Cdk inhibitor compounds

Abstract

Provided herein are CDK inhibitor compounds having a fused 6-6 bicyclic heteroaryl core, such as a naphthyridine, quinazoline, pyridopyrimidine or related isosteric core structure that is further substituted. The core structure can be substituted with an amino group, where the amino group is further substituted with a cyclic group having an appended hydrophilic group. Also provided herein are compositions including the subject CDK inhibitor compounds. In some embodiments, the CDK inhibitor compounds are CDK2 inhibitors, or CDK4 inhibitors. Also provided are methods for using compositions of the disclosure in research or as therapeutics.

Description

Atty. Docket No.: 39953-58778 (002WO) CDK INHIBITOR COMPOUNDS 1. CROSS-REFERENCE TO RELATED APPPLICATION

[0001] This application claims benefit of U.S. Provisional Application No.63 / 502,371, filed on May 15, 2023, which is herein incorporated by reference in its entirety. 2. INTRODUCTION

[0002] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. Heterodimerized with regulatory subunits known as cyclins, CDKs become fully activated and regulate key cellular processes including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. The deregulation of the CDK activity is associated with abnormal regulation of cell-cycle, and is detected in virtually all forms of human cancers.

[0003] CDK2 is a cyclin-dependent kinase that plays a critical role in regulating the transition from the G1 to S phase of the cell cycle. It is involved in several other cellular processes, including DNA replication and repair, transcription, RNA processing, and cytoskeletal organization, making it an attractive target for cancer therapy. CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in a variety of human cancers. Although CDK2 is mostly dispensable in the cell cycle of normally functioning cells, it is critical to the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two major protein binding partners of CDK2. Overexpression of CCNE1 occurs in many tumor cells, causing the cells to become dependent on CDK2 and cyclin E. Abnormal cyclin E activity is also observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemia and lymphoma. Likewise, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, while inhibition leads to decreased tumor growth.

[0004] Therefore, CDK2 and its cyclin binding partners represent possible therapeutic targets for new cancer therapeutics. CDK2 inhibitors are a class of small molecule drugs that block the activity of CDK2, leading to cell cycle arrest and potentially inducing cell death. However, identifying selective CDK2 inhibitors is difficult due to the extreme similarity between the active sites of CDK2 and other CDKs, for example CDK1. CDK1 is the only essential cyclin dependent kinase in the cell cycle, and its inhibition could lead to unintended side effects.Atty. Docket No.: 39953-58778 (002WO) 3. SUMMARY

[0005] Provided herein are CDK inhibitor compounds. The CDK inhibitor compounds can have fused 6-6 bicyclic core, such as a naphthyridine, quinazoline, pyridopyrimidine or related isosteric core structure that is further substituted. The core structure can substituted with an amino group, where the amino group is further substituted with a cyclic group having an appended hydrophilic group. The CDK inhibitor compounds can be CDK2 inhibitors. The CDK inhibitor compounds can be CDK4 inhibitors. Also provided herein are pharmaceutical compositions including the subject CDK inhibitor compounds. Also provided are methods for using compositions of the disclosure in research and as therapeutics.

[0006] Accordingly, this disclosure includes CDK inhibitor compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein: Y1is N or CR1; Y2is N or CR2; Y3is N or CR3; Y5is N or CR5; R6is of the formula, wherein: A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; Z is an optional hydrophilic group; L1and L2are optional linkers; and * represents the point of attachment of R6to the adjacent nitrogen atom; R4is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl; R1-R3, R5and R7are independently selected from H, optionally substituted (C1-6)alkyl, halo(C1-6)alkyl, -COR30, -OR30, halogen, and CN; andAtty. Docket No.: 39953-58778 (002WO) R30is H or optionally substituted (C1-6)alkyl.

[0007] In some embodiments of Formula (I), the compound is of Formula (IA): , or a pharmaceutically acceptable4. DETAILED DESCRIPTION

[0008] The CDK inhibitor compounds, compositions and methods of this disclosure are described in greater detail below. A particular class of CDK2 inhibitor compounds is described. Also described are pharmaceutical compositions that include the subject CDK inhibitor compounds. Methods in which the CDK inhibitor compounds and compositions find use are also described. 4.1 CDK inhibitor compounds

[0009] As summarized above, this disclosure provides CDK inhibitor compounds having a fused 6-6 bicyclic heteroaryl core structure. In some embodiments, the compound has a 2,6-naphthyridine core or related isosteric core. In some embodiments, the compound has a pyrido[3,4-d]pyrimidine core. In some embodiments, the compound has a quinazoline core. The naphthyridine core can be substituted with an amino group, wherein the amino group is further substituted with a cyclic group having an appended hydrophilic group attached via an optional linker. In some embodiments, the hydrophilic group is a non-electrophilic group. In some embodiments the CDK inhibitor is a classic inhibitor, where the inhibitor compound binds to a CDK and prevents other molecules from binding to the kinase. Classic inhibitors may not permanently bind to the receptor, i.e., they associate to the receptor and dissociate from the receptor reversibly, for example via hydrogen bonding or Van der Waals interactions.

[0010] In some embodiments, the hydrophilic group is an electrophilic reactive moiety. In general, an electrophilic reactive moiety is a chemical group that is capable of covalently conjugating with a biological target. In some embodiments, the CDK inhibitor that includes an electrophilic reactive moiety is referred to as a covalent inhibitor, where the covalent inhibitor can bind to the CDK target at a desired binding site, and form a covalent, chemicalAtty. Docket No.: 39953-58778 (002WO) bond to the receptor. In some embodiments, the covalent, chemical bond formed is not reversible. In some embodiments, the CDK inhibitor is a covalent reversible inhibitor. Such inhibitors can form a covalent bond with the receptor, but this chemical conjugation reaction is reversible. In some embodiments, the CDK is CDK2. In some embodiments, the CDK is CDK4.

