Compounds, compositions, and methods of use thereof

Abstract

The present disclosure relates to compounds that bind to and / or degrade one or more cyclin dependent kinases, as well as pharmaceutical compositions comprising the compounds disclosed herein, and methods for treating diseases, disorders, and conditions mediated, at least in part, by cyclin dependent kinases.

Description

Attorney Docket No.78AW-385397-WO COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Number 63 / 697,347, filed September 20, 2024, the contents of which is hereby incorporated by reference in its entirety. FIELD

[0002] The present disclosure provides compounds that bind to and / or degrade one or more cyclin dependent kinases, as well as pharmaceutical compositions comprising the compounds disclosed herein, and methods for treating diseases, disorders, and conditions mediated, at least in part, by cyclin dependent kinases. BACKGROUND

[0003] Cyclin-Dependent Kinases and related serine / threonine protein kinases are important cellular enzymes that perform essential features in regulating cell division and proliferation. CDKs 1-4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression whereas CDKs 3, 5, and 7-9 may play an indirect role (e.g., through activation of other CDKs, regulation of transcription or neuronal functions).

[0004] Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Such overexpression has been associated with poor outcomes in breast cancer including triple negative breast cancer.

[0005] As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target cancer-associated proteins, such as CDK, including CDK2, hold promise as therapeutic agents. Accordingly, there remains a need for compounds that target CDKs, especially CDK2, for degradation which compounds would be useful as therapeutic agents. SUMMARY

[0006] Disclosed are compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising said compounds or pharmaceutically acceptable salts thereof, and methods for use of said compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which bind to and / or degrade one or more cyclin dependent kinases (CDKs). An advantage of the compounds provided herein is that a broad range of pharmacological activities are possible, consistent with the degradation / inhibition of CDKs and modulation of targeted ubiquitination. In addition, the disclosure provides methods of using the compounds described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer, in a subject in need thereof.Attorney Docket No.78AW-385397-WO

[0007] The present disclosure, in one embodiment, provides compounds of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: L1is a bond, -, or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-; n is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; R is hydrogen, deuterium, or fluorine, each R1is independently halo, cyano, -OH, -NH2, -N(C1-3 alkyl)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy; each R1aand R1bis independently hydrogen, halo, -OH, or C1-6 alkyl; or R1aand R1btogether with the carbon atom attached thereto form a C3-6membered cycloalkyl; each R2aand R2bis independently hydrogen, halo, -OH, or C1-6alkyl; or R2aand R2btogether with the carbon atom attached thereto form a C3-6 cycloalkyl; R3is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R7)2, -OR7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -NR7C(O)OR7, -S(O)0-2R7, -NR7S(O)0-2R7, -S(O)0-2N(R7)2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5; each R5is independently selected from halo, cyano, -OR8, -N(R8)2, -NO2,-SF5, -C(O)R8, -C(O)OR8, -C(O)N(R8)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 memberedAttorney Docket No.78AW-385397-WO heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6 alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, hydroxy, -SH, -NH2, -N(C1-6 alkyl)2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-4-10 membered heterocyclyl, -L-C6-10aryl, or -L-5-10 membered heteroaryl; and each L is independently -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHS(O)-, -S(O)2NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -NHC(O)NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O-, -P(O)(O-C2-6alkynyl)O-, or -P(O)(O-C1-6 haloalkyl)O-; and wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl of Z1is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; provided that the compound is not: 3-[4-[[(2-furanylmethyl)amino]methyl]-2-oxobenz[cd]indol-1(2H)-yl]-2,6-piperidinedione (CAS No.2767646-92-2); 1,1-dimethylethyl N-[[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]methyl]carbamate (CAS No.2767589-31-9); or 1,1-dimethylethyl N-[3-[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]propyl]carbamate (CAS No.2912305-19-0).

[0008] Also provided herein are pharmaceutical compositions comprising a compound of Formula I as disclosed herein (or any subformula thereof), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or aAttorney Docket No.78AW-385397-WO pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided herein is a method for treating a disease or condition mediated, at least in part, by CDK2, or a disease characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2), or both CCNE1 and CCNE2, in a subject in need thereof, the method comprising administering to subject a therapeutically effective amount of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof). In some embodiments, the method is cancer.

[0010] Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising administering to subject a therapeutically effective amount of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof). DETAILED DESCRIPTION Definitions

[0011] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0012] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0013] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.Attorney Docket No.78AW-385397-WO

[0014] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0015] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0016] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2- pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and “propyl” includes n-propyl (i.e., -(CH2)2CH3), and isopropyl (i.e., -CH(CH3)2).

[0017] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl, and 1,3-butadienyl).

[0018] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0019] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively.Attorney Docket No.78AW-385397-WO

[0020] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.

[0021] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0022] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen.

[0023] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0024] “Alkylthio” refers to the group “alkyl-S-”.

[0025] “Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0027] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0028] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0029] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl).Attorney Docket No.78AW-385397-WO Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.

[0030] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0031] “Carboxyl ester” or “ester” refer to both -OC(O)Rxand -C(O)ORx, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0033] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0034] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.Attorney Docket No.78AW-385397-WO

[0035] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0036] “Heteroalkylene” refers to a divalent heteroalkyl group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain. The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkylene groups include, e.g., -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -OCH2-, -CH(CH3)O-, -CH2CH2O-, -CH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2O-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -SCH2-, -CH(CH3)S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NRyCH2-, -CH(CH3)NRyCH2-, -CH2CH2NRyCH2-, -CH2CH2NRyCH2CH2NRyCH2-, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term “heteroalkylene” does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.

[0037] “Heteroaryl” refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen,Attorney Docket No.78AW-385397-WO and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0038] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged- heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the attachment to the remainder of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, and oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl,Attorney Docket No.78AW-385397-WO decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2- oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7- tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0039] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0040] “Alkylsulfonyl” refers to the group -S(O)2R, where R is alkyl.

[0041] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0042] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0043] As used herein, the term “compound,” is meant to include any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0044] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.Attorney Docket No.78AW-385397-WO

[0045] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0046] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0047] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F,3H,11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0048] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its naturalAttorney Docket No.78AW-385397-WO abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0049] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0050] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0051] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3, or primary, secondary, tertiary amines, such as salts derived from a N-containing heterocycle, a N-containing heteroaryl, or derived from an amine of formula N(RN)3(e.g., HN+(RN)3or (alkyl)N+(RN)3) where each RNis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethylAttorney Docket No.78AW-385397-WO amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0052] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. In some embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0053] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0054] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible withAttorney Docket No.78AW-385397-WO the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0055] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0056] The term “pharmaceutically acceptable” as used herein indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.

[0057] The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0058] The terms “effective amount” or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0059] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; TheAttorney Docket No.78AW-385397-WO Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0060] The term “pharmaceutical composition” refers to a mixture of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof as provided herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0061] The terms “treat,” “treating,” and “treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0062] The term “preventing,” as used herein, is the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0063] The terms “subject,” “patient,” or “individual,” as used herein, are used interchangeably and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or needed. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0064] The terms “treatment regimen” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination.

[0065] The term “pharmaceutical combination,” as used herein, refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.

[0066] The term “combination therapy” as used herein refers to a dosing regimen of two different therapeutically active agents (i.e., the components or combination partners of the combination), wherein the therapeutically active agents are administered together or separately in a manner prescribed by a medical care taker or according to a regulatory agency as defined herein.Attorney Docket No.78AW-385397-WO

[0067] The term “modulate,” “modulating,” or “modulation,” as used herein, refers to a regulation or an adjustment (e.g., increase or decrease) and can include, for example agonism, partial agonism or antagonism. Compounds

[0068] Provided herein are compounds which bind to and / or degrade one or more cyclin dependent kinases (CDKs). In some embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: L1is a bond, -, or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-; n is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; R is hydrogen, deuterium, or fluorine; each R1is independently halo, cyano, -OH, -NH2, -N(C1-3 alkyl)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy; each R1aand R1bis independently hydrogen, halo, -OH, or C1-6 alkyl; or R1aand R1btogether with the carbon atom attached thereto form a C3-6 membered cycloalkyl; each R2aand R2bis independently hydrogen, halo, -OH, or C1-6alkyl; or R2aand R2btogether with the carbon atom attached thereto form a C3-6 cycloalkyl; R3is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R7)2, -OR7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -NR7C(O)OR7, -S(O)0-2R7, -NR7S(O)0-2R7, -S(O)0-2N(R7)2, C3-10 cycloalkyl, C6-10 aryl, 4-10 memberedAttorney Docket No.78AW-385397-WO heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5; each R5is independently selected from halo, cyano, -OR8, -N(R8)2, -NO2, -SF5, -C(O)R8, -C(O)OR8, -C(O)N(R8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6 alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, hydroxy, -SH, -NH2, -N(C1-6alkyl)2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10 cycloalkyl, -L-4-10 membered heterocyclyl, -L-C6-10 aryl, or -L-5-10 membered heteroaryl; and each L is independently -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHS(O)-, -S(O)2NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -NHC(O)NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O-, -P(O)(O-C2-6 alkynyl)O-, or -P(O)(O-C1-6haloalkyl)O-; and wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl of Z1is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; provided that the compound is not: 3-[4-[[(2-furanylmethyl)amino]methyl]-2-oxobenz[cd]indol-1(2H)-yl]-2,6-piperidinedione (CAS No.2767646-92-2); 1,1-dimethylethyl N-[[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]methyl]carbamate (CAS No.2767589-31-9); orAttorney Docket No.78AW-385397-WO 1,1-dimethylethyl N-[3-[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]propyl]carbamate (CAS No.2912305-19-0).

