DEGRADERS OF CYCLIN-DEPENDENT KINASE 12 (CDK12) AND USES THEREOF

Abstract

Provided herein are bifunctional compounds with a moiety (e.g., lenalidomide, thalidomide) that is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and another moiety that is a binder of a target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) to induce degradation of the target protein CDK9 and/or CDK12. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer))). Provided also are methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))), and methods of inducing apoptosis in a cell in a biological sample or subject by administering the bifunctional compound or composition described herein.

##STR00001##

Claims

1. A compound of Formula (I): ##STR00231## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: each instance of R.sup.1 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR.sup.D1, —N(R.sup.D1a).sub.2, or —SR.sup.D1; wherein R.sup.D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; wherein each occurrence of R.sup.D1a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R.sup.D1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each instance of R.sup.2 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR.sup.D1, —N(R.sup.D1a).sub.2, or —SR.sup.D1; R.sup.3 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; each instance of R.sup.X is independently halogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; each instance of R.sup.Y is independently halogen, optionally substituted acyl, optionally substituted alkyl, —SO.sub.2R.sup.Y1, —P(═O)(R.sup.Y2).sub.2, —OR.sup.Y1; or —N(R.sup.Y2).sub.2; R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to a oxygen atom; each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom; w is 0, 1, 2, 3, 4, 5, or 6; w1 is 0, 1, 2, 3, 4, or 5; x is 0, 1, or 2; y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; L1 is a bond, optionally substituted alkylene, —NR.sup.A—, —O—, or —S—; wherein R.sup.A is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; L2 is a linker; Ring A is of formula: ##STR00232## and D is an E3 ubiquitin ligase binding moiety.

2.-3. (canceled)

4. The compound of claim 1, wherein the compound is of formula: ##STR00233## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

5. The compound of claim 1, wherein the compound is of formula: ##STR00234## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

6. The compound of claim 1, wherein the compound is of formula: ##STR00235## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1 wherein R.sup.Y1 is optionally substituted C.sub.1-C.sub.6 alkyl, —C(═O)N(R.sup.y3).sub.2, or wherein each instance of R.sup.y3 is independently hydrogen or optionally substituted alkyl, or —P(═O)(R.sup.Y2).sub.2 wherein each instance of R.sup.Y2 is optionally substituted C.sub.1-C.sub.6 alkyl.

7. The compound of any one of claim 1, wherein the compound is of formula: ##STR00236## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1 wherein R.sup.Y1 is optionally substituted C.sub.1-C.sub.6 alkyl, —C(═O)N(R.sup.y3).sub.2 wherein each instance of R.sup.y3 is independently hydrogen or optionally substituted alkyl, or —P(═O)(R.sup.Y2).sub.2 wherein each instance of R.sup.Y2 is optionally substituted C.sub.1-C.sub.6 alkyl.

8.-14. (canceled)

15. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula: ##STR00237## wherein: X.sup.A is C(O) or C(R.sup.3A).sub.2; each R.sup.1A is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; each R.sup.3A is independently H or C.sub.1-C.sub.3 alkyl; each R.sup.3′ is independently C.sub.1-C.sub.3 alkyl; each R.sup.4A is independently H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; R.sup.5A is H, C.sub.1-C.sub.3 alkyl, or halogen; m is 0, 1, 2 or 3; n is 0, 1, or 2; and a1 is 0 or 1.

16.-22. (canceled)

23. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula: ##STR00238## wherein: —X.sup.1—X.sup.2— is —C(R.sup.3A)═N— or —C(R.sub.3A).sub.2—C(R.sup.3A).sub.2—; each R.sup.1A is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; R.sup.3A is H or C.sub.1-C.sub.3 alkyl; each R.sup.3′ is independently C.sub.1-C.sub.3 alkyl; each R.sup.4A is independently H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; R.sup.5A is H, C.sub.1-C.sub.3 alkyl, or halogen; m is 0, 1, 2, or 3; n is 0, 1, or 2; and a1 is 0 or 1.

24. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula: ##STR00239##

25. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula: ##STR00240## wherein: each R.sup.2′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; each R.sup.4′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; each R.sup.5′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; n1′ is 0, 1, 2, 3, 4, 5, or 6; n2′ is 0, 1, 2, 3, or 4; and n3′ is 0, 1, or 2.

26.-28. (canceled)

29. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula: ##STR00241##

30. The compound of claim 1, wherein the compound is of formula: ##STR00242## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R.sup.1 is halogen, optionally substituted C.sub.1-6 alkyl, —CF.sub.3, or —CN.

31. (canceled)

32. The compound of claim 1, wherein the compound is of formula: ##STR00243## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R.sup.1 is halogen, optionally substituted C.sub.1-6 alkyl, —CF.sub.3, or —CN.

33.-53. (canceled)

54. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L2 is: ##STR00244## ##STR00245## l.sup.R indicates the point of attachment to D, and l.sup.A indicates the point of attachment to the moiety of formula ##STR00246## n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6.

55.-66. (canceled)

67. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L2 is of the formula: ##STR00247## ##STR00248##

68. (canceled)

69. The compound of claim 1, wherein the compound is of the formula: ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

70.-71. (canceled)

72. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

73.-74. (canceled)

75. A method of treating a disease mediated by CDK9 and/or CDK12 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

76. The method of claim 75, wherein the disease is cancer.

77. (canceled)

78. The method of claim 76, wherein the cancer is ovarian cancer, breast cancer, or prostate cancer.

79.-84. (canceled)

85. A method of inducing the degradation of CDK9 and/or CDK12 in a cell, tissue, or biological sample, the method comprising: contacting the cell, tissue, or biological sample with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

86.-92. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] FIGS. 1-3 show the degradation rescued by pre-treatment with Carfilzomib and exemplary CDK12 irreversible inhibitor, THZ-5-31

##STR00013##

[0106] FIG. 1 shows the levels of CDK12, CDK13, and CDK9 as well as GAPDH in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells that are Jurkat (human T-lymphocyte cells) and Molt 4 cells (human Acute Lymphoblastic Leukemia cells). The degradation of CDK12, CDK13, CDK9 was rescued by 2 hour pre-treatment with exemplary CDK12 inhibitor THZ-5-31, exemplary protease inhibitor Carfilzomib (CFZ), thalidomide (Thal.) and MLN4924 (inhibitor of NEDD8-Activating Enzyme (NAE)) at the indicated concentrations before treatment with exemplary CDK12 inhibitor BSJ-0423 (BSJ-04-023) at 250 nM for 6 hours. BSJ-04-023 is of formula:

##STR00014##

and BSJ-04-026 is of

[0107] ##STR00015##

[0108] FIG. 2 shows the levels of CDK12, CDK13, and CDK9 as well as GAPDH in T-ALL Jurkat cells. Cells treated with DMSO or exemplary CDK12 degrader BSJ-0423 (BSJ-04-023) at 250 nM were collected and examined with Western blots at the indicated time points.

[0109] FIG. 3 shows the dose-dependent inhibitory antiproliferation activity (IC.sub.50) after treatment with exemplary CDK12 inhibitor THZ-5-31, and CDK12 degrader BSJ-04-023 at the indicated concentrations in T-ALL Jurkat cells with CRBN knockout (—/—) and without CRBN knockout (wt). CRBN knockout imparts ˜10× resistance to BSJ-0423, but not THZ-5-31, which demonstrates the activity of BSJ-04-023 in Jurkat cells (wt) is CRBN dependent.

[0110] FIG. 4A shows the levels of CDK12 and CDK13, as well as GAPDH in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells that are Jurkat (human T-lymphocyte cells). Cells treated with DMSO or with the CDK12 degraders BSJ-04-023, BSJ-04-071, BSJ-04-076, BSJ-04-077, BSJ-04-078, BSJ-04-079, and BSJ-04-100 at the indicated concentrations were collected and examined with Western blots at 6 hours.

[0111] FIG. 4B shows the levels of CDK12 and CDK13, as well as GAPDH in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells that are Jurkat (human T-lymphocyte cells). Cells treated with DMSO or with the CDK12 degraders BSJ-04-023, BSJ-04-086, BSJ-04-089, BSJ-04-098, BSJ-04-099, and BSJ-04-100 at the indicated concentrations were collected and examined with Western blots at 6 hours.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0112] The bifunctional compounds described herein interact with a target (e.g., a kinase, e.g., CDK, such as CDK9, CDK12) and an E3 ubiquitin ligase (e.g., Cereblon). As described herein, without wishing to be bound by any particular theory, the therapeutic effect may be the result of degradation, modulation, inhibition, or binding of a target (e.g., kinase (e.g., CDK (e.g., CDK9, CDK12))) by a compound described herein. The therapeutic effect may be a result of the bifunctional compound, which includes a binder of an E3 ubiquitin ligase (e.g., Cereblon) and a binder of a target (e.g., kinase (e.g., CDK (e.g., CDK9, CDK12))), thereby inducing the degradation of the target protein. The compounds may be used to induce degradation of the target (e.g., kinase (e.g., CDK (e.g., CDK9, CDK12))), for treating and/or preventing diseases (e.g., proliferative diseases, such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer)), for treating and/or preventing diseases associated with the target (e.g., a kinase (e.g., CDK (e.g., CDK9, CDK12))), and/or inducing apoptosis in a cell in a biological sample or subject.

[0113] In one aspect, disclosed are compounds of Formula (I):

##STR00016##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:

[0114] each instance of R.sup.1 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR.sup.D1, —N(R.sup.D1a).sub.2, or —SR.sup.D1; wherein R.sup.D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0115] wherein each occurrence of R.sup.D1a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R.sup.D1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0116] each instance of R.sup.2 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR.sup.D1, —N(R.sup.D1a).sub.2, or —SR.sup.D1;

[0117] R.sup.3 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;

[0118] each instance of R.sup.X is independently halogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;

[0119] each instance of R.sup.Y is independently halogen, optionally substituted acyl, optionally substituted alkyl, —SO.sub.2R.sup.Y1, —P(═O)(R.sup.Y2).sub.2, —OR.sup.Y1; or —N(R.sup.Y2).sub.2;

[0120] R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to a oxygen atom;

[0121] each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom;

[0122] w is 0, 1, 2, 3, 4, 5, or 6;

[0123] w1 is 0, 1, 2, 3, 4, or 5;

[0124] x is 0, 1, or 2;

[0125] y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0126] L1 is a bond, optionally substituted alkylene, —NR.sup.A—, —O—, or —S—; wherein R.sup.A is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;

[0127] L2 is a linker;

[0128] Ring A is of formula:

##STR00017##

and

[0129] D is an E3 ubiquitin ligase binding moiety.

Group D

[0130] In certain embodiments, D is an E3 ubiquitin ligase binding moiety. D includes all moieties that bind, or can bind, any E3 ubiquitin ligase. For example, in certain embodiments, D is capable of binding an E3 ubiquitin ligase, such as Cereblon. In certain embodiments, D is capable of binding to multiple different E3 ubiquitin ligases. In certain embodiments, D binds to Cereblon. In certain embodiments, D is based on an immunomodulatory imide drug. In certain embodiments, D is derived from lenalidomide. In certain embodiments, D is derived from thalidomide.