[0011] The disclosure includes CDK inhibitor compounds of Formula I:or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Y1is N or CR1; Y2is N or CR2; Y3is N or CR3; Y5is N or CR5; R6is of the formula, wherein A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; Z is an optional hydrophilic group; L1and L2are optional linkers; and * represents the point of attachment of R6to the nitrogen atom; R4is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl; R1-R3, R5and R7are independently selected from H, optionally substituted (C1-6)alkyl, halo(C1-6)alkyl, -COR30, -OR30, halogen, and CN; and R30is H or optionally substituted (C1-6)alkyl.

[0012] In some embodiments of the compound of Formula I, one or more of Y1-Y3is N. In some embodiments, Y3is N. In some embodiments, Y2is N. In some embodiments Y1isAtty. Docket No.: 39953-58778 (002WO) N. In some embodiments Y1and Y3are N. In some embodiments Y2and Y3are N. In some embodiments Y1and Y2are N.

[0013] In some embodiments of the compound of Formula I, the A ring is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments of Formula I, A is an optionally substituted aryl. In some embodiments of Formula I, A is an optionally substituted heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments the heteroaryl is pyridyl, pyridazine, pyrimidine or triazine.

[0014] In some embodiments of the compound of Formula I, R6comprises the structure 6A:wherein: Y6-Y10groups are independently selected from C-Z, CR12or N, wherein one of Y6- Y10is C-Z; each R12is independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, halogen, and CN; and Z is a group as described herein.

[0015] In some embodiments of 6A, Y8is C-Z. In some embodiments of 6A, Y6or Y10is C-Z. In some embodiments of 6A, Y7or Y9is C-Z.

[0016] In some embodiments of 6A, at least one of Y6-Y10is N. In some cases of 6A, Y6or Y10is N. In some cases of 6A, both Y6and Y10are N. In some cases of 6A, Y7or Y9is N. In some cases of 6A, both Y7and Y9are N. In some cases of 6A, Y8is N.

[0017] In some embodiments of 6A, one and only one of Y6-Y10is N. In some cases of 6A, Y6is N. In some cases of 6A, Y7is N.

[0018] In some embodiments of 6A, Z is attached to Y8, and Y6, Y7, Y9and Y10are each CR12. In some embodiments, each R12is H. In some embodiments, at least one R12is not H. In some embodiments, at least one R12is selected from (C1-3)alkyl, (C1-3)alkoxy, halogen, and nitrile. In some embodiments, R12is methyl. In some embodiments R12is Cl or F. In some embodiments, R12is nitrile.

[0019] In some embodiments of the compound of Formula I, R6is of the structure 6A1:Atty. Docket No.: 39953-58778 (002WO) wherein m is 0, 1, 2, 3 or 4, and Zherein.

[0020] In some embodiments of 6A1, m is 0. It will be understood that when m is 0, each of positions 2, 3, 5 and 6 of the aryl ring will have no non-hydrogen substituents.

[0021] In some embodiments of 6A1, m is more than 0, such as 1, 2, 3 or 4, and each R12is a non-hydrogen substituent. In some embodiments, each R12is independently selected from optionally substituted (C1-3)alkyl, optionally substituted (C1-3)alkoxy, hydroxy, halogen, and CN. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments m is 1 and R12is optionally substituted (C1-3)alkyl, optionally substituted (C1-3)alkoxy, hydroxy, halogen, or CN. In some embodiments, m is 2 and each R12is independently selected from optionally substituted (C1-3)alkyl, optionally substituted (C1-3)alkoxy, hydroxy, halogen, and CN.

[0022] In some embodiments of 6A1, R6is of the structure 6A2:wherein R12is selected from hydrogen, halogen (e.g., F), optionally substituted (C1-6)alkyl, and optionally substituted (C1-6)alkoxy.

[0023] In some embodiments of 6A2, R12is hydrogen. In some embodiments of 6A2, R12is halogen. In some embodiments, the halogen is F or Cl. In some embodiments of 6A2, R12is optionally substituted (C1-3)alkyl. In some embodiments, R12is methyl. In some embodiments, R12is trifluoromethyl. In some embodiments, R12is (C1-3)alkoxy. In some embodiments, R12is methoxy.

[0024] In some embodiments of the compound of Formula I, A is selected from optionally substituted cycloalkyl, and optionally substituted heterocyclyl. In some embodiments of Formula I, A is an optionally substituted cycloalkyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, the cycloalkyl is cyclopentyl. In some embodiments of Formula I, A is an optionally substituted heterocyclyl. In some embodiments, the heterocyclyl includes one or more nitrogen atoms. In some embodiments, the heterocyclyl includes one or more oxygen atoms. In some embodiments, the heterocyclylAtty. Docket No.: 39953-58778 (002WO) includes one or more sulfur atoms. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. In some embodiments the 6-membered heterocyclyl is selected from piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, dithiane, morpholine, and thiomorpholine. In some embodiments, the 6-membered heterocyclyl is piperidine. In some embodiments, the heterocyclyl is tetrahydropyran.

[0025] In some embodiments of Formula I, R6comprises the structure 6B:wherein: Y11is selected from O, S, CH2, C(R11)2, and NR9; R9is hydrogen, optionally substituted alkyl, -L2-Z, or Z; each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; L2is as described herein; k is 0 or 1; and n is an integer from 0 to 9.

[0026] In some embodiments of 6B, Y11is O. In some embodiments of 6B, Y11is S. In some embodiments of 6B, Y11is C(R11)2. In some embodiments, Y11is CH2. In some embodiments one R11is H and the other is selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN. In some embodiments of 6B, Y11is NR9. In some embodiments, Y11is NH. In some embodiments, Y11is NR9and R9is optionally substituted alkyl, -L2-Z, or Z. In some embodiments, R9is optionally substituted (C1-C3)alkyl. In some embodiments, R9is - L2-Z. In some embodiments, R9is Z.

[0027] In some embodiments of 6B, k is 0. In some embodiments of 6B, k is 1.