[0069] In some embodiments, each R1aand R1bis hydrogen.

[0070] In some embodiments, each R2aand R2bis independently hydrogen, halo, or C1-6 alkyl.

[0071] In some embodiments, L1is a bond, -C(O)-, -NHS(O)2NH-,a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-.

[0072] In some embodiments, L1is a bond.

[0073] In some embodiments, L1is a; wherein a denotes attachment to the -NH-.

[0074] In some embodiments, L1is -C(O)-.

[0075] In some embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R, R1, R3, m, n, and p are each independently as defined herein.

[0076] In some embodiments, L1is a 5-6 membered heteroaryl. In some embodiments, L1is oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyridazinyl, or pyrazinyl.

[0077] In some embodiments, L1is a 6 membered heteroaryl.

[0078] In some embodiments, L1is a 5 membered heteroaryl. In some embodiments, L1is .

[0079] In some embodiments, provided is a compound of Formula IB:Attorney Docket No.78AW-385397-WOor a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R, R1, R3, m, n, and p are each independently as defined herein.

[0080] In some embodiments, L1is; wherein a denotes attachment to the -NH-.

[0081] In some embodiments, provided is a compound of Formula IC:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R, R1, R3, m, n, and p are each independently as defined herein.

[0082] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0083] In some embodiments, each R1is independently halo.

[0084] In some embodiments, p is 0 or 1; and R1is halo. In some embodiments, p is 0 or 1; and R1is fluoro. In some embodiments, p is 1; and R1is halo. In some embodiments, p is 1; and R1is fluoro.

[0085] In some embodiments, n is 1. 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. In some embodiments, n is 3.

[0086] In some embodiments, R is hydrogen.

[0087] In some embodiments, provided is a compound of Formula IIA:Attorney Docket No.78AW-385397-WOor a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R3and m are each independently as defined herein.

[0088] In some embodiments, provided is a compound of Formula IIB:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R3and m are each independently as defined herein.

[0089] In some embodiments, provided is a compound of Formula IIC:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, wherein R3and m are each independently as defined herein.

[0090] In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0091] In some embodiments, R3is C1-6 alkyl, -N(R7)2, -C(O)R7, -NR7C(O)OR7, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein each C1-6alkyl, C3-10cycloalkyl, C6-10Attorney Docket No.78AW-385397-WO aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5.

[0092] In some embodiments, R3is C1-6alkyl optionally substituted with one to three R5.

[0093] In some embodiments, R3is -N(R7)2. In some embodiments, R3is -N(R7)2; and each R7is independently hydrogen or C1-6alkyl; wherein each C1-6alkyl is independently optionally substituted with one to five Z1.

[0094] In some embodiments, R3is -C(O)R7. In some embodiments, R3is -C(O)R7; and R7is C6-10aryl optionally substituted with one to five Z1.

[0095] In some embodiments, R3is -NR7C(O)OR7. In some embodiments, R3is -NR7C(O)OR7; and each R7is independently hydrogen or C1-6alkyl; wherein each C1-6alkyl is independently optionally substituted with one to five Z1. In some embodiments,

[0096] In some embodiments, R3is C3-10cycloalkyl optionally substituted with one to three R5.

[0097] In some embodiments, R3is C6-10aryl optionally substituted with one to three R5.

[0098] In some embodiments, R3is 4-10 membered heterocyclyl optionally substituted with one to three R5.

[0099] In some embodiments, R3is 5-10 membered heteroaryl optionally substituted with one to three R5.

[0100] In some embodiments, R3is methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, -NH2, -N(ethyl)2, -N(CH2-cyclohexyl)2,,Attorney Docket No.78AW-385397-WO,; wherein each is independently optionally substituted with one to three R5.

[0101] In some embodiments, each R5is independently selected from halo, cyano, -OR8, -SF5, -C(O)OR8, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1.

[0102] In some embodiments, each R7is independently hydrogen, C1-6alkyl, or C6-10aryl; wherein each C1-6 alkyl or C6-10 aryl is independently optionally substituted with one to five Z1.

[0103] In some embodiments, each R8is independently hydrogen or C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to three halo.

[0104] In some embodiments, each Z1is independently halo, C3-15 cycloalkyl, 4-10 membered heterocyclyl, or -O-C1-6alkyl; wherein the heterocyclyl of Z1is further independently optionally substituted with C1-6 alkyl.

[0105] In some embodiments, each R5is independently selected from halo, cyano, -OR8, -SF5, -C(O)OR8, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1and each Z1is independently halo, C3-15 cycloalkyl, 4-10 membered heterocyclyl, or -O-C1-6 alkyl; wherein the heterocyclyl of Z1is further independently optionally substituted with C1-6alkyl.

[0106] In some embodiments, R3is C1-6 alkyl, -N(R7)2, -C(O)R7, -NR7C(O)OR7, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5; each R5is independently selected from halo, cyano, -OR8, -SF5, -C(O)OR8, C1-6alkyl, C1-6haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1;Attorney Docket No.78AW-385397-WO each R7is independently hydrogen, C1-6 alkyl, or C6-10 aryl; wherein each C1-6 alkyl or C6-10 aryl, is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6alkyl; wherein each C1-6alkyl is independently optionally substituted with one to three halo; and each Z1is independently halo, C3-15cycloalkyl, 4-10 membered heterocyclyl, or -O-C1-6alkyl; wherein the heterocyclyl of Z1is further independently optionally substituted with C1-6 alkyl.

[0107] In some embodiments, provided is compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof: Table 1Attorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WO

[0108] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent any or all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those delineated in Table 2. In some embodiments, provided is compound selected from Table 2, or a pharmaceutically acceptable salt, tautomer, or isotopically enriched analog thereof: Table 2Attorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOTreatment Methods and Uses

[0109] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will becomeAttorney Docket No.78AW-385397-WO apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art. The compounds and compositions described herein are useful in methods for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2. In some embodiments, the CDK2 dependent disease or disorder is a disease characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2. The methods comprise administering to a subject suffering from a CDK2 dependent disease or disorder an effective amount of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.

[0110] In certain embodiments of the disclosure, the compound of Formula I is:or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: L1is a bond, -, or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-; n is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; R is hydrogen, deuterium, or fluorine,Attorney Docket No.78AW-385397-WO each R1is independently halo, cyano, -OH, -NH2, -N(C1-3 alkyl)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy; each R1aand R1bis independently hydrogen, halo, -OH, or C1-6alkyl; or R1aand R1btogether with the carbon atom attached thereto form a C3-6 membered cycloalkyl; each R2aand R2bis independently hydrogen, halo, -OH, or C1-6alkyl; or R2aand R2btogether with the carbon atom attached thereto form a C3-6 cycloalkyl; R3is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R7)2, -OR7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -NR7C(O)OR7, -S(O)0-2R7, -NR7S(O)0-2R7, -S(O)0-2N(R7)2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5; each R5is independently selected from halo, cyano, -OR8, -N(R8)2, -NO2,-SF5, -C(O)R8, -C(O)OR8, -C(O)N(R8)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, hydroxy, -SH, -NH2, -N(C1-6alkyl)2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-4-10 membered heterocyclyl, -L-C6-10 aryl, or -L-5-10 membered heteroaryl; and each L is independently -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHS(O)-, -S(O)2NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -NHC(O)NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O-, -P(O)(O-C2-6 alkynyl)O-, or -P(O)(O-C1-6 haloalkyl)O-; and wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl of Z1is further independently optionally substitutedAttorney Docket No.78AW-385397-WO with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy;

[0111] Thus, provided is a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), or a pharmaceutical composition comprising the same, for use in treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, CDK2, or a disease characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2. In one embodiment, provided is a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient for use in treating an CDK2 dependent disease or disorder.