[0131] Human Cereblon (CRBN) is a protein of 442 amino acids with an apparent molecular weight of ˜51 kDa (GenBank: AAH17419). (For the CRBN protein sequence see: Higgins et al., Neurology. 2004, 63, 1927-31. For additional information related to the CRBN structure, see Hartmann et al., PLoS One. 2015, 10, e0128342.) Human CRBN contains the N-terminal part (237-amino acids from 81 to 317) of ATP-dependent Lon protease domain without the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites. CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocyte, colon, brain, and retina. CRBN is located in the cytoplasm, nucleus, and peripheral membrane. (Chang et al., Int. J. Biochem. Mol. Biol. 2011, 2, 287-94.)

[0132] Cereblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as limb and auditory vesicle formation.

[0133] In certain embodiments, D is a modulator, binder, inhibitor, or ligand of Cereblon. In certain embodiments, D is a modulator of Cereblon. In certain embodiments, D is a binder of Cereblon. In certain embodiments, D is an inhibitor of Cereblon. In certain embodiments, D is a ligand of Cereblon. In certain embodiments, D is any modulator, binder, inhibitor, or ligand of Cereblon disclosed in U.S. patent application U.S. Ser. No. 14/792,414, filed Jul. 6, 2015, U.S. patent application U.S. Ser. No. 14/707,930, filed May 8, 2015, and International Patent Application, PCT/US2013/054663, filed Aug. 13, 2013, each of which is incorporated herein by reference. In certain embodiments, D has a binding affinity (K) to Cereblon of about 1-10 μM. In certain embodiments, D has a K.sub.d to Cereblon of about 3 μM. In certain embodiments, D has a binding affinity (K.sub.d) to Cereblon as disclosed in U.S. patent application U.S. Ser. No. 14/792,414, filed Jul. 6, 2015.

[0134] In certain embodiments, D is a modulator, binder, inhibitor, or ligand of a Cereblon variant. In certain embodiments, D is a modulator, binder, inhibitor, or ligand of a Cereblon isoform.

[0135] In certain embodiments, D comprises an optionally substituted heteroaryl ring. In certain embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring. In certain embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocyclic ring. In certain embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocyclic ring, where the heterocyclic ring contains at least one nitrogen. In certain embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocyclic ring, where the fused bicyclic heteroaryl ring and heterocyclic ring each contain at least one nitrogen. In certain embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocyclic ring, where the fused bicyclic heteroaryl ring and heterocyclic ring each contain one nitrogen. In certain embodiments, D comprises an optionally substituted phthalimido group, or an analogue or derivative thereof. In certain embodiments, D comprises an optionally substituted phthalimido-glutarimide group, or an analogue or derivative thereof.

[0136] In certain embodiments, D is of Formula (E-I):

##STR00018##

wherein:

[0137] Ring A is a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl ring;

[0138] each R.sup.1A is, independently, halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0139] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;

[0140] each R.sup.3′ is, independently, C.sub.1-C.sub.3 alkyl;

[0141] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

[0142] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl;

[0143] m is 0, 1, 2, or 3; and

[0144] n is 1 or 2.

[0145] In certain embodiments, Formula (E-I) is derived from an immunomodulatory imide drug (e.g., derived from lenalidomide or thalidomide). In certain embodiments, Formula (E-I) is of Formula (IA) or Formula (IB). In certain embodiments, the compounds of Formula (IA) or Formula (IB) are optionally further substituted.

[0146] In certain embodiments, D is of Formula (IA):

##STR00019##

wherein:

[0147] X.sup.A is C(O) or C(R.sup.3A).sub.2;

[0148] each R.sup.1A is independently halogen, —OH. C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0149] R.sup.3A is H or C.sub.1-C.sub.3 alkyl;

[0150] each R.sup.3′ is independently C.sub.1-C.sub.3 alkyl;

[0151] each R.sup.4A is independently H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

[0152] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, or halogen;

[0153] m is 0, 1, 2, or 3;

[0154] n is 0, 1 or 2; and

[0155] a1 is 0 or 1.

[0156] In certain embodiments, D is of Formula (IA-a):

##STR00020##

wherein:

[0157] X.sup.A is C(O) or C(R.sup.3A).sub.2;

[0158] each R.sup.1A is, independently, halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0159] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

[0160] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl; and

[0161] m is 0, 1, 2, or 3.

[0162] In certain embodiments, D is of Formula (IA-b):

##STR00021##

wherein:

[0163] X.sup.A is C(O) or C(R.sup.3A);

[0164] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and

[0165] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl.

[0166] In certain embodiments, D is of Formula (IA-c):

##STR00022##

wherein:

[0167] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and

[0168] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl.

[0169] In certain embodiments, D is of Formula (IA-d):

##STR00023##

wherein:

[0170] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and

[0171] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl.

[0172] In certain embodiments, D is of Formula (IB):

##STR00024##

wherein:

[0173] —X.sup.1—X.sup.2— is C(R.sup.3A)═N or C(R.sub.3A).sub.2—C(R.sup.3A).sub.2;

[0174] each R.sup.1A is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0175] R.sup.3A is H or C.sub.1-C.sub.3 alkyl;

[0176] each R.sup.3′ is independently C.sub.1-C.sub.3 alkyl;

[0177] each R.sup.4A is independently H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

[0178] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, or halogen;

[0179] m is 0, 1, 2, or 3;

[0180] n is 0, 1, or 2; and

[0181] a1 is 0 or 1.

[0182] In certain embodiments, D is of Formula (IB-a):

##STR00025##

wherein:

[0183] X.sup.1-X.sup.2 is C(R.sup.3A)═N or C(R.sup.3A).sub.2—C(R.sup.3A).sub.2;

[0184] each R.sup.1A is, independently, halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0185] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;

[0186] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

[0187] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl; and

[0188] m is 0, 1, 2, or 3.

[0189] In certain embodiments, D is of Formula (IB-b):

##STR00026##

wherein:

[0190] X.sup.1-X.sup.2 is C(R.sup.3A)═N or C(R.sup.3A).sub.2—C(R.sup.3A).sub.2;

[0191] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;

[0192] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and

[0193] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl.

[0194] In certain embodiments, D is of Formula (IB-c):

##STR00027##

wherein:

[0195] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon atom to which they are attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and

[0196] R.sup.5A is H, C.sub.1-C.sub.3 alkyl, F, or Cl.

[0197] Formulae (IA), (IA-a), and (IA-b) include substituent X.sup.A. In certain embodiments, X.sup.A is C(O). In certain embodiments, X.sup.A is C(R.sup.3A).sub.2.

[0198] Formulae (IA), (IA-a), and (IA-b) include substituents —X.sup.1—X.sup.2. In certain embodiments, —X.sup.1—X.sup.2— is C(R.sup.3A)═N. In certain embodiments, —X.sup.1—X.sup.2— is C(H)═N. In certain embodiments, —X.sup.1—X.sup.2— is C(C.sub.1-C.sub.3 alkyl)═N. In certain embodiments, —X.sup.1—X.sup.2— is C(R.sub.3A).sub.2—C(R.sup.3A).sub.2. In certain embodiments, —X.sup.1—X.sup.2— is C(H).sub.2—C(H).sub.2. In certain embodiments, —X.sup.1—X.sup.2— is C(H).sub.2—C(C.sub.1-C.sub.3 alkyl).sub.2. In certain embodiments, —X.sup.1—X.sup.2— is C(H).sub.2—C(C.sub.1-C.sub.3 alkyl).sub.2. In certain embodiments, —X.sup.1—X.sup.2− is C(H).sub.2—C(C.sub.1-C.sub.3 alkyl).sub.2. In certain embodiments, —X.sup.1—X.sup.2− is C(C.sub.1-C.sub.3 alkyl).sub.2-C(C.sub.1-C.sub.3 alkyl).sub.2.

[0199] In certain embodiments, D is a compound based on a ligand that binds to von Hippel-Lindau (a “VHL ligand”). In certain embodiments, D is derived from a VHL ligand.

In certain embodiments, D is of the formula:

##STR00028##

wherein:

[0200] each R.sup.2′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0201] each R.sup.4′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0202] each R.sup.5′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;

[0203] n1′ is 0, 1, 2, 3, 4, 5, or 6;

[0204] n2′ is 0, 1, 2, 3, or 4; and

[0205] n3′ is 0, 1, or 2.

[0206] In certain embodiments, D has zero instances of R.sup.2′. In certain embodiments, D has one or more instances of R.sup.2′. In certain embodiments, n1′ is 0. In certain embodiments, n1′ is 1. In certain embodiments, n1′ is 2. In certain embodiments, n1′ is 3. In certain embodiments, n1′ is 4. In certain embodiments, n1′ is 5. In certain embodiments, n1′ is 6. In certain embodiments, each instance of R.sup.2′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy. In certain embodiments, at least one instance of R.sup.2′ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.2′ is —OH. In certain embodiments, at least one instance of R.sup.2′ is unsubstituted C.sub.1-C.sub.6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In certain embodiments, at least one instance of R.sup.2′ is C.sub.1-C.sub.6 alkoxy (e.g., —O(unsubstituted C.sub.1-C.sub.6 alkyl)). In certain embodiments, at least one instance of R.sup.2′ is —O(Me). In certain embodiments, at least one instance of R.sup.2′ is —O(Et). In certain embodiments, at least one instance of R.sup.2′ is —O(n-propyl). In certain embodiments, at least one instance of R.sup.2′ is —O(isopropyl). In certain embodiments, at least one instance of R.sup.2′ is —O(n-butyl).

[0207] In certain embodiments, D has zero instances of R.sup.4′. In certain embodiments, D has one or more instances of R.sup.4′. In certain embodiments, n2′ is 0. In certain embodiments, n2′ is 1. In certain embodiments, n2′ is 2. In certain embodiments, n2′ is 3. In certain embodiments, n2′ is 4. In certain embodiments, each instance of R.sup.4′ is independently halogen, —OH, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6 alkoxy. In certain embodiments, at least one instance of R.sup.4′ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.2′ is —OH. In certain embodiments, at least one instance of R.sup.4′ is unsubstituted C.sub.1-C.sub.6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In certain embodiments, at least one instance of R.sup.4′ is C.sub.1-C.sub.6alkoxy (e.g., —O(unsubstituted C.sub.1-C.sub.6alkyl)). In certain embodiments, at least one instance of R.sup.4′ is —O(Me). In certain embodiments, at least one instance of R.sup.4′ is —O(Et). In certain embodiments, at least one instance of R.sup.4′ is —O(n-propyl). In certain embodiments, at least one instance of R.sup.4′ is —O(isopropyl). In certain embodiments, at least one instance of R.sup.4′ is —O(n-butyl).

[0208] In certain embodiments, D has zero instances of R.sup.5′. In certain embodiments, D has one or more instances of R.sup.5′. In certain embodiments, n3′ is 0. In certain embodiments, n3′ is 1. In certain embodiments, n3′ is 2. In certain embodiments, n3′ is 3. In certain embodiments, each instance of R.sup.5′ is independently halogen, —OH, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy. In certain embodiments, at least one instance of R.sup.5′ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.5′ is —OH. In certain embodiments, at least one instance of R.sup.5′ is C.sub.1-C.sub.6 alkyl. In certain embodiments, at least one instance of R.sup.5′ is unsubstituted C.sub.1-C.sub.6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In certain embodiments, at least one instance of R.sup.5′ is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.5′ is unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.5′ is unsubstituted n-propyl. In certain embodiments, at least one instance of R.sup.5′ is C.sub.1-C.sub.6alkoxy (e.g., —O(unsubstituted C.sub.1-C.sub.6alkyl)). In certain embodiments, at least one instance of R.sup.5′ is —O(Me). In certain embodiments, at least one instance of R.sup.5′ is —O(Et). In certain embodiments, at least one instance of R.sup.5′ is —O(n-propyl). In certain embodiments, at least one instance of R.sup.5′ is —O(isopropyl). In certain embodiments, at least one instance of R.sup.5′ is —O(n-butyl).