[0028] In some embodiments of the compound of Formula I, R6comprises the structure 6B1:(6B1).Atty. Docket No.: 39953-58778 (002WO)

[0029] In some embodiments of 6B1, n is 0, such that there are no R11substituents. In some embodiments of 6B1, n is 1, 2, 3 or 4, and each R11is independently selected from (C1-3)alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, and CN. In some embodiments, R11is independently selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro. In some embodiments, n is 1 and R11is selected from (C1-3)alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, and CN. In some embodiments, n is 1 and R11is selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro.

[0030] In some embodiments of 6B1, R6comprises the structure 6B2:

[0031] In some embodiments of the compound of Formula I, R6comprises the 6B3:.

[0032] In some embodiments of 6B3, n is 0, such that there are no R11substituents. In some embodiments of 6B3, n is 1, 2, 3 or 4, and each R11is independently selected from (C1-3)alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, and CN. In some embodiments, R11is independently selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro. In some embodiments, n is 1 and R11is selected from (C1-3)alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, and CN. In some embodiments, n is 1 and R11is selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro.

[0033] In some embodiments of 6B3, R6comprises the structure 6B4:.

[0034] In some embodiments of Formula I, R4is selected from substituted amine, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.

[0035] In some embodiments of Formula I, R4is optionally substituted alkynyl.

[0036] In some embodiments of Formula I, R4is optionally substituted cycloalkyl.

[0037] In some embodiments of Formula I, R4is optionally substituted cycloalkene.Atty. Docket No.: 39953-58778 (002WO)

[0038] In some embodiments of Formula I, R4is optionally substituted heterocyclyl.

[0039] In some embodiments of Formula I, R4is optionally substituted aryl.

[0040] In some embodiments of Formula I, R4is an optionally substituted heteroaryl.

[0041] In some embodiments of Formula I, R4is a monocyclic group.

[0042] In some embodiments of Formula I, R4is a bicyclic group. In some embodiments of R4the bicyclic group is a spirocyclic group. In some embodiments of R4, the bicyclic group is a fused bicyclic group.

[0043] In some embodiments of Formula I, R4is selected from substituted amine, (C2- C6)alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrazole, azetidine, azepane, pyridyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, oxindole, triazole, oxadiazole, cyclohexanone, wherein any one of the R4groups is optionally substituted.

[0044] In some embodiments of Formula I, R4is selected from an optionally substituted amine. In some embodiments, the amine is substituted with two C1-C6 alkyl groups.

[0045] In some embodiments of Formula I, R4is an optionally substituted C2-C3 alkynyl group. In some embodiments the alkynyl group is substituted with a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclyl group, or a substituted alkyl group.

[0046] In some embodiments of Formula I, R4is optionally substituted cyclobutane. In some embodiments, R4is optionally substituted cyclopentane. In some embodiments, R4is optionally substituted cyclohexane. In some embodiments, R4is optionally substituted cyclohexene.

[0047] In some embodiments of Formula I, R4is optionally substituted piperidinyl. In some embodiments, R4is optionally substituted pyrrolidine. In some embodiments, R4is optionally substituted pyrrole. In some embodiments, R4is optionally substituted pyrazole. In some embodiments, R4is optionally substituted azetidine. In some embodiments, R4is optionally substituted azepane. In some embodiments, R4is optionally substituted pyridyl. In some embodiments, R4is optionally substituted phenyl. In some embodiments, R4is optionally substituted pyrimidine. In some embodiments, R4is optionally substituted benzisoxazole. In some embodiments, R4is optionally substituted indazole. In some embodiments, R4is optionally substituted thiazole. In some embodiments, R4is optionally substituted dihydropyran. In some embodiments, R4is optionally substituted tetrahydropyran. In some embodiments, R4is optionally substituted azaindole. In some embodiments, R4is optionally substituted indoline. In some embodiments, R4is optionally substituted oxindole. In some embodiments, R4is optionally substituted triazole. In some embodiments, R4isAtty. Docket No.: 39953-58778 (002WO) optionally substituted oxadiazole. In some embodiments, R4is optionally substituted cyclohexanone.

[0048] In some embodiments of Formula I, R4is of Formula 4A: , wherein:X12is CH2, C(R15)2, O, or NR25; R15is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R25is H, optionally substituted (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and r is 0 or 1.

[0049] In some embodiments of Formula 4A, q is 0, such that there are no R15substituents. In some embodiments, q is 1-11, and each R15substituent is independently selected from (C1-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.

[0050] In some embodiments of Formula 4A, r is 0. In some embodiments of Formula 4A, r is 1.

[0051] In some embodiments of 4A, R4is of formula 4A1:, wherein R15, q and r are as described herein.

[0052] In some embodiments of 4A1, r is 0. In some embodiments of 4A1, r is 1.

[0053] In some embodiments of 4A1, q is 0, such that there are no R15substituents. In some embodiments, q is 1-11, and each R15substituent is independently selected from (C1- C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.Atty. Docket No.: 39953-58778 (002WO)

[0054] In some embodiments of 4A, R4is of formula 4A2: , wherein:R25is H, or optionally substituted (C1-6)alkyl; and R15and q are as described herein.

[0055] In some embodiments of 4A2, R25is H. In some embodiments of 4A2, R25is optionally substituted (C1-3)alkyl.

[0056] In some embodiments of 4A2, q is 0, such that there are no R15substituents. In some embodiments, q is 1-11, and each R15substituent is independently selected from (C1- C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.

[0057] In some embodiments of Formula I, R4is of Formula 4B:, wherein: X1is O or C(R26)2; R16is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; each R26is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0058] In some embodiments of Formula 4B, X1is C(R26)2. In some embodiments each R26is H (i.e., X1is CH2). In some embodiments of Formula 4B, X1is O.

[0059] In some embodiments of Formula 4B, s is 0, such that there are no R16substituents. In some embodiments, s is 1-9, and each R16substituent is independently selected from (C1-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R16is nitrile. In some embodiments, q is 1 and R16is hydroxy.Atty. Docket No.: 39953-58778 (002WO)

[0060] In some embodiments of Formula I, R4is of Formula 4C: wherein:R17is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and u is 0, 1, or 2.