[0112] In one embodiment, provided is the use of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), in the preparation of a medicament for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or a disease characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.

[0113] In one embodiment, the method relates to a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in manufacture of a medicament for reducing CDK2 protein levels where reduction of such protein levels treats or ameliorates the disease or disorder.

[0114] In one embodiment, the method relates a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), orAttorney Docket No.78AW-385397-WO a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient wherein the CDK2 degradation at 1 µM concentration of the compound as described herein is in the range of about 25%-99%. The CDK2 degradation is measured by the assay described in the biological example. In some embodiments, the CDK2 degradation is from about 25% to about 50%, from about 45% to about 70%, from about 65% to about 90% or from about 75% to about 99%. In some embodiments, the CDK2 degradation is from about 25% to about 35%, from about 35% to about 45%, from about 45% to about 55%, from about 55% to about 65%, from about 65% to about 75%, from about 75% to about 85%, from about 85% to about 99%. In some embodiments, the CDK2 degradation is more than 60%. In some embodiments, the CDK2 degradation is more than 70%. In some embodiments, the CDK2 degradation is more than 80%. In some embodiments, the CDK2 degradation is more than 90%.

[0115] In some embodiments, provided herein is a method for treating cancer. The method includes administering to a subject in need thereof, a therapeutically effective amount of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof).

[0116] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

[0117] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the cancer is ER+ / HER2-negative advanced breast cancer. In some embodiments, the cancer is ER+ / HER2-negative advanced breast cancer, which is resistant to CDK4 / 6 inhibitors, such as, but not limited to, palbociclib, ribociclib, and abemaciclib.

[0118] In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with an amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0119] CCNE1 amplification has been detected in a broad spectrum of human malignancies, more frequently in high-grade malignancies, which was in consistence with its biological functions in cell proliferation and differentiation. CCNE1 amplifications have been observed in more than 7.5% of many tumor types: uterine, breast, ovarian, pancreatic, bladder, gastric, esophageal, lung cancers, and sarcoma. Cyclin E1 controls the transition of quiescent cells to the cell cycle, as well as epithelial-mesenchymalAttorney Docket No.78AW-385397-WO transitions. Overexpression of cyclin E1 induces replication stress, forcing premature entry into the S phase, and functioning as a key factor for c-myc driven tumorigenesis. Activated cycle E1 further upregulates its own expression by phosphorylating Rb and releasing more E2F independent of mitogenic stimuli. This positive feedback network drives the mitotic transition from the G1 to the S phase, resulting in enhanced cellular proliferation and tumor progression. This aggressive phenotype partly contributes to poor survival in patients with metastatic malignancies harboring CCNE1 amplification, in addition to CCNE1 amplification mediated resistance to chemotherapy.

[0120] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar et al., Proc. Natl. Acad. Sci. USA, 2009, 106(31):12968-12973), K-Ras mutant lung cancers (see Hu, S., et al., Mol. Cancer Ther., 2015, 14(11):2576-85), and cancers with FBW7 mutation and CCNE1 overexpression (see Takada et al., Cancer Res., 2017, 77(18):4881-4893).

[0121] In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0122] In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

[0123] In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0124] In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0125] In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0126] Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenalAttorney Docket No.78AW-385397-WO gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

[0127] n some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSIhigh). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0128] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0129] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer.Attorney Docket No.78AW-385397-WO

[0130] In some embodiments, the compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0131] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0132] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).

[0133] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0134] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0135] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0136] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm’s tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0137] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.Attorney Docket No.78AW-385397-WO

[0138] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

[0139] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0140] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0141] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0142] In certain embodiments, the disclosure provides a method of treating a subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, comprising administering to the human subject a CDK2 inhibitor, wherein the human subject has been previously determined to: (i) (a) have a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (b) express a p16 protein, and (ii) (a) have an amplification of the CCNE1 gene and / or (b) have an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1.

[0143] CCNE1 and p16 have been identified as genes, in combination, useful in predicting responsiveness (e.g., improvement in disease as evidenced by disease remission / resolution) of a subject having a disease or disorder associated with CDK2 to a CDK2 inhibitor. p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a) acts as a negativeAttorney Docket No.78AW-385397-WO regulator of the proliferation of normal cells by interacting with CDK4 and CDK6. p16 is encoded by the cyclin dependent kinase inhibitor 2A (“CDKN2A”) gene (GenBank Accession No. NM_000077). The cytogenic location of the CDKN2A gene is 9p21.3, which is the short (p) arm of chromosome 9 at position 21.3. The molecular location of the CDKN2A gene is base pairs 21,967,752 to 21,995,043 on chromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Genetic and epigenetic abnormalities in the gene encoding p16 are believed to lead to escape from senescence and cancer formation (Okamoto et al., 1994, PNAS 91(23):11045-9).

[0144] Another aspect of the disclosure relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), or a pharmaceutically acceptable composition comprising the same.

[0145] It will be appreciated that the compounds and compositions, according to the method of the present disclosure, may be administered using any amount and any route of administration effective for the treatment of cancer and / or disorders associated with cell hyperproliferation. For example, when using the compounds for the treatment of cancer, the expression “effective amount” as used herein, refers to a sufficient amount of agent to inhibit proliferation, or refers to a sufficient amount to reduce the effects of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular anticancer agent, its mode of administration, and the like.

[0146] The present disclosure also provides methods of protecting against a proliferative disorder in a subject in need thereof or the treatment of a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound or composition as described herein to a subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present disclosure also provides the use of compound as described herein for the preparation of a medicament useful for the prevention of a proliferative disorder.

[0147] As used herein, the term “proliferative disorder” refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the disclosure encompass a variety of conditions wherein cell division is deregulated. Exemplary proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulatedAttorney Docket No.78AW-385397-WO tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A proliferative disorder includes a precancer or a precancerous condition. A proliferative disorder includes cancer. The methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors, as well as, hematologic tumors and / or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

[0148] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis, inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram- negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0149] A “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system. A proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system.

[0150] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols inAttorney Docket No.78AW-385397-WO Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0151] In certain embodiments, according to the methods of treatment of the present disclosure, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with a compound or composition, as described herein. Combination Therapies

[0152] In one embodiment, the compounds disclosed herein may be used in a combination therapy with one or more therapy or additional therapeutic agent. In some embodiments, the methods provided herein further include administration of a second therapeutic agent, wherein the second therapeutic agent is an anti- cancer agent.

[0153] As used herein, by “combination therapy” is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and anther compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances. In various embodiments, treatment with a combination therapy may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of a single compound of the disclosure alone. In some embodiments, a lower amount of each compound is used as part of a combination therapy compared to the amount generally used for individual therapy. Preferably, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a compound in a combination therapy than the amount generally used for individual compound or therapy. Preferably, the use of a small amount of compound results in a reduction in the number, severity, frequency, and / or duration of one or more side- effects associated with the compound.

[0154] Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with an additional chemotherapeutic agent, to an individual in need thereof.Attorney Docket No.78AW-385397-WO

[0155] “Chemotherapeutic agent” refers to any substance capable of reducing or preventing the growth, proliferation, or spread of a cancer cell, a population of cancer cells, tumor, or other malignant tissue. The term is intended also to encompass radiotherapy, or any antitumor or anticancer agent.

[0156] In certain embodiments, the additional chemotherapeutic agent binds to one or more cyclin- dependent kinase (e.g., one or more of CDK2, CDK4, CDK5, CDK6, CDK7, and CDK9). In certain embodiments, the additional chemotherapeutic agent binds to CDK4. In certain embodiments, the additional chemotherapeutic agent binds to CDK4 and CDK6 (i.e., CDK4 / 6). In certain embodiments, the additional chemotherapeutic agent comprises a selective inhibitor of key regulators of cell cycle checkpoints cyclin- dependent kinases (“CDK”) 2 / 4 / 6.

[0157] Additionally, the present disclosure provides pharmaceutically acceptable derivatives of the compounds described herein, and methods of treating a subject using such derivative, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.

[0158] Other therapies or anticancer agents that may be used in combination with the compounds and compositions disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6- Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of overview of cancer therapy see The Merck Manual, Twentieth Ed. 2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov / cder / cancer / druglistframe).