[0209] In certain embodiments, D is of the formula:

##STR00029##

In certain embodiments, D is of the formula:

##STR00030##

Ring A

[0210] Formula (I) includes Ring A. In certain embodiments, Ring A is of formula:

##STR00031##

In certain embodiments, Ring A is of formula:

##STR00032##

In certain embodiments, Ring A is of formula:

##STR00033##

In certain embodiments, on Ring A, there are zero instances of substituent R.sup.X. In certain embodiments, on Ring A, there are one or more instances of substituent R.sup.X. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, w is 3. In certain embodiments, w is 4. In certain embodiments, w is 5. In certain embodiments, w is 6. In certain embodiments, at least one instance of RX is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of RX is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.X is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl) (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl)). In certain embodiments, at least one instance of R.sup.X is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.X is optionally substituted methyl. In certain embodiments, at least one instance of R.sup.X is optionally substituted optionally substituted ethyl. In certain embodiments, at least one instance of R.sup.X is optionally substituted n-propyl. In certain embodiments, at least one instance of R.sup.X is optionally substituted isopropyl. In certain embodiments, at least one instance of R.sup.X is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, Ring A is of formula:

##STR00034##

In certain embodiments, Ring A is of formula:

##STR00035##

In certain embodiments, Ring A is of formula:

##STR00036##

[0211] In certain embodiments, Ring A is of formula

##STR00037##

wherein each instance of R.sup.Y is independently halogen, optionally substituted acyl, optionally substituted alkyl, —SO.sub.2R.sup.Y1, —P(═O)(R.sup.Y2).sub.2, —OR.sup.Y1; or —N(R.sup.Y2).sub.2; R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to a oxygen atom; each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom; and w1 is 0, 1, 2, 3, 4, or 5. In certain embodiments, on Ring A, there are zero instances of substituent R.sup.Y. In certain embodiments, on Ring A, there are one or more instances of substituent R.sup.Y. In certain embodiments, w1 is 0. In certain embodiments, w1 is 1. In certain embodiments, w1 is 2. In certain embodiments, w1 is 3. In certain embodiments, w1 is 4. In certain embodiments, w1 is 5. In certain embodiments, Ring A is of formula:

##STR00038##

In certain embodiments, Ring A is of formula:

##STR00039##

[0212] In certain embodiments, at least one instance of R.sup.Y is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.Y is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.Y is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl) (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl)). In certain embodiments, at least one instance of R.sup.Y is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.Y is optionally substituted methyl. In certain embodiments, at least one instance of R.sup.X is optionally substituted optionally substituted ethyl. In certain embodiments, at least one instance of R.sup.Y is optionally substituted n-propyl. In certain embodiments, at least one instance of R.sup.Y is optionally substituted isopropyl. In certain embodiments, at least one instance of R.sup.Y is optionally substituted acyl, optionally substituted alkyl, —SO.sub.2R.sup.Y1, —P(═O)(R.sup.Y2).sub.2, —OR.sup.Y1; or —N(R.sup.Y2).sub.2; R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to a oxygen atom; each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Y is optionally substituted acyl, —SO.sub.2R.sup.Y1, —P(═O)(R.sup.Y2).sub.2, —OR.sup.Y1; or —N(R.sup.Y2).sub.2. In certain embodiments, at least one instance of R.sup.Y is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.Y is —C(═O)N(R.sup.y3).sub.2, wherein each instance of R.sup.y3 is independently hydrogen or optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.Y is —C(═O)NH(R.sup.y3), wherein R.sup.y3 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.Y is —C(═O)NH(optionally substituted C.sub.1-C.sub.6alkyl). In certain embodiments, at least one instance of R.sup.Y is —C(═O)NH(Me). In certain embodiments, at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1, where R.sup.Y1 is hydrogen, acyl, or optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1, wherein R.sup.Y1 is optionally substituted C.sub.1-C.sub.6 alkyl. In certain embodiments, at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1, wherein R.sup.Y1 is optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, or optionally substituted n-pentyl. In certain embodiments, at least one instance of R.sup.Y is —SO.sub.2R.sup.Y1, wherein R.sup.Y1 is optionally substituted isopropyl. In certain embodiments, at least one instance of R.sup.Y is

##STR00040##

In certain embodiments, at least one instance of R.sup.Y is —P(═O)(R.sup.Y2).sub.2, wherein each instance of R.sup.Y2 is independently optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.Y is —P(═O)(R.sup.Y2).sub.2, wherein each instance of R.sup.Y2 is unsubstituted C.sub.1-C.sub.6alkyl. In certain embodiments, at least one instance of R.sup.Y is —P(═O)(R.sup.Y2).sub.2, wherein each instance of R.sup.Y2 is optionally substituted C.sub.1-C.sub.6 alkyl. In certain embodiments, at least one instance of R.sup.Y is —P(═O)(R.sup.Y2).sub.2, wherein each instance of R.sup.Y2 is independently optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, or optionally substituted n-pentyl. In certain embodiments, at least one instance of R.sup.Y is —P(═O)(R.sup.Y2).sub.2, wherein each instance of R.sup.Y2 is optionally substituted methyl. In certain embodiments, at least one instance of R.sup.Y is

##STR00041##

[0213] In certain embodiments, at least one instance of R.sup.Y is —OR.sup.Y1 or —N(R.sup.Y2).sub.2; wherein R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to a oxygen atom; each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Y is —OR.sup.Y1 (e.g., —OH or —O(optionally substituted C.sub.1-C.sub.6 alkyl)). In certain embodiments, at least one instance of R.sup.Y is —N(R.sup.Y2).sub.2 (e.g., —NH.sub.2, —NMe.sub.2)).

[0214] In certain embodiments, R.sup.Y1 is hydrogen, acyl, optionally substituted alkyl, or an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.Y1 is hydrogen. In certain embodiments, R.sup.Y1 is acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.Y1 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl) (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl)). In certain embodiments, R.sup.Y1 is an oxygen protecting group (e.g., methyl, methoxylmethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, tbutyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), methanesulfonate (mesylate), benzylsulfonate, or tosylate (Ts)). In certain embodiments, each instance of R.sup.Y2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Y2 is hydrogen. In certain embodiments, at least one instance of R.sup.Y2 is acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.Y2 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl) (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl)). In certain embodiments, at least one instance of R.sup.Y2 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0215] In certain embodiments, Ring A is of formula:

##STR00042##

In certain embodiments, Ring A is of formula:

##STR00043##

Linkers L1 and L2

[0216] Linker L1 connects the pyrimidine of Formula (I) and Ring A. In certain embodiments, L1 is a bond. In certain embodiments, L1 is optionally substituted alkylene. In certain embodiments, L1 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L1 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L1 is unsubstituted C.sub.2-6 alkylene. In certain embodiments, L1 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L1 is unsubstituted C.sub.4-6 alkylene. In certain embodiments, L1 is —CH.sub.2—. In certain embodiments, L1 is —NR.sup.A—, —O—, or —S—; wherein R.sup.A is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, L1 is —NR.sup.A—, wherein R.sup.A is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, L1 is —NH—. In certain embodiments, L1 is —N(optionally substituted alkyl)- (e.g., —N(optionally substituted C.sub.1-6 alkyl)-). In certain embodiments, L1 is —O—. In certain embodiments, L1 is —S—. In certain embodiments, L1 is —NH—, —O—, or —S—.

[0217] In Formula (I), L2 is a divalent moiety linking the group D to the piperidine moiety of Formula (I). In Formula (I), L2 is a divalent moiety. In certain embodiments, L2 is a substituted or unsubstituted C.sub.1-50 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.bb—, —S—, or a cyclic moiety, wherein R.sup.bb is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is a substituted or unsubstituted C.sub.1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is a substituted or unsubstituted C.sub.1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is a substituted or unsubstituted C.sub.1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with —O—. In certain embodiments, L2 is any “L0” group or “Linker” group recited in U.S. patent application, U.S.S.N. 1407,930, filed May 8, 2015, which is incorporated herein by reference. In certain embodiments, L2 is any “L” group recited in U.S. patent application, U.S.S.N. 14n92,414, filed Jul. 6, 2015, which is incorporated herein by reference.

[0218] In certain embodiments, the chain of linker L2 comprises up to 50 consecutive covalently bonded atoms in length as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, the chain of linker L2 comprises up to 50 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 46 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 45 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 40 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 35 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 32 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 30 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 25 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 25 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 23 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 20 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 14 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 15 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 12 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 11 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 10 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 9 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 8 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 7 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 6 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 5 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents. In certain embodiments, L2 comprises up to 3 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents.

[0219] In certain embodiments, any of the atoms in L2 can be substituted. In certain embodiments, none of the atoms in the linker L2 are substituted. In certain embodiments, none of the carbon atoms in the linker are substituted.

[0220] In certain embodiments, L2 is a linker that contains an asymmetric carbon/stereocenter, i.e., an sp.sup.3 hybridized carbon atom bearing 4 different groups attached thereto. In certain embodiments, the compound comprising such an L2 group is enantiomerically enriched or substantially enantiomerically enriched. In certain embodiments, the compound comprising such an L2 group is enantiomerically pure. In certain embodiments, the compound comprising such an L2 group is racemic.

[0221] In certain embodiments, L2 comprises substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, or combinations thereof. In certain embodiments, L2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene. In certain embodiments, L2 is a linker selected from the group consisting of the following divalent moieties: substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.

[0222] Reference to L2 being a combination of at least two instances of the divalent moieties described herein refers to a linker consisting of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, wherein the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and the instances of the first and second divalent moieties are consecutive covalently attached to each other. For example, when L2 is a combination of alkylene and heteroalkylene linkers -alkylene-heteroalkylene-, -alkylene-(heteroalkylene).sub.2-, and -heteroalkylene-alkylene-heteroalkylene- are all within the scope of L, wherein each instance of alkylene in any one of the linkers may be the same or different, and each instance of heteroalkylene in any one of the linkers may be the same or different.

[0223] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkylene, e.g., substituted or unsubstituted C.sub.1-6alkylene, substituted or unsubstituted C.sub.1-2alkylene, substituted or unsubstituted C.sub.2-3alkylene, substituted or unsubstituted C.sub.3-4alkylene, substituted or unsubstituted C.sub.4-5alkylene, substituted or unsubstituted C.sub.1-6alkylene, substituted or unsubstituted C.sub.3-6alkylene, or substituted or unsubstituted C.sub.4-6alkylene. Exemplary alkylene groups include unsubstituted alkylene groups such as methylene (—CH.sub.2—), ethylene (—(CH.sub.2).sub.2—), n-propylene (—(CH.sub.2).sub.3—), n-butylene (—(CH.sub.2).sub.4—), n-pentylene (—(CH.sub.2).sub.5—), and n-hexylene (—(CH.sub.2).sub.6—).

[0224] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkenylene, e.g., substituted or unsubstituted C.sub.2-6alkenylene, substituted or unsubstituted C.sub.2-3alkenylene, substituted or unsubstituted C.sub.3-4alkenylene, substituted or unsubstituted C.sub.4-5alkenylene, or substituted or unsubstituted C.sub.5-6alkenylene.