[0061] In some embodiments of Formula 4C, t is 0, such that there are no R17substituents. In some embodiments, t is 1-10, and each R17substituent is independently selected from (C1-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, t is 1 and R17is nitrile. In some embodiments, t is 1 and R17is hydroxy.

[0062] In some embodiments of Formula 4C, u is 0. In some embodiments of Formula 4C, u is 1. In some embodiments of Formula 4C, u is 2.

[0063] In some embodiments of Formula I, R4is of Formula 4D:, wherein: X14is O or NR25; R17is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; each R25is selected from H, (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; and k is 0, 1, 2, 3, 4, 5, 6, 7, or 8.Atty. Docket No.: 39953-58778 (002WO)

[0064] In some embodiments of Formula I, R4is of Formula 4E: , wherein:X2is selected from NR25, C(R26)2, C=O, O and S; X3and X4are each independently selected from N and CR26; R18is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R25is selected from H, optionally substituted C1-6 alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; each R26is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and v is 0, 1, 2, or 3.

[0065] In some embodiments of Formula 4E, X2is C(R26)2. In some embodiments each R26is H. In some embodiments, at least one R26group is optionally substituted alkyl. In some embodiments of Formula 4E, X2is O. In some embodiments of Formula 4E, X2is NR25. In some embodiments, R25is H. In some embodiments, R25is (C1-3)alkyl. In some embodiments of Formula 4E, X2is S. In some embodiments of Formula 4E, X2is C=O.

[0066] In some embodiments of Formula 4E, X3is N. In some embodiments of Formula 4E, X3is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0067] In some embodiments of Formula 4E, X4is N. In some embodiments of Formula 4E, X4is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0068] In some embodiments of Formula 4E, X2is NR25, X3is CR26and X4is CR26. In some embodiments of Formula 4E, X2is NR25, X3is N and X4is CR26. In some embodiments of Formula 4E, X2is O, X3is CR26and X4is N.Atty. Docket No.: 39953-58778 (002WO)

[0069] In some embodiments of Formula 4E, v is 0, such that there are no R18substituents. In some embodiments, v is 1-3, and each R18substituent is independently selected from (C1-3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, v is 1 and R18is (C1-3)alkyl. In some embodiments, the (C1-3)alkyl is methyl. In some embodiments, v is 1 and R18is halogen. In some embodiments the halogen is Cl or F.

[0070] In some embodiments of Formula 4E, R4is selected from one of the following structures:.

[0071] In some embodiments of Formula 4E, R4is selected from:wherein R25, R18and v are as defined herein.

[0072] In some embodiments of Formula 4E, R4is selected from :wherein R25, R18and v are as defined herein.

[0073] In some embodiments of Formula 4E, R4is selected from:or wherein R25, R18and v are as defined herein.

[0074] In some embodiments of of structure:Atty. Docket No.: 39953-58778 (002WO) wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen, and / or any two of R33– R37(e.g., R33and R34, and / or R36and R37) can be cyclically linked and together with the carbon atom(s) to which they are attached provide a C3-C7 carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, R33and R34together with the carbon atom to which they are attached is a C3- C7 carbocyclic ring (e.g., cyclopropyl, or cyclobutyl). In some embodiments, R36and R37together with the carbon atom to which they are attached is a C3-C7 carbocyclic ring (e.g., cyclopropyl, or cyclobutyl). In some embodiments, at least one of R33-R37is a halogen. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, one or two of R33-R35are CF3. In some embodiments, one of R33-R35is CF3. In some embodiments, two of R33-R35are CF3. In some embodiments, one or two of R33-R35are OH. In some embodiments, one of R33-R35is OH. In some embodiments, two of R33-R35are OH. In some embodiments, one or both of R36-R37are H. In some embodiments, R36is H, and R37is selected from CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen. In some embodiments, both R36and R37are H.

[0075] In some embodiments of Formula 4E, R25is of structure:wherein: R33– R37, if present, are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2). In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, h is 2. In some embodiments, h is 1.

[0076] In some embodiments of Formula 4E, R25isor , and R33– R37, if present, are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen.

[0077] In some embodiments of is of structure:.

[0078] In some embodiments of Formula 4E, R25is of structure:Atty. Docket No.: 39953-58778 (002WO) .

[0079] In some embodiments of compound is: 1wherein R8and v are as defined herein.

[0080] In some embodiments of Formula 4E, the compound is:wherein R18and v are as defined herein.

[0081] In some embodiments of Formula 4E, the compound is:wherein R18and v are as defined herein.

[0082] In some embodiments of Formula 4E, the compound is:wherein R18and v are as defined herein.

[0083] In some embodiments of Formula I, R4is of Formula 4F:, wherein: X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3and X4are each independently selected from N and CR26; R24is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionallyAtty. Docket No.: 39953-58778 (002WO) substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R29and R30are each independently H, or optionally substituted C1-6alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; and y is 0, 1, 2, or 3.

[0084] In some embodiments of Formula 4F, X9is C(R26)2. In some embodiments each R26is H. In some embodiments, at least one R26group is optionally substituted alkyl. In some embodiments of Formula 4F, X9is O. In some embodiments of Formula 4F, X9is NR25. In some embodiments, R25is H. In some embodiments, R25is (C1-C3)alkyl. In some embodiments of Formula 4F, X2is S. In some embodiments of Formula 4F, X2is C=O.

[0085] In some embodiments of Formula 4F, X10is C(R26)2. In some embodiments each R26is H. In some embodiments, at least one R26group is optionally substituted alkyl. In some embodiments of Formula 4F, X10is O. In some embodiments of Formula 4F, X10is NR25. In some embodiments, R25is H. In some embodiments, R25is (C1-C3)alkyl. In some embodiments of Formula 4F, X10is S. In some embodiments of Formula 4F, X10is C=O.