[0159] In certain embodiments, a pharmaceutical composition as described herein, comprising a compound as disclosed herein, further comprise one or more additional therapeutically active ingredients (e.g., a chemotherapeutic agent and / or a palliative agent). For purposes of the disclosure, the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and / or side effects of a therapeutic regimen, but is not considered to be curative. For example, palliative treatments encompass painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinkingAttorney Docket No.78AW-385397-WO tumors and reducing pressure, bleeding, pain and other symptoms of cancer). In some embodiments, the compound of Formula I, Formula I, or Formula III, or any subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is the sole active agent for a pharmaceutical composition described herein or for a method disclosed herein.

[0160] One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti- inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt- 3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4 / 6 kinase inhibitors such as, for example, those described in WO 2006 / 056399 can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

[0161] In some embodiments, the CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0162] The compounds as disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitors therapies for the treatment of diseases, such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapies include those as described herein. Examples of cancers include solid tumors and non-solid tumors, such as liquid tumors, blood cancers. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-DR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFQR, PDGFQR, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), an EGFR inhibitor (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathway blocker (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,Attorney Docket No.78AW-385397-WO vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), a PARP inhibitor (e.g., olaparib, rucaparib, veliparib or niraparib), a JAK inhibitor (JAK1 and / or JAK2, e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), an IDO inhibitor (e.g., epacadostat, NLG919, or BMS- 986205, MK7162), an LSD1 inhibitor (e.g., GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., parsaclisib (INCB50465) or INCB50797), a PI3K-gamma inhibitor such as PI3K- gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer; e.g., INCB081776), an adenosine receptor antagonist (e.g., A2a / A2b receptor antagonist), an HPK1 inhibitor, a chemokine receptor inhibitor (e.g., CCR2 or CCR5 inhibitor), a SHP1 / 2 phosphatase inhibitor, a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g., tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinations thereof.

[0163] In some embodiments, a compound described herein is used in combination with a PI3Kδ inhibitor. In some embodiments, a compound described herein is used in combination with a JAK inhibitor. In some embodiments, a compound described herein is used in combination with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, a compound described herein is used in combination with a JAK1 inhibitor. In some embodiments, a compound described herein is used in combination with a JAK1 inhibitor, which is selective over JAK2.

[0164] Example antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

[0165] Additional examples of chemotherapeutics include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0166] In some embodiments, a compound described herein is used in combination with a corticosteroid such as dexamethasone or prednisone.

[0167] In some embodiments, a compound described herein is used in combination with a Bcr-Abl inhibitor. Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, or a pharmaceutically acceptable thereof.

[0168] In some embodiments, a compound described herein is used in combination with a Flt-3 inhibitor. Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate,Attorney Docket No.78AW-385397-WO sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, or a pharmaceutically acceptable thereof.

[0169] In some embodiments, a compound described herein is used in combination with a RAF inhibitor. Example suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, or a pharmaceutically acceptable thereof.

[0170] In some embodiments, a compound described herein is used in combination with a FAK inhibitor. Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, or a pharmaceutically acceptable thereof.

[0171] In some embodiments, a compound described herein is used in combination with a CDK4 / 6 inhibitor. Example suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and their pharmaceutically acceptable salts.

[0172] In some embodiments, a compound described herein is used in combination with a kinase inhibitor. In some embodiments, a compound described herein is used in combination with a kinase inhibitors such as imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.

[0173] In some embodiments, a compound described herein is used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr- Abl, Flt-3, RAF and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0174] In some embodiments, each compound is administered in a single or continuous dosage form, or are administered simultaneously or sequentially as separate dosage forms.

[0175] In some embodiments, a compound described herein can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections.Attorney Docket No.78AW-385397-WO

[0176] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the disclosure where the dexamethasone is administered intermittently as opposed to continuously.

[0177] In some embodiments, a compound described herein can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0178] In some embodiments, a compound described herein can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM- CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, a compound described herein can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, a compound described herein can be combined with dendritic cells immunization to activate potent anti-tumor responses.

[0179] In some embodiments, a compound described herein can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0180] In some embodiments, combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and / or after a bone marrow transplant or stem cell transplant. In some embodiments, a compound described herein can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.

[0181] In some embodiments, a compound described herein can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

[0182] Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplexAttorney Docket No.78AW-385397-WO viruses, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

[0183] Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.

[0184] Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.

[0185] Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0186] When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).

[0187] In some embodiments, a compound described herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases, such as cancer or infections. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1B), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

[0188] In some embodiments, a compound described herein can be used in combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B).Attorney Docket No.78AW-385397-WO

[0189] In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti- PD-L1 antibody, or anti-CTLA-4 antibody.

[0190] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab).

[0191] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1 / PD-L1 bispecific antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0192] In some embodiments, the inhibitor is MCLA-145.

[0193] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0194] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0195] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0196] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0197] In some embodiments, the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.Attorney Docket No.78AW-385397-WO

[0198] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0199] In some embodiments, a compound described herein can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβ receptor.

[0200] In some embodiments, a compound described herein can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

[0201] In some embodiments, a compound described herein can be used in combination with one or more CDK4 inhibitor, CDK4 / 6 inhibitor, SERD, and / or SERM.

[0202] A selective estrogen receptor degrader or downregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and, in the process of doing so, causes the ER to be degraded and thus downregulated. Non-limiting examples include fulvestrant, ZB716 (Fulvestrant boronic acid), giredestrant, amcenestrant (SAR439859), camizestrant (AZD9833), rintodestrant (G1T48), LSZ102, imlunestrant (LY3484356), elacestrant, ZN-c5, taragarestrant (D-0502), SHR9549, vepdegestrant (ARV-471), Brilanestrant, or etacstil (combined SERM and SERD).

[0203] Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist / antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists (that is, full agonists and silent antagonists) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Non-limiting examples include Evista (raloxifene), Nolvadex (tamoxifen), Soltamox (tamoxifen), and Fareston (toremifene). Pharmaceutical Compositions and Modes of Administration

[0204] Compounds provided herein are usually administered in the form of pharmaceutical compositions.

[0205] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example,Attorney Docket No.78AW-385397-WO inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0206] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0207] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0208] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof), the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0209] Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.Attorney Docket No.78AW-385397-WO

[0210] The compositions that include at least one compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof) can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0211] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound as disclosed herein (e.g., Formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof). When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0212] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0213] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local orAttorney Docket No.78AW-385397-WO systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, in one embodiment, orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0214] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet formulation

[0215] The following ingredients are mixed intimately and pressed into single scored tablets.Formulation Example 2 - Capsule formulation

[0216] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsuleFormulation Example 3 - Suspension formulation

[0217] The following ingredients are mixed to form a suspension for oral administration.Attorney Docket No.78AW-385397-WOFormulation Example 4 - Injectable formulation

[0218] The following ingredients are mixed to form an injectable formulation.Formulation Example 5 - Suppository Formulation

[0219] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:6. Dosing

[0220] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of theAttorney Docket No.78AW-385397-WO subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In certain embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. In certain embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7. Synthesis of the Compounds

[0221] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0222] It will be appreciated that where typical process conditions (i.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 solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0223] Additionally, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein. For example, protecting groups for alcohols, such as hydroxy, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p- methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxycarbonyl, removed by concentratedAttorney Docket No.78AW-385397-WO strong acid (such as HCl or CF3COOH), or by heating to greater than about 80 °C, 9- fluorenylmethyloxycarbonyl, removed by base, such as piperidine, acetyl, removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide), troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride.

[0224] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0225] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). General Synthesis

[0226] Scheme I illustrates general methods which can be employed for the synthesis of compounds described herein (e.g., Formula I), where each R, R1, R1a, R1b, R2a, R2b, R3, m, n, and p are independently as defined herein, and L1*is a group comprising L1and a leaving group (e.g., halo, hydroxy, alkoxy, etc.), or L1*is a precursor group to L1.Attorney Docket No.78AW-385397-WO Scheme I

[0227] In Scheme I, compounds of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. For compounds of Formula I where L1is -C(O), L1* may be -C(O)-LG, where LG is a leaving group (e.g., halo, hydroxy, alkoxy, etc.), the reaction conditions may comprise a coupling agent and optionally a base (such as HOBt in DMF). For compounds of Formula I where L1is a heteroaryl, such as an oxadiazole, L1*may be a heteroaryl precursor, such as 1,3,4-oxadiazol-2(3H)-one. For compounds of Formula I where L1is a bond, L1*may be a leaving group (e.g., halo, hydroxy, alkoxy, etc.).

[0228] Upon reaction completion, compounds of Formula I can be recovered and purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. In addition, further derivatization of the product formed by process outlined in Scheme I can provide additional compounds of Formula I.

