaryl or 6-membered aryl, each of which is optionally substituted with one or more R5.

39. The compound of claim 32, wherein B is selected from159.

160. , and162.

163. , wherein R5is as defined in claim 32.164.N40. The compound of claim 32, wherein B is selected from:

166.

167. *168.F N F F N169.F171.

172. F N173., and41. The compound of claim 32, wherein A-L-B is selected from:

175.

176. (R5)0-3177.N178.(R5)0-5180.

181. (R5)0-3, and (R5)0-3, wherein each R5is as defined in claim 33. The compound of claim 32, wherein A-L-B is selected from:

182.

185.

43. The compound of claim 32, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5.

44. The compound of claim 32, wherein when A and B are fused together, A and B are190.

45. The compound of claim 32, wherein when A and B are fused together, A and B are194.

196.

46. The compound of claim 32, wherein R4ais C1-C6-alkyl, haloalkyl, halo, or cycloalkyl, wherein each of alkyl, haloalkyl, and cycloalkyl is optionally substituted with one or more R6.

47. The compound of claim 32, wherein R3atogether with the atom that it is attached, forms a cycloalkyl or heterocyclyl ring with A, wherein the cycloalkyl and heterocyclyl is optionally substituted with one or more R7.

201.

203.

51. The compound of claim 32, wherein the compound is a compound of Formula (II-a):

207.

208. (II-a), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, A, B, and subvariables therein are as defined in claim 32.

52. The compound of claim 32, wherein the compound is a compound of Formula (II-e):210.'N^\211.R4b(R5)O-3 J. x>212.> N O X? (R5)O-3213.R4X 1 1 X JN214.S'^N X215.H ' '217.

218. Ra R(Il-e) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined in claim 32.

53. The compound of claim 32, wherein the compound is a compound of Formula (II-g):R4b221.

222. R3aR (II-g) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, A, B, and subvariables therein are as defined in claim 32.

54. The compound of claim 32, wherein the compound is a compound of Formula (Il-h):224.nt225.S'^N N226.H228.

229. (II-h), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of R3a, R3b, R4a, R4b, R5, and subvariables therein are as defined in claim 32; and X is N or CR5.

55. The compound of claim 32, wherein the compound is selected from a compound listed in Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

56. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

57. A method of modulating the rate of degradation of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) or (II) as described in claim 1.

58. The method of claim 57, wherein the compound increases the rate of degradation of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

59. A method of modulating the level of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) or (II) as described in claim 1.

60. The method of claim 59, wherein the compound reduces the level of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

61. A method of modulating the activity of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) or (II) as described in claim 1.

62. The method of claim 61, wherein the compound inhibits the activity of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

63. A method of modulating the rate of degradation of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) or (II) as described in claim 1.

64. The method of claim 63, wherein the compound increases the rate of degradation of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

65. A method for treating a disease or disorder in a subject comprising administering to the subject a compound of Formula (I) or (II) according to claim 1.

66. The method of claim 65, wherein the disease or disorder comprises a proliferative disease (e.g., cancer, a benign neoplasm, or angiogenesis).

67. The method of claim 66, wherein the disease or disorder comprises cancer.

68. The method of claim 67, wherein the cancer is selected from bladder cancer, blood cancer, breast cancer, colorectal cancer, gastro-esophageal cancer, lung cancer, ovarian cancer, prostate cancer, salivary cancer, skin cancer, or uterine cancer.

69. The method of claim 65, wherein the disease or disorder comprises a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease.

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