[0086] In some embodiments of Formula 4F, X9is NR25, and X10is C(R26)2. In some embodiments of Formula 4F, X2is NR25, and X4is C=O. In some embodiments of Formula 4F, X9is C(R26)2, and X10is NR25. In some embodiments of Formula 4F, X9is C=O, and X10is NR25.

[0087] In some embodiments of Formula 4F, y is 0, such that there are no R24substituents. In some embodiments, y is 1-3, and each R24substituent is independently selected from (C1-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, y is 1 and R24is (C1-C3)alkyl. In some embodiments, y is 1 and R24is halogen. In some embodiments the halogen is Cl or F.

[0088] In some embodiments of Formula 4F, the is selected from:, or wherein R24, R25, R29, R30, and y are as defined herein.

[0089] In some embodiments of Formula 4F, R29and R30are each independently H, or optionally substituted (C1-3)alkyl. In some embodiments, one of R29and R30is H, and theAtty. Docket No.: 39953-58778 (002WO) other is optionally substituted (C1-3)alkyl. In some embodiments, both R29and R30are H. In some embodiments, both R29and R30are optionally substituted (C1-3)alkyl.

[0090] In some embodiments of Formula 4F, R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group. In some embodiments, the spirocyclic group is optionally substituted spirocyclopropyl. In some embodiments, the spirocyclic group is optionally substituted spirocyclobutyl.

[0091] In some embodiments of Formula 4F, the compound is selected from:wherein R24, R25, and y are as defined herein.

[0092] In some embodiments of Formula I, R4is of Formula 4G:, wherein: X8is N or CR26; R21and R22are each independently optionally substituted (C1-C6)alkyl; and R26is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile.

[0093] In some embodiments of Formula 4G, X8is N. In some embodiments of Formula 4G, X8is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0094] In some embodiments of Formula 4G, R21and R22are each a (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl. In some embodiments of Formula 4G, R21and R22are the same. In some embodiments of Formula 4G, R21and R22are different.

[0095] In some embodiments of Formula 4G, X8is N and R21and R22are each a different C1-C6 alkyl. In some embodiments R21is methyl and R22is isopropyl. In some embodiments, R21is methyl and R22is ethyl. In some embodiments, R21is methyl and R22isAtty. Docket No.: 39953-58778 (002WO) propyl. In some embodiments, R21is methyl and R21is butyl. In some embodiments, R21is methyl and R22is t-butyl.

[0096] In some embodiments of Formula 4G, X8is CR26and R21and R22are the same. In some embodiments, R21and R22are both methyl. In some embodiments, R21and R22are both ethyl. In some embodiments, R21and R22are both propyl.

[0097] In some embodiments of any one of Formula I, R4is of Formula 4H: ,wherein: R27and R28are each independently H, or optionally substituted (C1-C6)alkyl; or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group.

[0098] In some embodiments of Formula 4H, R27is H. In some embodiments R27is optionally substituted (C1-C6)alkyl. In some embodiments of Formula 4H, R28is H. In some embodiments, R28is optionally substituted (C1-C6)alkyl. In some embodiments R27and R28are different. In some embodiments, R27and R28are the same.

[0099] In some embodiments of Formula 4H, R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group. In some embodiments, the cyclic group is selected from a 5, 6 or 7 membered heterocyclic group. In some cases, the heterocyclic group is an optionally substituted piperidinyl. In some cases, the heterocyclic group is an optionally substituted piperazinyl.

[0100] In some embodiments of Formula I, R4is of Formula 4I:, wherein: R23is H, optionally substituted (C1-C6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.

[0101] In some embodiments of Formula 4I, R23is H. In some embodiments of Formula 4I, R23is optionally substituted (C1-C6)alkyl. In some embodiments, R23is methyl, ethyl or propyl. In some embodiments, R23is optionally substituted cycloalkyl. In some embodiments the cycloalkyl selected from cyclobutene, cyclopentane or cyclohexane. In some embodiments, R23is optionally substituted cycloalkene. In some embodiments, R23isAtty. Docket No.: 39953-58778 (002WO) optionally substituted heterocyclyl. In some embodiments, R23is optionally substituted heteroaryl. In some embodiments, R23is and optionally substituted aryl.

[0102] In some embodiments of Formula 4I, R23is selected from: ,X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, and X7are each independently selected from N and CR26; each R18-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R25is H, or optionally substituted (C1-6)alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0103] In some embodiments of R23Formula 4F(4F).

[0104] In some embodiments of Formula 4I, R23is selected from one of the following structures:Atty. Docket No.: 39953-58778 (002WO) R29

[0105] In some embodiments of Formula I, R4is of any one of Formulae 4J-4L: ,wherein: X5is N or CR26; R19is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R26is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and w is 0 to 4.

[0106] In some embodiments of Formula 4J, X5is N. In some embodiments of Formula 4J, X5is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R26is nitrile. In some embodiments, R26is amino. In some embodiments, R26is hydroxy.

[0107] In some embodiments of Formula 4J, w is 0, such that there are no R19substituents. In some embodiments, w is 1-4, and each R19substituent is independently selected from optionally substituted (C1-C3)alkyl, optionally substituted (C1-C3)alkoxy, amino, hydroxy, halogen, and nitrile. In some embodiments, w is 1 and R19is C1-C3 alkyl. In some embodiments, w is 1 and R19is C1-C3 alkyl substituted with hydroxy or alkoxy. In some embodiments, w is 1 and R19is C1-C3alkoxy. In some embodiments, R19is -OCF3. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is hydroxy.

[0108] In some embodiments of Formula 4K, X5is N. In some embodiments of Formula 4K, X5is CR26. In some embodiments, R26is H. In some embodiments, R26is optionallyAtty. Docket No.: 39953-58778 (002WO) substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R26is nitrile. In some embodiments, R26is amino. In some embodiments, R26is hydroxy.