[0229] It should be understood that the starting compounds shown in Scheme I may be prepared using traditional methods or purchased from commercial sources. For example, compounds of Formula I-1 for use in Scheme I to provide compounds of Formula I can be provided in Scheme II. In Scheme II, R, R1, R1a, R1b, n, and p are each independently as defined herein, each X is independently halo (e.g., Br), and PG is a protecting group (e.g., Boc, etc.). Scheme IIAttorney Docket No.78AW-385397-WO

[0230] In Scheme II, compound II-3 is prepared by coupling compound II-1 with compound II-2. Reacting compound II-3 with compound II-4 under suitable coupling conditions in the presence of a palladium catalyst provides compound II-5. Deprotection of compound II-5 provides compound I-1. Upon reaction completion, compound I-1 can be recovered and purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. In addition, further derivatization of the product formed by process outlined in Scheme II can provide additional compounds of Formula I.

[0231] Further derivatization of the compound provided by the steps outlined in Scheme I or Scheme II, or any intermediate, provides additional compounds of Formula I or Formula II. It should be understood that any of the compounds or intermediates shown in Scheme I or Scheme II may be prepared using traditional methods or purchased from commercial sources. In addition, any of the intermediates or any product obtained by the process outlined in Scheme I or Scheme II can be derivatized at any step to provide various compounds of Formula I or Formula II. In certain embodiments, the various substituents of the compounds or intermediates as used in Scheme I or Scheme II are as defined herein (e.g., for Formula I).

[0232] In certain embodiments, provided is a process for providing a compound of Formula I, comprising: 1) contacting a compound of Formula I-1:with a compound of Formula I-2:under conditions sufficient to provide the compound of Formula I; wherein each R, R1, R1a, R1b, R2a, R2b, R3, m, n, and p are independently as defined herein, and L1*is a group comprising L1and a leaving group (e.g., halo, hydroxy, alkoxy, etc.), or L1*is a precursor group to L1. EXAMPLES

[0233] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those skilled in the art that the techniques disclosed in the examples which followAttorney Docket No.78AW-385397-WO represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes of its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1: Synthesis of [1-(2,6-dioxo-3-piperidyl)-2-oxo-1-aza-4-acenaphthenyl]methyl (2- spiro[3.3]heptyl)methanecarbamate (Compound 1):Step 1:

[0234] To a solution of 5-bromo-1H,3H-benzo[de]isochromene-1,3-dione (6.5 g, 23.46 mmol, 1 eq) in pyridine (60 mL) was added hydroxylamine hydrochloride (1.63 g, 23.46 mmol, 1 eq) at 25 °C. The mixture was stirred at 115 °C for 1 hour. TsCl (8.95 g, 46.92 mmol, 2 eq) was added and the mixture was stirred at 115°C for 1 hour. The reaction mixture was poured into water (50 mL). The solid was filtered and the filter cake was washed with saturated NaHCO3 solution (150 mL) and H2O (150 mL). The filter cake was dissolved in EtOH (40 mL) and H2O (50 mL), and then NaOH (1.4 M, 84.5 mL, 5.04 eq) was added. The reaction mixture was stirred at 80 °C for 1 hour. HCl (12 M, 39 mL, 19.95 eq) was added at 75°C. The solid was filtered and was purified by prep-HPLC (column: Phenomenex luna C18250 × 150mm × 15 µm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 25%-55% B over 20.0 min) to give 4-bromobenzo[cd]indol-2(1H)- one.1H NMR (400 MHz, d6-DMSO) δ 10.89 (br s, 1H), 8.45 (s, 1H), 8.16 - 8.09 (m, 1H), 7.91 - 7.79 (m, 1H), 7.58 - 7.49 (m, 1H), 7.10 - 6.98 (m, 1H). Step 2:Attorney Docket No.78AW-385397-WO

[0235] To a solution of NaH (5.32 g, 133.02 mmol, 60%, 10 eq) in THF (200 mL) was added 4- bromobenzo[cd]indol-2(1H)-one (3.3 g, 13.30 mmol, 1 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hours. 3-Bromopiperidine-2,6-dione (17.88 g, 93.12 mmol, 7 eq) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then heated to 60 °C and stirred for 1 hour. The reaction mixture was poured into NH4Cl (sat aq, 100 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 × 150 mL). The combined organic phase was washed with brine (3 × 150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with ethyl acetate to give 3-(4-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione.1H NMR (400 MHz, d6-DMSO) δ 11.15 (br s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 7.69 - 7.53 (m, 2H), 7.21 (d, J = 7.0 Hz, 1H), 5.46 (br dd, J = 5.3, 12.8 Hz, 1H), 3.02 - 2.87 (m, 1H), 2.83 - 2.71 (m, 1H), 2.66 (br d, J = 17.6 Hz, 1H), 2.12 (br dd, J = 5.8, 11.9 Hz, 1H). Step 3:

[0236] To a solution of 3-(4-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (0.65 g, 1.81 mmol, 1 eq), potassium;(tert-butoxycarbonylamino)methyl-trifluoro-boranuide (1.07 g, 4.52 mmol, 2.5 eq) and Cs2CO3(1.77 g, 5.43 mmol, 3 eq) in dioxane (15 mL) and H2O (3 mL) was added cataCXiumA Pd G2 (121.00 mg, 180.97 μmol, 0.1 eq) under N2. The resulting mixture was stirred at 100 °C for 0.5 hours. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 1 to 100% ethyl acetate in petroleum ether) to give tert-butyl ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4- yl)methyl)carbamate.1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 8.09 - 7.97 (m, 2H), 7.67 - 7.59 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 5.44 (br dd, J = 5.3, 12.9 Hz, 1H), 4.41 (br d, J = 6.1 Hz, 2H), 3.29 (s, 1H), 3.01 - 2.88 (m, 1H), 2.82 - 2.73 (m, 1H), 2.66 (br d, J = 16.6 Hz, 1H), 2.10 (td, J = 5.2, 10.4 Hz, 1H), 1.40 (s, 9H).Attorney Docket No.78AW-385397-WO Step 4:

[0237] A solution of tert-butyl ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4- yl)methyl)carbamate (0.35 g, 854.84 μmol, 1 eq) in HCl / dioxane (5 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate to give 3-(4-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione.1H NMR (400 MHz, d6-DMSO) δ 11.14 (s, 1H), 8.51 (br s, 3H), 8.33 (s, 1H), 8.27 (s, 1H), 7.71 - 7.65 (m, 1H), 7.62 - 7.55 (m, 1H), 7.21 (d, J = 7.1 Hz, 1H), 5.47 (dd, J = 5.3, 12.8 Hz, 1H), 4.35 (br d, J = 4.5 Hz, 2H), 3.02 - 2.89 (m, 1H), 2.84 - 2.74 (m, 1H), 2.67 (br d, J = 17.5 Hz, 1H), 2.21 - 2.04 (m, 1H). Step 5:

[0238] To a solution of spiro[3.3]heptan-2-ylmethanol (12.24 mg, 96.99 μmol, 1 eq) and DSC (24.85 mg, 96.99 μmol, 1 eq) in MeCN (1 mL) was added DIEA (31.34 mg, 242.47 μmol, 42.23 μL, 2.5 eq) at 25°C. The mixture was stirred at 25 °C for 1 hour.3-(4-(Aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine- 2,6-dione (30 mg, 96.99 μmol, 1 eq) was added. The mixture was stirred at 25 °C for 1 hour. The residue was purified by prep-HPLC (column: Phenomenex luna C18100 × 40 mm × 3 µm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 45%-75% B over 8.0 min) to give [1-(2,6-dioxo-3-piperidyl)-2-oxo-1-aza-4- acenaphthenyl]methyl (2-spiro[3.3]heptyl)methanecarbamate.1H NMR (400 MHz, d6-DMSO) δ 11.12 (br s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.87 (br t, J = 5.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 5.44 (br dd, J = 5.3, 12.8 Hz, 1H), 4.45 (br d, J = 6.0 Hz, 2H), 3.92 (br d, J = 6.8 Hz, 2H), 3.00 - 2.88 (m, 1H), 2.80 (s, 1H), 2.75 (br dd, J = 4.3, 13.1 Hz, 1H), 2.66 (br d, J = 16.6 Hz, 1H), 2.41 - 2.30 (m, 1H), 2.14 - 2.06 (m, 1H), 2.05 - 1.91 (m, 4H), 1.90 - 1.83 (m, 2H), 1.80 - 1.59 (m, 5H). Example 2: Synthesis of [1-(2,6-dioxo-3-piperidyl)-2-oxo-1-aza-4-acenaphthenyl]methyl (2- spiro[3.5]nonyl)methanecarbamate (Compound 2):Attorney Docket No.78AW-385397-WO