[0225] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkynylene, e.g., substituted or unsubstituted C.sub.2-6alkynylene, substituted or unsubstituted C.sub.2-3alkynylene, substituted or unsubstituted C.sub.3-4alkynylene, substituted or unsubstituted C.sub.4-5alkynylene, or substituted or unsubstituted C.sub.5-6alkynylene.

[0226] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkylene, e.g., substituted or unsubstituted heteroC.sub.1-6alkylene, substituted or unsubstituted heteroC.sub.1-2alkylene, substituted or unsubstituted heteroC.sub.2-3alkylene, substituted or unsubstituted heteroC.sub.3-4alkylene, substituted or unsubstituted heteroC.sub.4-5 alkylene, or substituted or unsubstituted heteroC.sub.5-6alkylene. Exemplary heteroalkylene groups include unsubstituted heteroalkylene groups, such as —(CH.sub.2).sub.2—O(CH.sub.2).sub.2—, —OCH.sub.2—, —CH.sub.2O—, —O(CH.sub.2).sub.2—, —(CH.sub.2).sub.2O—, —O(CH.sub.2).sub.3—, —(CH.sub.2).sub.3O—, —O(CH.sub.2).sub.4—, —(CH.sub.2).sub.4O—, —O(CH.sub.2).sub.5—, —(CH.sub.2).sub.5O—, —O(CH.sub.2).sub.6—, and —O(CH.sub.2).sub.6O—, and amide groups (e.g., —NH—C(═O)—and —C(═O)NH—).

[0227] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkenylene, e.g., substituted or unsubstituted heteroC.sub.2-6alkenylene, substituted or unsubstituted heteroC.sub.2-3alkenylene, substituted or unsubstituted heteroC.sub.3-4 alkenylene, substituted or unsubstituted heteroC.sub.4-5alkenylene, or substituted or unsubstituted heteroC.sub.5-6alkenylene.

[0228] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkynylene, e.g., substituted or unsubstituted heteroC.sub.2-6alkynylene, substituted or unsubstituted heteroC.sub.2-3alkynylene, substituted or unsubstituted heteroC.sub.3-4 alkynylene, substituted or unsubstituted heteroC.sub.4-5alkynylene, or substituted or unsubstituted heteroC.sub.5-6alkynylene.

[0229] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted carbocyclylene, e.g., substituted or unsubstituted C.sub.3-6carbocyclylene, substituted or unsubstituted C.sub.3-4carbocyclylene, substituted or unsubstituted C.sub.4-5 carbocyclylene, or substituted or unsubstituted C.sub.5-6 carbocyclylene.

[0230] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heterocyclylene, e.g., substituted or unsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted 3-4 membered heterocyclylene, substituted or unsubstituted 4-5 membered heterocyclylene, or substituted or unsubstituted 5-6 membered heterocyclylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 5-8 membered heterocyclyl group with 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a six-membered heterocyclyl group with 1-3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine or piperazine. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperazine. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with morpholine.

[0231] In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted arylene, e.g., substituted or unsubstituted phenylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group. In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroarylene, e.g., substituted or unsubstituted 5- to 6-membered heteroarylene.

[0232] In certain embodiments, L2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —NR.sup.b—, and each instance of R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R.sup.b is hydrogen. In certain embodiments, at least one instance of R.sup.b is substituted or unsubstituted C.sub.1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl). In certain embodiments, at least one instance of R.sup.b is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0233] In certain embodiments, L2 is an optionally substituted C.sub.145 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-45 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C.sub.1-24 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-24 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C.sub.1-20 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-20 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C.sub.1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.1-30 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with —O—. In certain embodiments, L2 is an unsubstituted C.sub.1-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.1-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—. In certain embodiments, L2 is an unsubstituted C.sub.1-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—. In certain embodiments, L2 is an unsubstituted C.sub.5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.5-15 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.15-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is an unsubstituted C.sub.20-25 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR.sup.b—. In certain embodiments, L2 is a substituted or unsubstituted C.sub.1-45 hydrocarbon chain. In certain embodiments, L2 is a substituted or unsubstituted C.sub.5-40 hydrocarbon chain. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with —C(═O)—, —O—, —S—, —NR.sup.b—, —N═, or ═N—. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with —C(═O)—, —O—, or —NR.sup.b—, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C.sub.1-26 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with —O—.

[0234] In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-45 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-30 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-26 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-24 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-20 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C.sub.1-20 hydrocarbon chain as the shortest path between D and the piperidine moiety of Formula (I), excluding hydrogen atoms and substituents.

[0235] In certain embodiments, L2 is a bond.

[0236] In certain embodiments, L2 includes the moiety

##STR00044##

wherein g is 1, 2, 3, 4, 5, or 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.

[0237] In certain embodiments, L2 includes the moiety —NHC(═O)—.

[0238] In certain embodiments, L2 includes the moiety —NH—.

[0239] In certain embodiments, L2 is of the formula:

##STR00045## ##STR00046##

wherein l.sup.R indicates the point of attachment to D, and l.sup.A indicates the point of attachment to the moiety of formula

##STR00047##

n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In certain embodiments, L2 is of the formula:

##STR00048##

wherein l.sup.R indicates the point of attachment to D, and l.sup.A indicates the point of attachment to the moiety of formula

##STR00049##

n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In certain embodiments, L2 is of the formula:

##STR00050##

wherein l.sup.R indicates the point of attachment to D, and l.sup.A indicates the point of attachment to the moiety of formula

##STR00051##

n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n2 is 0. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n2 is 7. In certain embodiments, n2 is 8. In certain embodiments, n2 is 9. In certain embodiments, n2 is 10. In certain embodiments, n3 is 1. In certain embodiments, n3 is 2. In certain embodiments, n3 is 3. In certain embodiments, n3 is 4. In certain embodiments, n3 is 5. In certain embodiments, n3 is 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.

[0240] In certain embodiments, L2 is of the formula:

##STR00052## ##STR00053##

[0241] In certain embodiments, L2 is of the formula:

##STR00054##

[0242] In certain embodiments, L2 is of the formula:

##STR00055##

[0243] In certain embodiments, L2 is of the formula:

##STR00056##

In certain embodiments, L2 is of the formula:

##STR00057##

In certain embodiments, L2 is of the formula:

##STR00058##

In certain embodiments, L2 is of the formula:

##STR00059##

In certain embodiments, L2 is of the formula

##STR00060##

In certain embodiments, L2 is of the formula

##STR00061##

In certain embodiments, L2 is of the formula

##STR00062##

In certain embodiments, L2 is of the formula

##STR00063##

In certain embodiments, L2 is of the formula

##STR00064##

In certain embodiments, L2 is of the formula:

##STR00065##

wherein: n1 is 0 or 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; n3 or 2; and g is 2 or 3. In certain embodiments, L2 is of the formula:

##STR00066##

wherein: n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n2 is 7. In certain embodiments, n2 is 8. In certain embodiments, n3 is 1. In certain embodiments, n3 is 2. In certain embodiments, n3 is 3. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4.

[0244] In certain embodiments L2 is of the formula:

##STR00067## ##STR00068##

[0245] In certain embodiments, L2 is of the formula:

##STR00069## ##STR00070##

Substituents R.sup.1, R.sup.2, and R.sup.3

[0246] Formula (I) includes zero or more instances of substituent R.sup.1 on the pyrimidine ring. In certain embodiments, Formula (I) includes one instance of substituent R.sup.1 on the pyrimidine ring. In certain embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is 6. In certain embodiments, at least one instance of R.sup.1 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.1 is Cl. In certain embodiments, at least one instance of R.sup.1 is —Br. In certain embodiments, at least one instance of R.sup.1 is —F. In certain embodiments, at least one instance of R.sup.1 is —I. In certain embodiments, at least one instance of R.sup.1 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.1 is optionally substituted C.sub.1-6 alkyl.

[0247] In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1 is substituted methyl. In certain embodiments, at least one instance of R.sup.1 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.1 is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.1 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.1 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.1 is benzyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1 is —CN. In certain embodiments, at least one instance of R.sup.1 is —OR.sup.D1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.1 is —N(R.sup.D1a).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.1 is —SR.sup.D1 (e.g., —SMe).

[0248] In certain embodiments, at least one instance of R.sup.1 is —OR.sup.D1, —N(R.sup.D1a).sub.2, or —SR.sup.D1, and R.sup.D1 is as defined herein. In certain embodiments, R.sup.D1 is hydrogen. In certain embodiments, R.sup.D1 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.D1 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.D1 is substituted or unsubstituted methyl. In certain embodiments, R.sup.D1 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.D1 is substituted or unsubstituted propyl. In certain embodiments, R.sup.D1 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.D1 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.D1 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.D1 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.D1 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.D1 is benzyl. In certain embodiments, R.sup.D1 is optionally substituted phenyl. In certain embodiments, R.sup.D1 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.D1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D1 is a sulfur protecting group when attached to a sulfur atom.

[0249] In certain embodiments, at least one instance of R.sup.D1a is hydrogen. In certain embodiments, at least one instance of R.sup.D1a is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one R.sup.D1a is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.D1a is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.D1a is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.D1a is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.D1a is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.D1a is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.D1a is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.D1a is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.D1a is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.D1a is benzyl. In certain embodiments, at least one instance of R.sup.D1a is optionally substituted phenyl. In certain embodiments, at least one instance of R.sup.D1a is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.D1a is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, two instances of R.sup.D1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, the pyrimidine ring of Formula (I) is of formula:

##STR00071##

In certain embodiments, the pyrimidine ring of Formula (I) is of formula:

##STR00072##

In certain embodiments, the pyrimidine ring of Formula (I) is of formula:

##STR00073##

[0250] Formula (I) includes zero or more instances of substituent R.sup.2 on the piperidine ring. In certain embodiments, Formula (I) includes zero instances of substituent R.sup.2 on the piperidine ring. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is 4. In certain embodiments, n1 is 5. In certain embodiments, y is 6. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is 4. In certain embodiments, y is 5. In certain embodiments, y is 6. In certain embodiments, y is 7. In certain embodiments, y is 8. In certain embodiments, y is 9. In certain embodiments, at least one instance of R.sup.2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.2 is Cl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.2 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.2 is substituted methyl. In certain embodiments, at least one instance of R.sup.2 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.2 is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.2 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.2 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.2 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.2 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.2 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.2 is benzyl. In certain embodiments, at least one instance of R.sup.2 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.2 is —CN. In certain embodiments, at least one instance of R.sup.2 is —OR.sup.D1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.2 is —N(R.sup.D1a).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.2 is —SR.sup.D1 (e.g., —SMe). In certain embodiments, the piperidine ring of Formula (I) is of formula:

##STR00074##

In certain embodiments, the piperidine ring of Formula (I) is of formula:

##STR00075##

[0251] Formula (I) includes substituent R.sup.3. In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.3 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.3 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is substituted or unsubstituted methyl. In certain embodiments, R.sup.3 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.3 is unsubstituted ethyl. In certain embodiments, R.sup.3 is substituted or unsubstituted propyl. In certain embodiments, R.sup.3 is unsubstituted n-propyl. In certain embodiments, R.sup.3 is unsubstituted methyl or isopropyl. In certain embodiments, R.sup.3 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.3 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.3 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.3 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.3 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.3 is benzyl. In certain embodiments, R.sup.3 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.3 is unsubstituted phenyl. In certain embodiments, R.sup.3 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.3 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0252] In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00076##