[0109] In some embodiments of Formula 4K, w is 0, such that there are no R19substituents. In some embodiments, w is 1-4, and each R19substituent is independently selected from optionally substituted (C1-C3)alkyl, optionally substituted (C1-C3)alkoxy, amino, hydroxy, halogen, and nitrile. In some embodiments, w is 1 and R19is C1-C3alkyl. In some embodiments, w is 1 and R19is C1-C3alkyl substituted with hydroxy or alkoxy. In some embodiments, w is 1 and R19is C1-C3 alkoxy. In some embodiments, R19is -OCF3. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is hydroxy.

[0110] In some embodiments of Formula 4L, X5is N. In some embodiments of Formula 4L, X5is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R26is nitrile. In some embodiments, R26is amino. In some embodiments, R26is hydroxy.

[0111] In some embodiments of Formula 4L, w is 0, such that there are no R19substituents. In some embodiments, w is 1-4, and each R19substituent is independently selected from optionally substituted (C1-C3)alkyl, optionally substituted (C1-C3)alkoxy, amino, hydroxy, halogen, and nitrile. In some embodiments, w is 1 and R19is C1-C3 alkyl. In some embodiments, w is 1 and R19is C1-C3alkyl substituted with hydroxy or alkoxy. In some embodiments, w is 1 and R19is C1-C3alkoxy. In some embodiments, R19is -OCF3. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is nitrile. In some embodiments, w is 1 and R19is hydroxy.

[0112] In some embodiments of Formula I, R4is of Formula 4M:, wherein: X6is selected from NR25, C(R26)2, C=O, O and S; X7is N or CR26; R20is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R25is selected from H, or optionally substituted C1-C6alkyl;Atty. Docket No.: 39953-58778 (002WO) each R26is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and x is 0, 1, or 2.

[0113] In some embodiments of Formula 4M, X6is C(R26)2. In some embodiments each R26is H. In some embodiments, at least one R26group is optionally substituted alkyl. In some embodiments of Formula 4M, X6is O. In some embodiments of Formula 4M, X6is NR25. In some embodiments, R25is H. In some embodiments, R25is C1-C3alkyl. In some embodiments of Formula 4M, X2is S.

[0114] In some embodiments of Formula 4M, X7is N. In some embodiments of Formula 4M, X7is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0115] In some embodiments of Formula 4M, X6is NR25and X7is CR26. In some embodiments of Formula 4M, X2is S and X7is N.

[0116] In some embodiments of Formula 4M, x is 0, such that there are no R20substituents. In some embodiments, x is 1 or 2, and each R20substituent is independently selected from C1-C3 alkyl, hydroxy, halogen, and nitrile. In some embodiments, x is 1 and R20is C1-C3alkyl.

[0117] In some embodiments of Formula 4M, the compound is:.

[0118] In some embodiments of Formula 4M, the compound is:wherein R25is as defined herein. wherein R24, R25and y are as defined herein.

[0119] In some embodiments of Formula I, R6comprises a hydrophilic group (Z). In some embodiments, Z comprises a hydrophilic moiety that is substantially biologically inert. In some embodiments, Z comprises an electrophilic reactive moiety capable of covalently conjugating a biological target.

[0120] In some embodiments of Formula I, Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide,Atty. Docket No.: 39953-58778 (002WO) carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, thioester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof. In some embodiments, Z comprises a sulfonyl. In some embodiments, Z comprises a sulfone. In some embodiments, Z comprises a sulfimide. In some embodiments, Z comprises a sulfoximine. In some embodiments, Z comprises a sulfonimidamide. In some embodiments, Z comprises a sulfonate. In some embodiments, Z comprises a carboxamide. In some embodiments, Z comprises a carboxy. In some embodiments, Z comprises a hydroxy or a hydroxyalkyl. In some embodiments, Z comprises an aldehyde. In some embodiments, Z comprises an ester. In some embodiments, Z comprises a thioester. In some embodiments, Z comprises an alkoxy. In some embodiments, Z comprises a nitrile. In some embodiments, Z comprises a halogen. In some embodiments, Z comprises a thiolactone. In some embodiments, Z comprises a carboxamide and a thiolactone.

[0121] In some embodiments of Formula I, Z is alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl or heterocyclylsulfonyl. In some embodiments, Z is alkylsulfonyl. In some embodiments, Z is cycloalkylsulfonyl. In some embodiments, Z is alkenylsulfonyl. In some embodiments, Z is alkynylsulfonyl. In some embodiments, Z is heterocyclylsulfonyl.

[0122] In some embodiments of Formula I, Z is alkylsulfoximine, cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, or alkylsulfonamide. In some embodiments, Z is alkylsulfoximine. In some embodiments, Z is cycloalkylsulfoximine. In some embodiments, Z is heterocyclylsulfoximine. In some embodiments, Z is sulfonamide. In some embodiments, Z is alkylsulfonamide.

[0123] In some embodiments of Formula I, R6comprises one or more linkers (L1and / or L2). In some embodiments, the one or more linkers are optionally substituted (C1-6)alkylene. In some embodiments, the one or more linkers are independently -CH2-, -(CH2)2-, or -(CH2)3- . In some embodiments of Formula I, L1and L2are absent. In some embodiments, L1is absent and L2is an optionally substituted (C1-6)alkylene. In some embodiments, L2is absent and L1is an optionally substituted (C1-6)alkylene. In some embodiments both L1and L2are optionally substituted (C1-6)alkylene.

[0124] In some embodiments of Formula I, R6is of the formula .

[0125] In some embodiments of Formula I, Z is selected from a sulfone, a sulfonate, carboxy, ester, hydroxy, hydroxyalkyl, aldehyde, an optionally substituted thiolactone, and an optionally substituted carboxamide. In some embodiments, Z is a sulfone. In someAtty. Docket No.: 39953-58778 (002WO) embodiments, Z is a sulfonate. In some embodiments, Z is an optionally substituted carboxamide. In some embodiments, Z is a carboxamide substituted with a thiolactone group. In some embodiments the thiolactone is a γ-thiolactone. In some embodiments, Z is a carboxy group. In some embodiments, Z is a hydroxy or a hydroxyalkyl group. In some embodiments, Z is an aldehyde. In some embodiments, Z is an ester. In some embodiments, Z is an ester. In some embodiments, Z is a thioester (e.g., -COSR12where R12is optionally substituted (C1-6)alkyl). In some embodiments, Z comprises an optionally substituted thiolactone. In some embodiments the thiolatone is a γ-thiolactone.