[0239] To a solution of bis(1-imidazolyl)methanone (42.2 mg, 3 eq., 260 µmol) in THF (1 ml) at 0 °C was added (2-spiro[3.5]nonyl)methanol (20.1 mg, 1.5 eq., 130 µmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. A solution of 3-[4-(aminomethyl)-2-oxo-1-aza-1-acenaphthenyl]-2,6- piperidinedione—hydrogen chloride (1 / 1) (30 mg, 1 eq., 86.8 umol), triethylamine (176 mg, 2 eq., 174 µmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (13.2 mg, 1 eq., 86.8 µmol) in DMF (1 ml) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solution was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 0 to 50% 3:1 v / v ethyl acetate:EtOH in heptane) to give purified on silica gel column washed with 0-50% EtOAc-EtOH (3:1) / heptane to give [1-(2,6-dioxo-3-piperidyl)-2-oxo-1-aza-4-acenaphthenyl]methyl (2- spiro[3.5]nonyl)methanecarbamate. m / z (ESI+) 490 (M+H)+.1H NMR (499 MHz, d6-DMSO) δ 11.12 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 1.1 Hz, 1H), 7.88 (t, J = 6.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 7.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 5.44 (dd, J = 12.9, 5.3 Hz, 1H), 4.46 (d, J = 6.1 Hz, 2H), 3.95 (d, J = 6.6 Hz, 2H), 2.95 (ddd, J = 17.5, 13.4, 5.3 Hz, 1H), 2.76 (qd, J = 13.0, 4.4 Hz, 1H), 2.44 (q, J = 7.6 Hz, 1H), 2.13 – 2.06 (m, 1H), 1.76 (t, J = 10.4 Hz, 2H), 1.46 – 1.39 (m, 3H), 1.35 (s, 4H), 1.27 (s, 1H), 1.25 (d, J = 12.8 Hz, 1H). Example 3: Synthesis of 3-(2-oxo-4-{[5-(p-trifluoromethoxyphenyl)-1,3,4-oxadiazol-2-ylamino]methyl}- 1-aza-1-acenaphthenyl)-2,6-piperidinedione (Compound 3):Attorney Docket No.78AW-385397-WOStep 1:

[0240] To a solution p-trifluoroanisic acid (200 mg, 970 mmol) and catalytic amount of DMF in DCM (3 mL) was added oxalyl dichloride (185 mg, 1460 mmol). The reaction mixture was stirred at rt for 1 h, then the solvent and excessive amount of oxalyl dichloride were removed. The resulting residue was dissolved in DCM (3 mL) followed by addition of DCM (0.5 mL) solution of (tert-butyl )carbazate (154 mg, 1160 mmol) and triethylamine (196 mg, 1940 mmol). The reaction mixture was stirred at rt for 1 h, then quenched with water. The reaction mixture was extracted with EtOAc, then washed with 10% citric acid aq., sat. NaHCO3 aq. then brine. The organic layer was dried over Na2SO4and concentrated after filtration. The resulting white solid was dissolved in DCM (3 mL). After TFA (3 mL) was added, the reaction mixture was stirred at room temperature for 40 minutes. The solvent was removed in vacuo and the resulting solid was washed with Heptane / Et2O 1:1, v / v to give hydrazino(p-trifluoromethoxyphenyl)methanone.trifluoroacetic acid. m / z (ESI+) 221 (M+H)+.1H NMR (499 MHz, d6-DMSO) δ 11.16 (s, 1H), 8.03 – 7.91 (m, 2H), 7.57 – 7.50 (m, 2H). Step 2:

[0241] To a solution of hydrazino(p-trifluoromethoxyphenyl)methanone.trifluoroacetic acid (50 mg, 150 mmol) and N-ethylbis(isopropyl)amine (58 mg, 449 mmol) in DCM (2 mL) was added a DCM solution of trichloromethoxytrichloromethylformylate (58 mg, 195 mmol) at 0 °C. The reaction mixture was stirred atAttorney Docket No.78AW-385397-WO room temperature for 1 hour, then quenched with 10% citric acid aq. The reaction mixture was extracted with EtOAc, then washed with brine. The organic layer was dried over Na2SO4and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 50 to 100% ethyl acetate in heptane) to give 5-(p-trifluoromethoxyphenyl)-1,3,4-oxadiazol-2(3H)-one.1H NMR (499 MHz, d6-DMSO) δ 7.95 – 7.88 (m, 2H), 7.62 – 7.51 (m, 2H). Step 3:

[0242] To a solution of 3-[4-(aminomethyl)-2-oxo-1-aza-1-acenaphthenyl]-2,6-piperidinedione.hydrogen chloride (20 mg, 57 mmol), 1H-1,2,3-benzotriazol-1-yloxytridimethylaminophosphonium hexafluoridophosphate (50 mg, 114 mmol) and 5-(p-trifluoromethoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (14 mg, 57 mmol) in DMF (2 mL) was added N-ethylbis(isopropyl)amine (22 mg, 171 mmol). The reaction mixture was stirred at room temperature for 2 days, then quenched with water. The reaction mixture was extracted with EtOAc, then washed with brine. The organic layer was dried over Na2SO4and concentrated in vacuo to give a residue. The residue was purified by trituration with EtOAc, DCM and MeOH to give 3-(2- oxo-4-{[5-(p-trifluoromethoxyphenyl)-1,3,4-oxadiazol-2-ylamino]methyl}-1-aza-1-acenaphthenyl)-2,6- piperidinedione. m / z (ESI+) 538 (M+H)+.1H NMR (499 MHz, DMSO) δ 11.12 (s, 1H), 8.64 (t, J = 6.2 Hz, 1H), 8.24 (d, J = 1.1 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 5.44 (dd, J = 13.0, 5.5 Hz, 1H), 4.76 (d, J = 6.0 Hz, 2H), 2.99 – 2.89 (m, 2H), 2.81 – 2.69 (m, 2H). Example 4: Synthesis of 3-[2-oxo-4-({5-(2-spiro[3.3]heptyl)-1,3,4-oxadiazol-2-ylamino}methyl)-1-aza-1- acenaphthenyl]-2,6-piperidinedione (Compound 4):Attorney Docket No.78AW-385397-WO Step 1:

[0243] To a solution 2-spiro[3.3]heptanecarboxylic acid (300 mg, 2.14 mmol) and catalytic amount of DMF in DCM (3 mL) was added oxalyl dichloride (407 mg, 3.21 mmol). The reaction mixture was stirred at room temperature for 4 hours, then the solvent and excessive amount of oxalyl dichloride were removed in vacuo to give a residue. The residue was dissolved in DCM (3 mL) followed by addition of DCM (0.5 mL) solution of (tert-butyl )carbazate (339 mg, 2.57 mmol) and triethylamine (433 mg, 4.28 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then quenched with water. The reaction mixture was extracted with EtOAc, then washed with 10% citric acid aq., sat. NaHCO3 aq. then brine. The organic layer was dried over Na2SO4and concentrated in vacuo. The resulting white solid was dissolved in DCM (3 mL). After TFA (2 mL) was added, the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give hydrazino(2-spiro[3.3]heptyl)methanone.trifluoroacetic acid.1H NMR (499 MHz, d6-DMSO) δ 10.63 (s, 1H), 2.18 – 2.11 (m, 1H), 2.13 (s, 2H), 2.14 – 2.05 (m, 2H), 2.08 – 1.97 (m, 2H), 1.87 (dd, J = 8.6, 5.9 Hz, 2H), 1.82 – 1.70 (m, 2H). Step 2:

[0244] To a solution of hydrazino(2-spiro[3.3]heptyl)methanone—trifluoroacetic acid (1 / 1) (450 mg, 1680 mmol) and N-ethylbis(isopropyl)amine (1300 mg, 10.1 mmol) in DCM (6 mL) was added DCM solution of trichloromethoxytrichloromethylformylate (647 mg, 2.18 mmol) at -78 C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 10% citric acid aq. then extracted with EtOAc, then washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 30 to 100% ethyl acetate in heptane) to give 5-(2-spiro[3.3]heptyl)-1,3,4-oxadiazol-2(3H)-one.1H NMR (499 MHz, d6-DMSO) δ 12.04 (s, 1H), 3.25 (p, J = 8.4 Hz, 1H), 2.29 (ddt, J = 11.6, 8.2, 1.6 Hz, 2H), 2.22 – 2.14 (m, 2H), 2.09 – 1.96 (m, 2H), 1.94 – 1.83 (m, 2H), 1.83 – 1.71 (m, 2H). Step 3:Attorney Docket No.78AW-385397-WO