L2 is an unsubstituted C.sub.1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, at least one instance of R.sup.1 is halogen, R.sup.3 is hydrogen or optionally substituted C.sub.1-6 alkyl, y is 0, x is 1, and D is of the formula:

##STR00077##

(IA), wherein X.sup.A, R.sup.1A, R.sup.3A, R.sup.3′, R.sup.4A, R.sup.5A, m, n, and a1 are as defined herein. In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00078##

L2 is of the formula:

##STR00079## ##STR00080##

R.sup.3 is halogen, R.sup.3 is hydrogen, y is 0, x is 1, and D is of the formula:

##STR00081##

[0253] In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00082##

L2 is of

[0254] ##STR00083## ##STR00084##

R.sup.3 is halogen, R.sup.3 is hydrogen, y is 0, x is 1, and D is of the formula:

##STR00085##

[0255] In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00086##

L2 is an unsubstituted C.sub.1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR.sup.b—, —S—, or a cyclic moiety, wherein R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, at least one instance of R.sup.1 is halogen, R.sup.3 is hydrogen or optionally substituted C.sub.1-6 alkyl, y is 0, x is 1, and D is of the formula:

##STR00087##

wherein R.sup.2′, R.sup.4′, R.sup.5′, n1, n2, and n3 are as defined herein. In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00088##

L2 is of the formula:

##STR00089## ##STR00090##

R.sup.3 is halogen, R.sup.3 is hydrogen, y is 0, x is 1, and D is of the formula:

##STR00091##

[0256] In certain embodiments, L1 is a bond, Ring A is of formula:

##STR00092##

L2 is of the formula:

##STR00093## ##STR00094##

R.sup.3 is halogen, R.sup.3 is hydrogen, y is 0, x is 1, and D is of the formula:

##STR00095##

[0257] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00096##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0258] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00097##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0259] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00098##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein D is of the formula:

##STR00099##

and L2 is of the formula:

##STR00100##

[0260] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00101##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein D is of the formula:

##STR00102##

and L2 is of the formula:

##STR00103##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0261] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00104##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0262] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00105##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0263] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00106##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein D is of the formula:

##STR00107##

and
L2 is of the formula:

##STR00108##

n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0264] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00109##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein D is of the formula:

##STR00110##

and L2 is of the formula:

##STR00111##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0265] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00112##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0266] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00113##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof;

##STR00114##

wherein D is of the formula:

##STR00115##

and L2 is of the formula:
n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0267] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00116##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein D is of the formula:

##STR00117##

and L2 is of the formula:

##STR00118##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0268] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00119##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is of the formula:

##STR00120##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0269] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00121##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0270] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00122##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0271] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00123##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0272] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00124##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;
L2 is of the formula:

##STR00125##

[0273] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00126##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0274] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0275] L2 is of the formula:

##STR00127##

[0276] n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0277] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00128##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0278] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00129## ##STR00130##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0279] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00131##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein L2 is of the formula:

##STR00132##

[0280] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00133##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0281] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00134##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0282] wherein L2 is of the formula:

##STR00135##

[0283] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00136##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0284] wherein L2 is of the formula:

##STR00137##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0285] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00138##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0286] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00139##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0287] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl; and L2 is of the formula:

##STR00140##

[0288] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00141##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0289] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0290] and L2 is of the formula:

##STR00142##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0291] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00143##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0292] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00144##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0293] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00145##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0294] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00146##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0295] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00147## ##STR00148## ##STR00149## ##STR00150##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0296] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00151##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0297] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00152##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
wherein
R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl; and L2 is of the formula:

##STR00153##

[0298] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00154##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0299] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0300] L2 is of the formula:

##STR00155##

[0301] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00156##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0302] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0303] L2 is of the formula:

##STR00157##

[0304] n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1 or 2; and g is 2 or 3.

[0305] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00158##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0306] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0307] L2 is of the formula:

##STR00159##

[0308] n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0309] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00160##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0310] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00161##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0311] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00162## ##STR00163## ##STR00164## ##STR00165##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0312] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00166##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0313] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00167##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof;

[0314] wherein L2 is of the formula:

##STR00168##

[0315] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00169##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein L2 is of the formula:

##STR00170##

[0316] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00171##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0317] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00172##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0318] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00173##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0319] wherein L2 is of the formula:

##STR00174##

[0320] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00175##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0321] wherein L2 is of the formula:

##STR00176##

[0322] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00177##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0323] wherein L2 is of the formula:

##STR00178##

n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1 or 2; and g is 2 or 3.

[0324] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00179##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0325] wherein L2 is of the formula:

##STR00180##

n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0326] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00181## ##STR00182##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0327] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00183##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0328] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00184## ##STR00185##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0329] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl; and L2 is of the formula:

##STR00186##

[0330] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00187##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0331] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

[0332] and L2 is of the formula:

##STR00188##

[0333] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00189## ##STR00190##

##STR00191##

[0334] n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1 or 2; and g is 2 or 3.

[0335] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00192##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

[0336] wherein R.sup.1 is halogen or optionally substituted C.sub.1-6 alkyl;

##STR00193##

[0337] n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3.

[0338] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein each of R.sup.1, R.sup.3, n1; n2; n3; and g are as described herein.

[0339] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0340] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0341] In certain embodiments, the compound of Formula (I) is a compound provided in any one of the Examples below. In certain embodiments, the compound of Formula (I) is a compound provided in Table 1.

[0342] In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the compound of Formula (I) selectively binds CDK12 over another protein. In some embodiments, the compound of Formula (I) selectively binds a specific CDK (e.g., CDK9 and/or CDK12) over another CDK. In some embodiments, the compound of Formula (I) selectively binds CDK12 over another CDK. In some embodiments, the compound of Formula (I) selectively binds CDK12 over CDK13. In some embodiments, the compound of Formula (I) selectively binds CDK9 over another protein. In some embodiments, the compound of Formula (I) selectively binds CDK9 over another CDK. In some embodiments, the compound of Formula (I) selectively binds CDK9 and/or CDK12 over other CDK's (e.g., CDK2, CDK4, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18). In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0344] In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK12 over other proteins in the proteome. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK12 over other kinases. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK12 over other CDK's. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK12 over CDK13. In some embodiments, the compound of Formula (I) induces selective degradation of CDK12 over other kinases. In some embodiments, the compound of Formula (I) induces selective degradation of CDK12 over other CDK's. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK12 over CDK13. In some embodiments, the compound of Formula (I) induces the selective degradation of CDK12 over CDK13. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK9 over other proteins in the proteome. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK9 over other kinases. In some embodiments, the compound of Formula (I) leads to the selective degradation of CDK9 over other CDK's. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0345] In some embodiments, the compound of Formula (I) selectively binds E3 ligase over another protein. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0346] In certain embodiments, the compound of Formula (I) induces the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of the target kinase at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In certain embodiments, the compound of Formula (I) induces the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of the target CDK at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In certain embodiments, the compound of Formula (I) induces the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of the target protein CDK9 and/or CDK12 at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

[0347] In certain embodiments, the compound of Formula (I) increases the rate of degradation of the target kinase up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In certain embodiments, the compound of Formula (I) increases the rate of degradation of the target CDK up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In certain embodiments, the compound of Formula (I) increases the rate of degradation of the target protein CDK9 and/or CDK12 up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

Pharmaceutical Compositions, Kits, and Administration

[0348] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0349] In certain embodiments, the compound of Formula (I) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof.

[0350] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0351] In certain embodiments, the effective amount is an amount effective for inducing the degradation of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target kinase in a cell. In certain embodiments, the effective amount is an amount effective for inducing the degradation of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target CDK in a cell. In certain embodiments, the effective amount is an amount effective for inducing the degradation of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target protein CDK9 and/or CDK12 in a cell. In certain embodiments, the effective amount is an amount effective for inducing the degradation of the target protein CDK9 and/or CDK12 in a cell by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0352] The present disclosure provides pharmaceutical compositions comprising a compound that interacts with a E3 ubiquitin ligase (e.g., cereblon) and the target kinase (e.g., CDK) for use in treating a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising a compound that interacts with a E3 ubiquitin ligase (e.g., cereblon) and the target protein CDK9 and/or CDK12 for use in treating a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the composition is for use in treating cancer. In certain embodiments, the composition is for use in treating ovarian cancer, breast cancer, or prostate cancer. In certain embodiments, the composition is for use in treating ovarian cancer. In certain embodiments, the composition is for use in treating breast cancer. In certain embodiments, the composition is for use in treating prostate cancer.