[0126] In some embodiments of Formula I, -L2-Z or Z is of one of Z1-Z6: ,wherein: Y9is absent, -O-, -NR9-, -(C1-6)alkylene-O-, -(C1-6)alkylene-NR9-; X11is O, or NH; R51is selected from halogen, R8, -NR9R10, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, and substituted versions thereof; R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone (e.g., of formula Z1), or a thiolactone (e.g., of formula Z2); and R52is H, optionally substituted (C1-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; m is 0, 1, or 2; and p, q, s and t are independently 0, 1, 2, 3, 4, 5 or 6.

[0127] In some embodiments of the Formula Z1A:(Z1A), wherein:Atty. Docket No.: 39953-58778 (002WO) R51is halogen, -NR9R10, optionally substituted (C1-6)alkyl, or optionally substituted (C2-6)alkenyl.

[0128] In some embodiments of Z1A, R51is halogen. In some embodiments of Z1A, R51is F. In some embodiments of Z1A, R51is (C1-6)alkyl. In some embodiments of Z1A, R51is - NR9R10. In some embodiments of Z1A, R51is (C2-6)alkenyl.

[0129] In some embodiments of Z1, -L2-Z or Z is of the Formula Z1B:wherein: X11is O, or NH; and R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof.

[0130] In some embodiments of Z1B, X11is O. In some embodiments of Z1B, X11is NH. In some embodiments of Z1B, R8is (C1-6)alkyl. In some embodiments of Z1B, R8is methyl. In some embodiments of Z1B, R8is (C2-6)alkenyl. In some embodiments of Z1B, R8is -CH=CH2 or -C(CH3)=CH2. In some embodiments of Z1B, R8is (C2-6)alkynyl. In some embodiments of Z1B, R8is -CCH or -CC-CH3. In some embodiments of Z1B, R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Z1B, R8is optionally substituted (C3-7)heterocyclyl. In some embodiments of Z1B, R8is R8is (C3-4)cycloalkyl. In some embodiments of Z1B, R8is (C2-4)heterocyclyl.

[0131] In some embodiments of Z1B, X11is NH, R8is (C1-6)alkyl. In some embodiments of Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Z1B, X11is NH, and R8is heterocyclyl.

[0132] In some embodiments of Z1B, X11is O, R8is (C1-6)alkyl. In some embodiments of Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Z1B, X11is O, and R8is heterocyclyl.

[0133] In some embodiments of Z1, -L2-Z or Z is of the Formula Z1C: (Z1C), wherein: X11is O, or NH; R9is H or optionally substituted (C1-6)alkyl; andAtty. Docket No.: 39953-58778 (002WO) R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl.

[0134] In some embodiments of Z1C, X11is O. In some embodiments of Z1C, X11is NH. In some embodiments of Z1C, R9is H. In some embodiments of Z1C, R9is (C1-6)alkyl. In some embodiments of Z1C, R10is H. In some embodiments of Z1C, R10is (C1-6)alkyl. In some embodiments of Z1C, R10is optionally substituted cycloalkyl. In some embodiments of Z1C, R10is optionally substituted heterocyclyl. In some embodiments of Z1C, R9is H, and R10is (C1-6)alkyl. In some embodiments of Z1C, R9is H, and R10H.

[0135] In some embodiments of Z1C, X11is NH, R9is H and R10is (C1-6)alkyl. In some embodiments of Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Z1C, X11is NH, R9is H and R10is ethyl.

[0136] In some embodiments of Z1C, X11is O, R9is H and R10is (C1-6)alkyl. In some embodiments of Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Z1C, X11is O, R9is H and R10is ethyl.

[0137] In some embodiments of Z4, -L2-Z or Z is of the Formula Z4A:wherein: R9is H; and R10is -SO2R38; and R38is optionally substituted alkyl, or amino.

[0138] In some embodiments of Z4A, R38is (C1-6)alkyl. In some embodiments of Z4A, R18is methyl. In some embodiments of Z4A, R38is ethyl.

[0139] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z4B:, wherein: R9is H; and R10is -SO2R38wherein R38is optionally substituted alkenyl, or R10is optionally substituted thiolactone.Atty. Docket No.: 39953-58778 (002WO)

[0140] In some embodiments of Formula Z4B, R10is optionally substituted alkenyl. In some cases, R10is -CH=CH2. In some embodiments of Z4B, R10is thiolactone. In some embodiments, R10is γ-thiolactone.

[0141] In some embodiments Z4B is of the Formula Z4C: , wherein m is 0, 1, or 2. In somem is 1. In some embodiments, m is 2.

[0142] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z2:wherein m is 0, 1, or 2. In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, m is 2.

[0143] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z3:wherein: R52is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and t is 0, 1, or 2.

[0144] In some embodiments of Z3, R52is (C1-6)alkyl. In some embodiments of Z3, R52is optionally substituted aryl. In some embodiments of Z3, R52is optionally substituted heterocyclyl. In some embodiments, -OR12is a leaving group, such that Z3 can be characterized as an active ester. In some R52is:.

[0145] In some embodiments of Z3, t is 1. In some embodiments of Z3, t is 2. In some embodiments of Z3, t is 0.Atty. Docket No.: 39953-58778 (002WO)

[0146] In some embodiments, Z3 is of the Formula Z3A: wherein R52is H.

[0147] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z5:wherein q is 0, 1, or 2.

[0148] In some embodiments of Z5, q is 0. In some embodiments of Z5, q is 1. In some embodiments of Z5, q is 2.