[0245] To a solution of 3-[4-(aminomethyl)-2-oxo-1-aza-1-acenaphthenyl]-2,6-piperidinedione— hydrogen chloride (1 / 1) (33 mg, 95 mmol), 1H-1,2,3-benzotriazol-1-yloxytridimethylaminophosphonium hexafluoridophosphate (84 mg, 191 mmol) and 5-(2-spiro[3.3]heptyl)-1,3,4-oxadiazol-2(3H)-one (43 mg, 239 mmol) in DMF (2 mL) was added N-ethylbis(isopropyl)amine (49 mg, 382 mmol). The reaction mixture was stirred at 40 °C overnight, then quenched with water. The reaction mixture was extracted with EtOAc, then washed with brine. The organic layer was dried over Na2SO4and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 50 to 100% ethyl acetate in heptane) to give 3-[2-oxo-4-({5-(2-spiro[3.3]heptyl)-1,3,4-oxadiazol-2-ylamino}methyl)-1-aza-1-acenaphthenyl]-2,6- piperidinedione. m / z (ESI+) 472 (M+H)+.1H NMR (499 MHz, d6-DMSO) δ 11.12 (s, 1H), 8.20 – 8.14 (m, 2H), 8.10 (s, 1H), 7.65 (t, J = 9.4 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.13 (t, J = 6.6 Hz, 1H), 5.43 (s, 1H), 4.63 (d, J = 6.2 Hz, 2H), 3.41 – 3.34 (m, 2H), 2.93 (d, J = 12.0 Hz, 2H), 2.75 (d, J = 13.4 Hz, 1H), 2.67-1.86 (m, 10H). Example 5: Synthesis of [1-(2,6-dioxo-3-piperidyl)-2-oxo-1-aza-5-acenaphthenyl]methyl (2- spiro[3.3]heptyl)methanecarbamate (Compound 5):Step 1:

[0246] To a solution of 1,5-dibromonaphthalene (10 g, 34.97 mmol, 1 eq), 2-chloroacetyl chloride (8.69 g, 76.93 mmol, 6.13 mL, 2.2 eq) in DCE (10 mL) was added AlCl3(11.98 g, 89.87 mmol, 4.91 mL, 2.57 eq) atAttorney Docket No.78AW-385397-WO 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into ice water (50mL), diluted with water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 0 to 10% ethyl acetate in petroleum ether) to give 2-chloro-1-(4,8-dibromonaphthalen-1-yl)ethan-1-one (8 g, 63%).1H NMR (400 MHz, d6-DMSO) δ 8.37 (d, J = 8.6 Hz, 1H), 8.10 (dd, J = 7.8, 9.8 Hz, 2H), 7.69 (t, J = 8.1 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 5.05 (s, 2H). Step 2:

[0247] To a solution of 2-chloro-1-(4,8-dibromonaphthalen-1-yl)ethan-1-one (8 g, 22.07 mmol, 1 eq) in H2SO4(80 mL) was added NaNO2(1.60 g, 23.18 mmol, 0.01 mL, 1.05 eq) at 0 °C. The mixture was stirred at 65 °C for 2 hours. The reaction mixture was quenched with water (20 mL) at 0 °C, filtered and concentrated under reduced pressure to give 4,8-dibromo-1-naphthoic acid (4 g, 55%) which was used for next step directly without purification.1H NMR (400 MHz, d6-DMSO) δ 13.64 - 13.09 (m, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.71 - 7.53 (m, 2H). Step 3:

[0248] To a solution of 4,8-dibromo-1-naphthoic acid (4 g, 12.12 mmol, 1 eq) in NH3.H2O (60 mL) was added Cu (231.10 mg, 3.64 mmol, 25.79 μL, 0.3 eq). The mixture was stirred at 80°C for 3 hours. 1M HCl (2 mL) was added, washed with MeOH, filtered and concentrated under reduced pressure to give 5- bromobenzo[cd]indol-2(1H)-one (2.5 g, 83%) which was used for next step directly without purification.1H NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.69 - 7.58 (m, 1H), 7.57 - 7.50 (m, 1H), 7.06 (d, J = 7.0 Hz, 1H). Step 4:Attorney Docket No.78AW-385397-WO

[0249] To a solution of 5-bromobenzo[cd]indol-2(1H)-one (500 mg, 2.02 mmol, 1 eq) in THF (10 mL) was added NaH (2.42 g, 60.47 mmol, 40.31 μL, 60% purity, 30 eq) at 0 °C under N2, after addition, the mixture was stirred at 25 °C for 30 minutes. 3-bromopiperidine-2,6-dione (2.71 g, 14.11 mmol, 7 eq) in THF (5 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 60 °C for 1 hour under N2. Saturated aqueous ammonium chloride solution (10 mL) was added, and the aqueous layer extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc (3 mL). After filteration, the filter cake was collected to give 3-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6- dione (200 mg, 28%).1H NMR (400 MHz, d6-DMSO) δ 11.24 - 11.01 (m, 1H), 8.13 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.78 - 7.54 (m, 2H), 7.26 (d, J = 6.8 Hz, 1H), 5.46 (dd, J = 5.4, 12.9 Hz, 1H), 3.00 - 2.88 (m, 1H), 2.80 - 2.65 (m, 2H), 2.18 - 2.05 (m, 1H) Step 5:

[0250] To a solution of 3-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (200 mg, 556.83 μmol, 1 eq) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (275.59 mg, 1.39 mmol, 2.5 eq) in dioxane (6 mL) and H2O (0.8 mL) was added Cs2CO3 (544.28 mg, 1.67 mmol, 3 eq). CataCXiumA Pd G2 (37.23 mg, 55.68 μmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 30 minutes under N2. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5- yl)methyl)carbamate which was used in the next step directly without purification. m / z (ESI+) 353.8 (M+H)+. Step 6:Attorney Docket No.78AW-385397-WO

[0251] To a solution of tert-butyl ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5- yl)methyl)carbamate (390 mg, 952.53 μmol, 1 eq) in DCM (10 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 14.13 eq). The mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150 mm × 25 mm × 5 µm; mobile phase: [water (TFA)-ACN]; gradient: 0% - 20% B over 10 min) to give 3-(5-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (104 mg, 26% yield, TFA).1H NMR (400 MHz, d6-DMSO) δ 11.14 (s, 1H), 8.40 (br s, 2H), 8.20 (d, J = 7.1 Hz, 1H), 7.96 - 7.77 (m, 2H), 7.67 - 7.59 (m, 1H), 7.23 (d, J = 7.3 Hz, 1H), 5.47 (dd, J = 5.3, 12.8 Hz, 1H), 4.64 (s, 2H), 3.00 - 2.90 (m, 1H), 2.85 - 2.74 (m, 1H), 2.71 - 2.61 (m, 1H), 2.16 - 2.00 (m, 1H). Step 7:

[0252] To a solution of spiro[3.3]heptan-2-ylmethanol (29.81mg, 236.21 μmol, 2 eq) in THF (1 mL) was added triphosgene (110.15 mg, 735.34 μmol, 3 eq) and DIEA (90.15 mg, 0.71 mmol, 246.87 μL, 6 eq). 3-(5- (aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (50 mg, 118.11 μmol, 1 eq, TFA) was added. The mixture was stirred at 70 °C for 2 hours. Saturated NaHCO3 solution (5 mL) was added at 0 °C, and then diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150 mm × 25 mm × 5 µm; mobile phase: [water (TFA)-ACN]; gradient: 0% - 20% B over 10 min) give [1-(2,6-dioxo-3-piperidyl)-2- oxo-1-aza-5-acenaphthenyl]methyl (2-spiro[3.3] heptyl)methanecarbamate (22.28 mg, 41%).1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.89 (br t, J = 5.9 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.16 (d, J = 7.3 Hz, 1H), 5.44 (dd, J = 5.1, 13.0 Hz, 1H), 4.72 (br d, J = 5.8 Hz, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.02 - 2.89 (m, 1H), 2.82 - 2.61 (m, 2H), 2.39 - 2.30 (m, 1H), 2.20 - 1.91 (m, 5H), 1.89 - 1.82 (m, 2H), 1.78 - 1.63 (m, 4H).

[0253] Additional compounds of Table 1 were prepared following the procedures set forth above using the appropriate starting materials. Select data is set forth in the table below.Attorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOAttorney Docket No.78AW-385397-WOBiological Assay CDK2 degradation assay

[0254] HiBiT- CDK2 HEK293T cells were harvested ca.75% confluent with trypsin and plated (500,000 cells / well) in a 6-well tissue culture plate in 2 mL of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.