[0353] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0354] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0355] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0356] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0357] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0358] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0359] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0360] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0361] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0362] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0363] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0364] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0365] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0366] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0367] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0368] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0369] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, Eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, Litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0370] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0371] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0372] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0373] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0374] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0375] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0376] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0377] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0378] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0379] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0380] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0381] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0382] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0383] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0384] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0385] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0386] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0387] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0388] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0389] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, biological sample, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, biological sample, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0390] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0391] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inducing the degradation of a target protein, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve their ability to cross the blood-brain barrier, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, tissue, or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0392] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0393] The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is abiraterone acetate (e.g., ZYTIGA), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine (e.g., KADCYLA), afatinib dimaleate (e.g., GILOTRIF), aldesleukin (e.g., PROLEUKIN), alemtuzumab (e.g., CAMPATH), anastrozole (e.g., ARIMIDEX), arsenic trioxide (e.g., TRISENOX), asparaginase Erwinia chrysanthemi (e.g., ERWINAZE), axitinib (e.g., INLYTA), azacitidine (e.g., MYLOSAR, VIDAZA), BEACOPP, belinostat (e.g., BELEODAQ), bendamustine hydrochloride (e.g., TREANDA), BEP, bevacizumab (e.g., AVASTIN), bicalutamide (e.g., CASODEX), bleomycin (e.g., BLENOXANE), blinatumomab (e.g., BLINCYTO), bortezomib (e.g., VELCADE), bosutinib (e.g., BOSULIF), brentuximab vedotin (e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN), cabazitaxel (e.g., JEVTANA), cabozantinib-s-malate (e.g., COMETRIQ), CAF, capecitabine (e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT, PARAPLATIN), carboplatin-taxol, carfilzomib (e.g., KYPROLIS), carmustine (e.g., BECENUM, BICNU, CARMUBRIS), carmustine implant (e.g., GLIADEL WAFER, GLIADEL), ceritinib (e.g., ZYKADIA), cetuximab (e.g., ERBITUX), chlorambucil (e.g., AMBOCHLORIN, AMBOCLORIN, LEUKERAN, LINFOLIZIN), chlorambucil-prednisone, CHOP, cisplatin (e.g., PLATINOL, PLATINOL-AQ), clofarabine (e.g., CLOFAREX, CLOLAR), CMF, COPP, COPP-ABV, crizotinib (e.g., XALKORI), CVP, cyclophosphamide (e.g., CLAFEN, CYTOXAN, NEOSAR), cytarabine (e.g., CYTOSAR-U, TARABINE PFS), dabrafenib (e.g., TAFINLAR), dacarbazine (e.g., DTIC-DOME), dactinomycin (e.g., COSMEGEN), dasatinib (e.g., SPRYCEL), daunorubicin hydrochloride (e.g., CERUBIDINE), decitabine (e.g., DACOGEN), degarelix, denileukin diftitox (e.g., ONTAK), denosumab (e.g., PROLIA, XGEVA), Dinutuximab (e.g., UNITUXIN), docetaxel (e.g., TAXOTERE), doxorubicin hydrochloride (e.g., ADRIAMYCIN PFS, ADRIAMYCIN RDF), doxorubicin hydrochloride liposome (e.g., DOXIL, DOX-SL, EVACET, LIPODOX), enzalutamide (e.g., XTANDI), epirubicin hydrochloride (e.g., ELLENCE), EPOCH, erlotinib hydrochloride (e.g., TARCEVA), etoposide (e.g., TOPOSAR, VEPESID), etoposide phosphate (e.g., ETOPOPHOS), everolimus (e.g., AFINITOR DISPERZ, AFINITOR), exemestane (e.g., AROMASIN), FEC, fludarabine phosphate (e.g., FLUDARA), fluorouracil (e.g., ADRUCIL, EFUDEX, FLUOROPLEX), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant (e.g., FASLODEX), gefitinib (e.g., IRESSA), gemcitabine hydrochloride (e.g., GEMZAR), gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate (e.g., ZOLADEX), Hyper-CVAD, ibritumomab tiuxetan (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE, idelalisib (e.g., ZYDELIG), ifosfamide (e.g., CYFOS, IFEX, IFOSFAMIDUM), imatinib mesylate (e.g., GLEEVEC), imiquimod (e.g., ALDARA), ipilimumab (e.g., YERVOY), irinotecan hydrochloride (e.g., CAMPTOSAR), ixabepilone (e.g., IXEMPRA), lanreotide acetate (e.g., SOMATULINE DEPOT), lapatinib ditosylate (e.g., TYKERB), lenalidomide (e.g., REVLIMID), lenvatinib (e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin calcium (e.g., WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3 MONTH, LUPRON DEPOT-4 MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR), liposomal cytarabine (e.g., DEPOCYT), lomustine (e.g., CEENU), mechlorethamine hydrochloride (e.g., MUSTARGEN), megestrol acetate (e.g., MEGACE), mercaptopurine (e.g., PURINETHOL, PURIXAN), methotrexate (e.g., ABITREXATE, FOLEX PFS, FOLEX, METHOTREXATE LPF, MEXATE, MEXATE-AQ), mitomycin c (e.g., MITOZYTREX, MUTAMYCIN), mitoxantrone hydrochloride, MOPP, nelarabine (e.g., ARRANON), nilotinib (e.g., TASIGNA), nivolumab (e.g., OPDIVO), obinutuzumab (e.g., GAZYVA), OEPA, ofatumumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA), omacetaxine mepesuccinate (e.g., SYNRIBO), OPPA, oxaliplatin (e.g., ELOXATIN), paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticle formulation (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE), pamidronate disodium (e.g., AREDIA), panitumumab (e.g., VECTIBIX), panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT), pegaspargase (e.g., ONCASPAR), peginterferon alfa-2b (e.g., PEG-INTRON), peginterferon alfa-2b (e.g., SYLATRON), pembrolizumab (e.g., KEYTRUDA), pemetrexed disodium (e.g., ALIMTA), pertuzumab (e.g., PERJETA), plerixafor (e.g., MOZOBIL), pomalidomide (e.g., POMALYST), ponatinib hydrochloride (e.g., ICLUSIG), pralatrexate (e.g., FOLOTYN), prednisone, procarbazine hydrochloride (e.g., MATULANE), radium 223 dichloride (e.g., XOFIGO), raloxifene hydrochloride (e.g., EVISTA, KEOXIFENE), ramucirumab (e.g., CYRAMZA), R-CHOP, recombinant HPV bivalent vaccine (e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV) nonavalent vaccine (e.g., GARDASIL 9), recombinant human papillomavirus (e.g., HPV) quadrivalent vaccine (e.g., GARDASIL), recombinant interferon alfa-2b (e.g., INTRON A), regorafenib (e.g., STIVARGA), rituximab (e.g., RITUXAN), romidepsin (e.g., ISTODAX), ruxolitinib phosphate (e.g., JAKAFI), siltuximab (e.g., SYLVANT), sipuleucel-t (e.g., PROVENGE), sorafenib tosylate (e.g., NEXAVAR), STANFORD V, sunitinib malate (e.g., SUTENT), TAC, tamoxifen citrate (e.g., NOLVADEX, NOVALDEX), temozolomide (e.g., METHAZOLASTONE, TEMODAR), temsirolimus (e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa, topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON), tositumomab and iodine I 131 tositumomab (e.g., BEXXAR), TPF, trametinib (e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g., CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vinblastine sulfate (e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR PFS), vincristine sulfate liposome (e.g., MARQIBO), vinorelbine tartrate (e.g., NAVELBINE), vismodegib (e.g., ERIVEDGE), vorinostat (e.g., ZOLINZA), XELIRI, XELOX, ziv-aflibercept (e.g., ZALTRAP), or zoledronic acid (e.g., ZOMETA). In certain embodiments, the additional pharmaceutical agent is ENMD-2076, PCI-32765, AC220, dovitinib lactate (e.g., TKI258, CHIR-258), BIBW 2992 (e.g., TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (e.g., VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (e.g., AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (e.g., Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (e.g., CCI-779), everolimus (e.g., RAD-001), ridaforolimus, AP23573 (e.g., Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapy (e.g., cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase, cyclophosphamide, or etoposide)). Exemplary chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine. In certain embodiments, the additional pharmaceutical agent is an epigenetic modifier, such as azacitidine or romidepsin. In certain embodiments, the additional pharmaceutical agent is ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a tyrosine kinase. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5′-chloro-2′-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4′-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., CDK). In certain embodiments, the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is a tyrosine kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and Vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the additional pharmaceutical agent is a glucocorticoid (e.g., cortisol, cortisone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, or deoxycorticosterone acetate). In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is an immunomodulator. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor. In certain embodiments, the PD-1 inhibitor is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, or AMP-224. In certain embodiments, the PD-L1 inhibitor is atezolizumab, durvalumab, BMS-936559, avelumab, or CA-170. In certain embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In certain embodiments, the additional pharmaceutical agent is an aromatase inhibitor. In certain embodiments, the additional pharmaceutical agent is an PI3K inhibitor. In certain embodiments, the additional pharmaceutical agent is an mTOR inhibitor. In certain embodiments, the additional pharmaceutical agent is an endocrine therapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with chemotherapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with immunotherapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with chemotherapy or immunotherapy.

[0394] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0395] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof.

[0396] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inducing the degradation of target (e.g., kinase (e.g., CDK (e.g., CDK9, CDK12))) in a subject, biological sample, tissue, or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Methods of Treatment and Uses

[0397] The compounds described herein are capable of binding (e.g., reversibly binding or irreversibly binding) an E3 ubiquitin ligase (e.g., Cereblon) and the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) and inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))). The present disclosure thus also provides methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) in a subject, biological sample, tissue, or cell. The compounds described herein are capable of binding (e.g., reversibly binding or irreversibly binding) an E3 ubiquitin ligase (e.g., Cereblon) and the target protein (e.g., CDK9 and/or CDK12) and inducing the degradation of the target protein CDK9 and/or CDK12. The present disclosure thus also provides methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) in a subject, biological sample, tissue, or cell. The present disclosure thus also provides methods of inducing the degradation of the target protein (e.g., CDK9 and/or CDK12) in a subject, biological sample, tissue, or cell. The present disclosure further provides methods of inducing apoptosis in a cell in a cell, tissue, biological sample, or subject. The present disclosure further provides methods for the treatment of diseases, such as proliferative diseases in a subject in need thereof.

[0398] In certain embodiments, the application provides a method of binding an ubiquitin receptor E3 ubiquitin ligase (e.g., Cereblon) and promoting the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))). In certain embodiments, the application provides a method of binding an ubiquitin receptor E3 ubiquitin ligase (e.g., Cereblon) and promoting the degradation of the target protein CDK9 and/or CDK12. In another aspect, the present disclosure provides methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) in a subject in need thereof, the methods comprise administering to the subject an effective amount of a compound or pharmaceutical composition described herein. In another aspect, the present disclosure provides methods of inducing the degradation of the target protein CDK9 and/or CDK12 in a subject in need thereof, the methods comprise administering to the subject an effective amount of a compound or pharmaceutical composition described herein. In another aspect, the present disclosure provides methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) in a biological sample, tissue, or cell, the methods comprise contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein. In another aspect, the present disclosure provides methods of inducing the degradation of the target protein CDK9 and/or CDK12 in a biological sample, tissue, or cell, the methods comprise contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein.

[0399] In another aspect, the present disclosure provides methods of inducing apoptosis in a cell in a biological sample, tissue, or cell, the methods comprise contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein.

[0400] In certain embodiments, the application provides a method of binding an E3 ubiquitin ligase (e.g., Cereblon) and the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) and selectively inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))).

[0401] Use of a bifunctional compound that binds an E3 ubiquitin ligase (e.g., Cereblon) and the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) provides a strategy for treating diseases associated with (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) (e.g. proliferative diseases), as research tools for studying the role of CDK9 and/or CDK12 in the cell, or as research tools for studying diseases associated with (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) (e.g. proliferative diseases).

[0402] The present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, for use in the treatment of diseases, such as proliferative diseases, in a subject in need thereof.

[0403] The present disclosure also provides uses of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, in the manufacture of a medicament for the treatment of diseases, such as proliferative diseases, in a subject in need thereof.

[0404] In certain embodiments, the methods of the disclosure comprise administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0405] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0406] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as the compound of Formula (I), or at different times than the compound of Formula (I). For example, the compound of Formula (I) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound of Formula (I) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formula (I) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.

[0407] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of diseases, such as proliferative diseases, in a subject in need thereof. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a proliferative disease. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of an inflammatory disease. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of proliferative diseases.

[0408] In another aspect, the present disclosure provides methods for inducing the degradation of a target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0409] In another aspect, the present disclosure provides methods for binding an E3 ubiquitin ligase and promoting the degradation and/or ubiquitination of a target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0410] All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the disease (e.g., proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) to be treated or prevented using the compounds described herein is cancer. All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is recurring breast cancer. In certain embodiments, the cancer is mutant breast cancer. In certain embodiments, the cancer is HER2+ breast cancer. In certain embodiments, the cancer is HER2− breast cancer. In certain embodiments, the cancer is triple-negative breast cancer (TNBC). In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is colon cancer.

[0411] In still another aspect, the present disclosure provides the pharmaceutical compositions described herein for use in binding an E3 ubiquitin ligase and CDK9 and/or CDK12 and promoting the degradation of a target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))); inducing apoptosis in a cell in a subject, biological sample, tissue, or cell; and treating and/or preventing proliferative diseases.

EXAMPLES

[0412] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0413] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. It will be appreciated that where typical or preferred 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 solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

Example 1. Synthetic Preparation of Exemplary Compounds of Formula (I)

[0414] Compounds of Formula (I) may be prepared using the synthetic schemes and procedures described in detail below.