[0255] Representative compounds were evaluated for their ability to degrade CDK2 in the following assay. The CDK2 degradation assays were carried out by harvesting the HiBiT- CDK2 HEK293T reporter cell lines and resuspending the cells in media formulated for reduced background fluorescence. The respective cell lines were seeded at a density of 4,000 cells / well into 384 well white opaque TC plates (Greiner 781080-20). The cells were incubated overnight to allow for attachment to the assay plate (37°C with humidified air and 5% CO2 for all incubations). Dilutions of the compounds were prepared in dimethyl sulfoxide (DMSO) from 10 mM compound stock solutions in DMSO. The assay plates were treated withAttorney Docket No.78AW-385397-WO appropriate concentrations of the compounds by dispensing the DMSO dilutions in quadruplicate wells with an upper limit of 0.5% final DMSO. After a 6-hour incubation with the compounds. HiBiT lytic buffer, 1:100 LgBiT and 1:50 HiBiT were added at 30 μL / well, and plates were incubated at room temperature for 2 hours covered with foil. Images were acquired using the ClarioStar plate reader system (cells maintained at 37 °C during imaging). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose-response curves and calculation of degradation DC50s (GraphPad Prism). Table 3 shows results from the assay described above. The percent degradation amounts were calculated visually from the curves generated at a concentration of 1 and 10 micromolar. Table 3Attorney Docket No.78AW-385397-WO

Claims

Attorney Docket No.78AW-385397-WO CLAIMS:

1. A compound of Formula I,or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: L1is a bond, -, or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-; n is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; R is hydrogen, deuterium, or fluorine, each R1is independently halo, cyano, -OH, -NH2, -N(C1-3 alkyl)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy; each R1aand R1bis independently hydrogen, halo, -OH, or C1-6alkyl; or R1aand R1btogether with the carbon atom attached thereto form a C3-6 membered cycloalkyl; each R2aand R2bis independently hydrogen, halo, -OH, or C1-6alkyl; or R2aand R2btogether with the carbon atom attached thereto form a C3-6 cycloalkyl; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -N(R7)2, -OR7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -NR7C(O)OR7, -S(O)0-2R7, -NR7S(O)0-2R7, -S(O)0-2N(R7)2, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5;Attorney Docket No.78AW-385397-WO each R5is independently selected from halo, cyano, -OR8, -N(R8)2, -NO2, -SF5, -C(O)R8, -C(O)OR8, -C(O)N(R8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6 alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, hydroxy, -SH, -NH2, -N(C1-6 alkyl)2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-4-10 membered heterocyclyl, -L-C6-10aryl, or -L-5-10 membered heteroaryl; and each L is independently -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHS(O)-, -S(O)2NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -NHC(O)NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O-, -P(O)(O-C2-6alkynyl)O-, or -P(O)(O-C1-6 haloalkyl)O-; and wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl of Z1is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; provided that the compound is not: 3-[4-[[(2-furanylmethyl)amino]methyl]-2-oxobenz[cd]indol-1(2H)-yl]-2,6-piperidinedione (CAS No.2767646-92-2); 1,1-dimethylethyl N-[[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]methyl]carbamate (CAS No.2767589-31-9); or 1,1-dimethylethyl N-[3-[1-(2,6-dioxo-3-piperidinyl)-1,2-dihydro-2-oxobenz[cd]indol-4- yl]propyl]carbamate (CAS No.2912305-19-0).

2. The compound of claim 1, wherein R is hydrogen.Attorney Docket No.78AW-385397-WO 3. The compound of claim 1 or 2, wherein L1is a bond, -C(O)-, -NHS(O)2NH-,, , or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-.

4. The compound of claim 1 or 2, wherein L1is a bond.

5. The compound of claim 1 or 2, wherein L1is a 5-6 membered heteroaryl.

6. The compound of any preceding claim, wherein n is 1.

7. The compound of any preceding claim, wherein m is 0 or 1.

8. The compound of any preceding claim, wherein p is 1.

9. The compound of claim 8, wherein R1is halo.

10. The compound of any one of claims 1-7, wherein p is 0.

11. The compound of any preceding claim, wherein each R1aand R1bis independently hydrogen.

12. The compound of any preceding claim, wherein each R2aand R2bis independently hydrogen, halo, or C1-6alkyl.

13. The compound of any preceding claim, wherein R3is C1-6alkyl, -N(R7)2, -C(O)R7, -NR7C(O)OR7, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein each C1-6 alkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5.

14. The compound of any preceding claim, wherein each R5is independently selected from halo, cyano, -OR8, -SF5, -C(O)OR8, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1.

15. The compound of any preceding claim, wherein each R7is independently hydrogen, C1-6 alkyl, or C6-10aryl; wherein each C1-6alkyl or C6-10aryl is independently optionally substituted with one to five Z1.

16. The compound of any preceding claim, wherein each R8is independently hydrogen or C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to three halo.

17. The compound of any preceding claim, wherein each Z1is independently halo, C3-15cycloalkyl, 4-10 membered heterocyclyl, or -O-C1-6 alkyl; wherein the heterocyclyl of Z1is further independently optionally substituted with C1-6alkyl.Attorney Docket No.78AW-385397-WO 18. A compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof, selected from Table 1 or Table 2.

19. A pharmaceutical composition comprising the compound of any one of claims 1-18, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

20. A method for treating a disease or condition mediated, at least in part, by CDK2, or a disease characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2), or both CCNE1 and CCNE2, the method comprising administering an effective amount of the compound of any one of claims 1-18, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, or the pharmaceutical composition of claim 19, to a subject in need thereof.

21. The method of claim 20, wherein the disease or condition is cancer.

22. The method of claim 21, wherein the cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1).

23. The method of claim 22, wherein the cancer is uterine cancer, breast cancer, ovarian cancer, pancreatic cancer, bladder cancer, gastric cancer, esophageal cancer, lung cancer, or sarcoma.

24. A method for treating a tumor in a subject, comprising administering an effective amount of the compound of any one of claims 1-18, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, or the pharmaceutical composition of claim 19, to a subject in need thereof.

25. A method for treating an estrogen receptor-positive (ER+) breast cancer in a subject, comprising administering an effective amount of the compound of any one of claims 1-18, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, or the pharmaceutical composition of claim 19, to a subject in need thereof.

26. The cancer of claim 25, wherein the cancer is ER+ / HER2-negative advanced breast cancer.

27. The cancer of claim 25 or 26, wherein the cancer is resistant to CDK4 / 6 inhibitors.

28. The method of any one of claims 20-27, further comprising administering to the subject one or more additional therapy or therapeutic agent.

29. The method of claim 28, wherein the one or more additional therapy or therapeutic agent is selected from a CDK4 inhibitor, a CDK4 / 6 inhibitor, a SERD, and a SERM.

30. The method of claim 29, wherein the one or more additional therapy or therapeutic agent is selected from fulvestrant, tomoxifen, Raloxifene, and Toremifene.Attorney Docket No.78AW-385397-WO 31. A process for providing a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: L1is a bond, -, or a 5-6 membered heteroaryl; wherein a denotes attachment to the -NH-; n is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; R is hydrogen, deuterium, or fluorine, each R1is independently halo, cyano, -OH, -NH2, -N(C1-3 alkyl)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy; each R1aand R1bis independently hydrogen, halo, -OH, or C1-6alkyl; or R1aand R1btogether with the carbon atom attached thereto form a C3-6 membered cycloalkyl; each R2aand R2bis independently hydrogen, halo, -OH, or C1-6 alkyl; or R2aand R2btogether with the carbon atom attached thereto form a C3-6cycloalkyl; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -N(R7)2, -OR7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -NR7C(O)OR7, -S(O)0-2R7, -NR7S(O)0-2R7, -S(O)0-2N(R7)2, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10aryl, 4-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted with one to three R5; each R5is independently selected from halo, cyano, -OR8, -N(R8)2, -NO2, -SF5, -C(O)R8, -C(O)OR8, -C(O)N(R8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 memberedAttorney Docket No.78AW-385397-WO heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl; wherein each C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally substituted with one to five Z1; each R8is independently hydrogen or C1-6 alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, hydroxy, -SH, -NH2, -N(C1-6 alkyl)2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-4-10 membered heterocyclyl, -L-C6-10aryl, or -L-5-10 membered heteroaryl; and each L is independently -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHS(O)-, -S(O)2NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -NHC(O)NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O-, -P(O)(O-C2-6alkynyl)O-, or -P(O)(O-C1-6 haloalkyl)O-; and wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl of Z1is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; comprising: 1) contacting a compound of Formula I-1:with a compound of Formula I-2:Attorney Docket No.78AW-385397-WOunder conditions sufficient to provide the compound of Formula I; wherein L1*is a group comprising L1and a leaving group, or L1*is a precursor group to L1.

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