Synthesis of N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (BSJ-04-023)

[0415] ##STR00210##

(R)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (8)

[0416] To a solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (7) (404 mg, 1.0 mmol) in 5 mL of NMP was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (300 mg, 1.5 mmol) and DIPEA (0.52 mL, 3.0 mmol). The reaction mixture was heated to 125° C. and kept stirring overnight. The mixture was then warmed to room temperature, extracted with 100 mL of Ethyl Acetate (EA) and 50 mL of water. The organic layer was washed with 50 mL of Saturated Na.sub.2CO.sub.3 and 50 mL of brine, dried over anhydrous Na.sub.2SO.sub.4, and evaporated to give a yellowish residue which was directly dissolved into 2.5 mL of DCM, followed by slow addition of 2.5 mL of TFA at ice-bath. The mixture was warmed to room temperature and stirred for 0.5 h. The solvent was then evaporated, and the residue was purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give 8 (TFA salt) as a yellow solid (407 mg, 87% in two steps). LC-MS: m/z 468 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.61 (s, 1H), 8.53-8.47 (m, 1H), 8.45-8.19 (m, 1H), 8.09 (d, J=7.8 Hz, 2H), 8.05-7.96 (m, 1H), 7.88-7.69 (m, 2H), 7.66-7.58 (m, 2H), 7.51-7.32 (m, 2H), 4.19 (br, 1H), 3.38-3.27 (m, 1H), 3.16 (d, J=1.5 Hz, 1H), 3.15-3.07 (m, 1H), 2.82 (q, J=11.0 Hz, 2H), 2.00 (br, 1H), 1.87 (br, 1H), 1.73 (br, 1H), 1.54 (br, 1H). .sup.13C NMR (126 MHz, DMSO) δ 159.49, 159.39, 158.13, 136.42, 135.18, 133.69, 130.11, 129.61, 129.58, 128.82, 128.73, 128.44, 127.06, 125.63, 124.41, 117.07, 115.17, 115.12, 112.92, 46.17, 44.96, 42.85, 28.18, 20.33.

(R)—N-(1-(7-aminoheptyl)piperidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (9)

[0417] To a solution of 8 (103 mg, 0.22 mmol) in DMSO (2 mL) was added tert-butyl (7-bromoheptyl)carbamate (4) (129 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol). The mixture was heated to 80° C. and kept stirring for 24 h. The mixture was then cooled down to room temperature, extracted, dried, filtered and concentrated to give a Boc-protected intermediate which was then dissolved into 2 mL of dioxane, followed by addition of 1 mL of 1N NaOH solution, and stirred at room temperature for 4 h. The reaction mixture was extracted with DCM, dried over anhydrous Na.sub.2SO.sub.4, and evaporated to give a brown residue, LC-MS: m/z 541 [M+1]. The residue was dissolved in 2 mL of DCM, then 2 mL of TFA was added at ice-bath. The resulting mixture was then warmed to room temperature and stirred for 0.5 h. Then, the solvent was evaporated and the residue was purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give 9 (TFA salt) as a light yellow solid (56.3 mg, 58% in three steps). LC-MS: m/z 441 [M+1].

N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (BSJ-04-023)

[0418] To a solution of 9 (18.6 mg, 0.0422 mmol) in 2 mL of DMF was added 6 (14 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol) and DIPEA (37 μL, 0.211 mmol). The resulting mixture was stirred for 1 h at room temperature, then evaporated the solvent and purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give BSJ-04-023 (TFA salt) as a light-yellow solid (30.7 mg, 83%). LC-MS: m/z 756 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.90 (d, J=3.3 Hz, 1H), 11.12 (s, 1H), 9.42 (s, 1H), 8.54-8.41 (m, 1H), 8.38-8.26 (m, 1H), 7.93 (q, J=5.8 Hz, 1H), 7.85-7.73 (m, 1H), 7.50 (d, J=7.3 Hz, 3H), 7.43-7.32 (m, 1H), 7.27-7.09 (m, 2H), 5.11 (dd, J=12.8, 5.4 Hz, 1H), 4.76 (d, J=3.3 Hz, 2H), 3.19-2.97 (m, 5H), 2.97-2.67 (m, 3H), 2.65-2.51 (m, 2H), 2.15-1.95 (m, 4H), 1.70-1.51 (m, 2H), 1.49-1.36 (m, 3H), 1.34-1.10 (m, 8H). .sup.13C NMR (126 MHz, DMSO) δ 172.80, 169.89, 166.73, 166.66, 165.54, 159.39, 158.27, 157.99, 155.04, 136.94, 136.07, 133.04, 131.11, 131.05, 126.21, 122.45, 120.75, 120.42, 116.83, 116.10, 113.84, 111.95, 67.68, 56.19, 48.81, 38.24, 30.95, 28.90, 28.09, 26.00, 25.93, 23.21, 22.00.

Synthesis of N-(6-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-2, BSJ-04-078)

[0419] I-2 was synthesized with similar procedures as I-1 from 3 (21.1 mg, 0.045 mmol), tert-butyl (4-bromohexyl)carbamate (12.6 mg, 0.045 mmol) and 6 (10 mg, 0.03 mmol). I-2 was obtained as an off-white solid (14.7 mg, 44% in 4 steps). LC-MS: m/z 741 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.90 (t, J=3.3 Hz, 1H), 11.12 (s, 1H), 9.43 (s, 1H), 8.48 (t, J=2.9 Hz, 1H), 8.39-8.28 (m, 1H), 8.03-7.90 (m, 1H), 7.85-7.75 (m, 1H), 7.55-7.48 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 5.15-5.07 (m, 1H), 4.76 (d, J=3.6 Hz, 2H), 3.20-2.98 (m, 5H), 2.96-2.70 (m, 3H), 2.64-2.53 (m, 2H), 2.15-1.71 (m, 4H), 1.71-1.37 (m, 5H), 1.35-1.03 (m, 6H).

Synthesis of N-(5-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)pentyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-3, BSJ-04-079)

[0420] I-3 was synthesized with similar procedures as I-1 from 3 (21.1 mg, 0.045 mmol), tert-butyl (5-bromopentyl)carbamate (11.9 mg, 0.045 mmol) and 6 (10 mg, 0.03 mmol). I-3 was obtained as an off-white solid (14.4 mg, 44% in 4 steps). LC-MS: m/z 727 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.89 (d, J=3.2 Hz, 1H), 11.12 (s, 1H), 9.44 (s, 1H), 8.48 (t, J=3.1 Hz, 1H), 8.31 (s, 1H), 8.02-7.91 (m, 1H), 7.85-7.75 (m, 1H), 7.50 (d, J=7.5 Hz, 3H), 7.42-7.36 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.12 (m, 1H), 5.11 (dd, J=12.8, 5.4 Hz, 1H), 4.76 (d, J=4.7 Hz, 2H), 3.22-2.99 (m, 6H), 2.95-2.71 (m, 4H), 2.65-2.53 (m, 2H), 2.15-1.94 (m, 3H), 1.72-1.57 (m, 2H), 1.55-1.37 (m, 3H), 1.34-1.13 (m, 4H).

Synthesis of N-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-4, BSJ-04-080)

[0421] I-4 was synthesized with similar procedures as I-1 from 3 (21.1 mg, 0.045 mmol), tert-butyl (4-bromobutyl)carbamate (11.4 mg, 0.045 mmol) and 6 (10 mg, 0.03 mmol). I-4 was obtained as an off-white solid (15.1 mg, 47% in 4 steps). LC-MS: m/z 713 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.90 (d, J=3.2 Hz, 1H), 11.12 (s, 1H), 9.50 (s, 1H), 8.48 (t, J=2.7 Hz, 1H), 8.32 (d, J=12.8 Hz, 1H), 8.03 (t, J=5.8 Hz, 1H), 7.85-7.74 (m, 1H), 7.50 (q, J=6.7 Hz, 3H), 7.43-7.35 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.13 (m, 1H), 5.15-5.05 (m, 1H), 4.77 (d, J=7.8 Hz, 2H), 3.67-3.27 (m, 2H), 3.23-3.07 (m, 5H), 2.96-2.69 (m, 3H), 2.64-2.52 (m, 2H), 2.09-1.93 (m, 3H), 1.92-1.59 (m, 4H), 1.56-1.39 (m, 3H).

Synthesis of N-(2-(2-(2-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-5, BSJ-04-026)

[0422] I-5 was synthesized with similar procedures as I-1 from 3 (21.1 mg, 0.045 mmol), tert-butyl (2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (16.0 mg, 0.045 mmol) and 6 (10 mg, 0.03 mmol). I-5 was obtained as an off-white solid (16.5 mg, 45% in 4 steps). LC-MS: m/z 817 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.90 (d, J=4.2 Hz, 1H), 11.13 (s, 1H), 9.63 (s, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.32 (s, 1H), 7.97 (t, J=5.7 Hz, 1H), 7.90-7.76 (m, 1H), 7.68-7.45 (m, 3H), 7.38 (dd, J=8.6, 2.2 Hz, 1H), 7.30-7.14 (m, 2H), 5.15-5.07 (m, 1H), 4.77 (s, 2H), 4.46-4.12 (br, 2H), 3.84-3.65 (m, 4H), 3.43-3.18 (m, 10H), 3.00-2.71 (m, 4H), 2.66-2.52 (m, 2H), 2.19-1.73 (m, 6H).

Synthesis of N-(2-(2-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-6, BSJ-04-098)

[0423] I-6 was synthesized with similar procedures as I-1 from 3 (21.1 mg, 0.045 mmol), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (14.0 mg, 0.045 mmol) and 6 (10 mg, 0.03 mmol). I-6 was obtained as an off-white solid (16.7 mg, 48% in 4 steps). LC-MS: m/z 772 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.89 (d, J=3.3 Hz, 1H), 11.12 (s, 1H), 9.63 (s, 1H), 8.48 (dd, J=5.2, 3.0 Hz, 1H), 8.32 (d, J=15.6 Hz, 1H), 8.03-7.90 (m, 1H), 7.85-7.75 (m, 1H), 7.49 (dd, J=7.4, 2.2 Hz, 3H), 7.38 (dd, J=9.4, 3.9 Hz, 1H), 7.27-7.10 (m, 2H), 5.11 (dd, J=12.9, 5.4 Hz, 1H), 4.76 (d, J=4.3 Hz, 2H), 3.81-3.64 (m, 3H), 3.63-3.50 (m, 4H), 3.44 (d, J=5.8 Hz, 2H), 3.41-3.22 (m, 6H), 2.99-2.73 (m, 3H), 2.65-2.53 (m, 1H), 2.13-1.92 (m, 3H), 1.92-1.73 (m, 2H).

N-(2-(2-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-7, BSJ-04-099)

[0424] I-7 was synthesized with similar procedures as I-1. LC-MS: m/z 801 [M+1].

Synthesis of N-(6-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-6-oxohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-8, BSJ-04-071)

[0425] I-8 was synthesized with similar procedures as I-1. LC-MS: m/z 756 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 11.11 (d, J=2.6 Hz, 1H), 8.49-8.41 (m, 1H), 8.27 (d, J=3.7 Hz, 1H), 7.98-7.91 (m, 1H), 7.84-7.71 (m, 1H), 7.52-7.43 (m, 2H), 7.41-7.34 (m, 2H), 7.33-7.03 (m, 3H), 5.15-5.06 (m, 1H), 4.75 (d, J=3.6 Hz, 2H), 4.53-3.88 (m, 4H), 3.21-3.10 (m, 1H), 3.08-2.96 (m, 2H), 2.95-2.83 (m, 2H), 2.83-2.69 (m, 1H), 2.65-2.53 (m, 2H), 2.43-2.21 (m, 1H), 2.14-1.90 (m, 3H), 1.86-1.72 (m, 1H), 1.69-0.90 (m, 9H).

N-(5-(4-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)piperazin-1-yl)pentyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-9, BSJ-04-077)

[0426] I-9 was synthesized with similar procedures as I-1. LC-MS: m/z 915 [M+1].

N-(3-(4-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)piperazin-1-yl)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-10, BSJ-04-076)

[0427] I-10 was synthesized with similar procedures as I-1. LC-MS: m/z 887 [M+1].

N-(7-(4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)piperazin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-11, BSJ-04-100)

[0428] I-11 was synthesized with similar procedures as I-1. LC-MS: m/z 943 [M+1].

N-(7-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-12, BSJ-04-086)

[0429] I-12 was synthesized with similar procedures as I-10. LC-MS: m/z 866 [M+1].

N-(7-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-13, BSJ-04-089)

[0430] I-13 was synthesized with similar procedures as I-10. LC-MS: m/z 852 [M+1].

Synthesis of N-(7-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-14; BSJ-04-116)

[0431] ##STR00211##

(R)-5-chloro-N.SUB.4.-(2-(isopropylsulfonyl)phenyl)-N.SUB.2.-(piperidin-3-yl)pyrimidine-2,4-diamine (3)

[0432] To a solution of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine 1 (345 mg, 1.0 mmol) in 5 mL of NMP was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (300 mg, 1.5 mmol) and DIPEA (0.52 mL, 3.0 mmol). The reaction mixture was heated to 125° C. and kept stirring overnight. The mixture was then warmed to room temperature, extracted with 100 mL of Ethyl Acetate (EA) and 50 mL of water. The organic layer was washed with 50 mL of Saturated Na.sub.2CO.sub.3 and 50 mL of brine, dried over anhydrous Na.sub.2SO.sub.4, and evaporated to give a yellowish residue which was directly dissolved into 2.5 mL of DCM, followed by slow addition of 2.5 mL of TFA at ice-bath. The mixture was warmed to room temperature and stirred for 0.5 h. The solvent was then evaporated, and the residue was purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give 3 (TFA salt) as a yellow solid (368 mg, 90% in two steps). LC-MS: m/z 410 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 8.81 (br, 2H), 8.29-8.10 (m, 1H), 7.92-7.82 (m, 1H), 7.78 (s, 1H), 7.37 (s, 1H), 4.03 (br, 1H), 3.50-3.40 (m, 1H), 3.39-3.28 (br, 1H), 3.23-3.13 (m, 1H), 2.90-2.74 (m, 3H), 1.97 (s, 1H), 1.93-1.82 (m, 1H), 1.72-1.61 (m, 1H), 1.55 (d, J=36.1 Hz, 1H), 1.18 (d, J=2.1 Hz, 3H), 1.16 (d, J=2.1 Hz, 3H). .sup.13C NMR (126 MHz, DMSO) δ 158.77, 158.49, 158.20, 154.97, 154.70, 153.93, 138.10, 135.07, 131.01, 123.37, 116.95, 114.62, 54.92, 46.26, 45.08, 43.03, 28.07, 20.55, 14.87, 14.83.

(R)—N.SUB.2.-(1-(7-aminoheptyl)piperidin-3-yl)-5-chloro-N.SUB.4.-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (5)

[0433] To a solution of 3 (90 mg, 0.22 mmol) in DMSO (2 mL) was added tert-butyl (7-bromoheptyl)carbamate (4) (129 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol). The mixture was heated to 80° C. and kept stirring for 24 h. The mixture was then cooled down to room temperature, extracted, dried, filtered and concentrated to give a light brown residue which was then dissolved into 1 mL of DCM, followed by slow addition of 1 mL of TFA at ice bath. The mixture was then warmed to room temperature and evaporated after 0.5 h. The residue was purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give 5 (TFA salt) as a light grey solid (115 mg, 65% in two steps). LC-MS: m/z 523 [M+1].

N-(7-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (I-14; BSJ-04-116)

[0434] To a solution of 5 (22 mg, 0.0422 mmol) in 2 mL of DMF was added 6 (14 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol) and DIPEA (37 μL, 0.211 mmol). The resulting mixture was stirred for 1 h at room temperature, then evaporated the solvent and purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give I-14; BSJ-04-116 (TFA salt) as an off-white solid (30.7 mg, 87%). LC-MS: m/z 838 [M+1]. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.12 (s, 1H), 9.52 (s, 1H), 9.41 (s, 1H), 8.63 (br, 1H), 8.19 (d, J=11.9 Hz, 1H), 7.93 (t, J=6.2 Hz, 1H), 7.87-7.71 (m, 3H), 7.50 (d, J=7.3 Hz, 1H), 7.43-7.26 (m, 3H), 5.11 (dd, J=12.9, 5.4 Hz, 1H), 4.76 (s, 2H), 3.49-3.31 (m, 3H), 3.20-3.11 (m, 2H), 3.10-2.97 (m, 2H), 2.95-2.77 (m, 2H), 2.75-2.53 (m, 2H), 2.10-2.00 (m, 2H), 2.00-1.88 (m, 2H), 1.86-1.53 (m, 3H), 1.52-1.36 (m, 4H), 1.33-1.20 (m, 6H), 1.20-1.11 (m, 6H). .sup.13C NMR (126 MHz, DMSO) δ 172.81, 169.89, 166.73, 166.66, 165.55, 158.31, 158.03, 155.04, 154.95, 136.96, 135.06, 133.04, 131.05, 120.43, 116.84, 116.12, 67.69, 56.16, 54.98, 48.82, 38.24, 30.95, 28.89, 28.08, 26.01, 25.91, 25.87, 23.19, 22.00, 14.92, 14.85, 14.81.

Synthesis of (2S,4R)-1-((S)-14-(tert-butyl)-1-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-15; BSJ-05-063)

[0435] ##STR00212##

((R)-11-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanoic Acid (11)

[0436] To a solution of 3 (90 mg, 0.22 mmol) in DMSO (2 mL) was added tert-butyl 11-bromoundecanoate (11) (150 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol). The mixture was heated to 80° C. and kept stirring for 24 hours. The mixture was then cooled down to room temperature, extracted, dried, filtered and concentrated to give a light brown residue which was then dissolved into 1 mL of DCM, followed by slow addition of 1 mL of TFA at ice bath. The mixture was then warmed to room temperature and evaporated after 0.5 hours. The residue was purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give 11 (TFA salt) as a light-yellow oil (94 mg, 70% in two steps). LC-MS: m/z 594 [M+1].

(Synthesis of (2S,4R)-1-((S)-2-(11-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-15, BSJ-05-063)

[0437] To a solution of 11 (26 mg, 0.0422 mmol) in 2 mL of DMF was added 12 (19 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol) and DIPEA (37 μL, 0.211 mmol). The resulting mixture was stirred for 1 hour at room temperature, then evaporated the solvent and purified by reverse phase HPLC (5-95% MeOH in H.sub.2O) to give BSJ-06-63 (TFA salt) as an off-white solid (33 mg, 75%). LC-MS: m/z 1020 [M+1].

(2S,4R)-1-((S)-14-(tert-butyl)-1-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-16; BSJ-05-064)

[0438] ##STR00213##

[0439] Compound I-16 (BSJ-05-064) was synthesized with similar procedures as for the synthesis of compound I-16 (BSJ-05-064) from 3 (47.4 mg, 0.0844 mmol), tert-butyl 3-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)propanoate (30 mg, 0.0844 mmol) and 12 (23.3 mg, 0.0844 mmol). Compound I-16 (BSJ-05-064) was obtained as a yellow solid (20.6 mg, 24% in 4 steps). LC-MS: m/z 1041 [M+1].

(2R,4S)-1-((S)-2-(11-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-17; ZXH-7-091)

[0440] Compound I-17 was a negative control of compound I-15. It was synthesized using similar procedures as for compound I-15. LC-MS: m/z 1020 [M+1].

Example 2. CDK12 Biology Assays

[0441] Cyclin-dependent kinase 12 and 13 (CDK12/13) are elongation regulators of RNA polymerase II-mediated transcription through kinase function of phosphorylation on the C-terminal repeat domain (CTD) of RNA polymerase II. CDK12 plays a critical role in mediating genome stability and its deletion impairs the expression of several critical regulators of genome stability. Mutations of CDK12 have been identified in variety of tumors including ovary, breast, and prostate. Previous CDK12 inhibitors including, for example, covalent THZ531 (see above for chemical structure), as well as others, are not selective and potent inhibition of CDK13 is also observed.

[0442] The presently disclosed novel bifunctional compounds conjugate CDK12 inhibitors with E3 ligase ligands to induce CDK12 protein degradation (see Brief Description of the Drawings, and Table 1 below for chemical structures of exemplary CDK inhibitors). CDK12 degradation activity of exemplary compounds is shown in Table 1.

[0443] Assays for the degradation of CDK12 by exemplary compounds of Formula (I) were conducted. The results for the assays for the degradation of CDK12 by exemplary CDK12 degrader compounds depicted in Table 1 are shown in FIGS. 1-3. Table 1 also shows the CDK12 degradation activity of exemplary CDK12 inhibitor compounds 1-13 depicted in Table 1 below, wherein “+++” indicates a greater than 90% degradation, “++” indicates 80% degradation and “+” indicates 60% degradation of CDK12 at 100 nM. “N/A” indicates that the activity is undetectable at up to 500 nM via Western blotting.

TABLE-US-00002 TABLE 1 Exemplary CDK12 Degrader Compounds CDK12 degradation Compound Structure activity I-1 (BSJ-04-023) [00214] +++ I-2 (BSJ-04-078) [00215] ++ 1-3 (BSJ-04-079) [00216] N/A 1-4 (BSJ-04-080) [00217] N/A 1-5 (BSJ-04-026) [00218] ++ 1-6 (BSJ-04-026) (BSJ-04-098) [00219] N/A 1-7 (BSJ-04-099) [00220] N/A 1-8 (BSJ-04-071) [00221] N/A 1-9 (BSJ-04-77) [00222] ++ 1-10 (BSJ-04-076) [00223] + I-11 (BSJ-04-100) [00224] N/A 1-12 (BSJ-04-086) [00225] ++ 1-13 (BSJ-04-089) [00226] ++ 1-14 (BSJ-04-116) [00227] +++ 1-15 (BSJ-05-063) [00228] +++ 1-16 (BSJ-05-064) [00229] +++ 1-17 (ZXH-7-091) [00230] N/A

Example 3. Pharmacokinetic Studies of Exemplary Compounds

[0444] Standard pharmacokinetic parameters were determined by administration of exemplary compound BSJ-05-063 to male C57BI/6 mice, and conducting standard pharmacokinetic studies. A single 2 mg/kg intravenous (IV) injection of compound BSJ-05-063 solution in 5/5/90 DMSO/Cremophor EL/water was delivered, and the pharmacokinetic parameters were evaluated. The plasma concentrations of BSJ-05-063 were reported at each of the 8 time points (5 minutes, 15 minutes, 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, and 8 hours post-dosing) are the average values from 3 test animals (male C57BI/6 mice). The results for the pharmacokinetic studies for exemplary compound BSJ-05-063 are shown in Table 2 below.

TABLE-US-00003 TABLE 2 Average pharmacokinetic parameters for exemplary compound BSJ-05-063 (IV administration). T.sub.1/2 T.sub.max C.sub.max C.sub.max AUC.sub.last AUC.sub.last AUC.sub.INF_obs AUC Cl_.sub.obs MRT.sub.INF_obs Vss_obs hr hr ng/mL μM min * ng/mL μM .Math. hr min * ng/mL % Extrap mL/min/kg hr L/kg 2.21 0.08 4573 4.49 343429 5.61 368545 6.27 6.04 2.41 0.84

EQUIVALENTS AND SCOPE

[0445] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0446] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0447] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0448] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.