[0149] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z6:wherein p is 0, 1, 2, 3, 4, or 5. In some embodiments p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0150] In some embodiments of Formula I, -L2-Z or Z is a non-electrophilic hydrophilic group.

[0151] In some embodiments, of Formula I, Z is a non-electrophilic hydrophilic group of the formula Z1, wherein R51is optionally substituted alkyl or amino. In some embodiments, Z is Z1, and R51is amino. In some embodiments, Z is Z1 and R51is optionally substituted alkyl. As such, in some embodiments of Formula I, Z is an alkylsulfone. In some embodiments, Z is an alkylsulfone of Formula Z1D:wherein R53is H or optionally substituted C1-C6alkyl. In some embodiments of Z1D, R53is H. In some embodiments of Z1D, R13is C1-C3alkyl.

[0152] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z4, wherein; R9is H; and R10is of the formula -SO2R38; and R38is optionally substituted alkyl, or amino.Atty. Docket No.: 39953-58778 (002WO)

[0153] In some embodiments of Formula I, Z is a carboxamide of Formula Z4, R10is - SO2R38, and R38is methyl. In some embodiments, Z is a carboxamide of Formula Z4, R10is of the formula -SO2R38, and R38is amino.

[0154] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z6, wherein p is 0, 1 or 2. In some embodiments, p is 0, such that Z6 is -OH. In some embodiments, p is 1, such that Z6 is -CH2OH. In some embodiments, p is 2, such that Z6 is CH2CH2OH.

[0155] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of formula Z3, where R52is H (i.e., Z is -CO2H).

[0156] In some embodiments of Formula I, Z is an electrophilic reactive hydrophilic group.

[0157] In some embodiments, of Formula I, Z is an electrophilic reactive hydrophilic group of the formula Z1, wherein R51is optionally substituted (C2-6)alkenyl. As such, in some embodiments of Formula I, Z is an alkenylsulfone (e.g., a vinylsulfone). In some embodiments, Z is an alkenylsulfone of Formula Z1E:wherein R14is H or optionally substituted (C1-6)alkyl. In some embodiments of Z1E, R14is H. In some embodiments of Z1E, R14is optionally substituted C1-C3 alkyl.

[0158] In some embodiments of Formula I, Z is a carboxamide of Formula Z4, R10is - SO2R38, or thiolactone, where R38is optionally substituted alkenyl. In some embodiments, Z is a carboxamide of Formula Z4, R10is -SO2R38, and R38is substituted alkenyl. In some cases, R38is -CH=CH2. In some embodiments, Z is a carboxamide of Formula Z4, R10is thiolactone. In some embodiments, Z is of Formula Z4C.

[0159] In some embodiments of Formula I, Z is a thiolactone of Formula Z2. In some embodiments Z is of Formula Z2, and m is 0. In some embodiments Z is of Formula Z2, and m is 1. In some embodiments Z is of Formula Z2, and m is 2.

[0160] In some embodiments of Formula I, Z is of Formula Z1A, where R51is halogen. In some embodiments, R51is F.

[0161] In some embodiments of Formula I, Z is of Formula Z3, wherein R52is optionally substituted (C1-6)alkyl or a heterocyclyl. In some embodiments, Z is of Formula Z3, where R52is a heterocycle. In some embodiments, R52is:Atty. Docket No.: 39953-58778 (002WO)

[0162] In some embodiments of theof Formula I, two or more of Y1-Y3are CR1, CR2and CR3respectively. In some embodiments of the compound of Formula I, Y1-Y3are CR1, CR2and CR3respectively. In some embodiments, each of R1-R3are H. In some embodiments, at least one of R1-R3is not H. In some embodiments, Y2is CR2, and R2is not H. In some embodiments R2is selected from optionally substituted alkyl, alkyl halide, or - COR30, where R30is H or C1-6 alkyl.

[0163] In some embodiments of the compound of Formula I, Y3is N and Y1and Y2are each CR1and CR2respectively. In some embodiments of the compound of Formula I, Y1is N and Y2and Y3are each CR2and CR3respectively. In some embodiments of the compound of Formula I, Y2is N and Y1and Y3are each CR1and CR3respectively.

[0164] In some embodiments of Formula I, Y5is CR5. In some embodiments, R5is selected from H, CH3, CF3, and halogen. In some embodiments, R5is CH3. In some embodiments, R5is CF3. In some embodiments, R5is halogen. In some embodiments, R5is F or Cl. In some embodiments, R5is H.

[0165] In some embodiments of Formula I, Y5is N.

[0166] In some embodiments of Formula I, R7is selected from H, CH3, CF3, and halogen. In some embodiments R7is CH3. In some embodiments R7is CF3. In some embodiments R7is halogen. In some embodiments R7is F or Cl. In some embodiments, R7is H.

[0167] In some embodiments of Formula I, Y1is CR1. In some embodiments, R1is selected from H, CH3, CF3, and halogen. In some embodiments, R1is CH3. In some embodiments, R1is CF3. In some embodiments, R1is halogen. In some embodiments, R1is F or Cl. In some embodiments, R1is H.

[0168] In some embodiments of Formula I, Y1is N.

[0169] In some embodiments of Formula I, Y2is CR2. In some embodiments, R2is selected from H, CH3, CF3, - CHF2, -CH2Cl, halogen, -C(=O)H, and -(CH2)zOH, where z is 1, 2 or 3. In some embodiments, R2is CH3. In some embodiments, R2is CF3. In some embodiments, R2is -CHF2. In some embodiments, R2is -CH2Cl. In some embodiments, R2is halogen. In some embodiments, R2is F or Cl. In some embodiments, R2is -C(=O)H. In some embodiments, R2is -(CH2)zOH, where z is 1. In some embodiments, R2is -(CH2)zOH,Atty. Docket No.: 39953-58778 (002WO) where z is 2. In some embodiments, R2is -(CH2)zOH, where z is 3. In some embodiments, R2is H.

[0170] In some embodiments of Formula I, Y2is N.

[0171] In some embodiments of Formula I, the compound is of Formula IA:or a pharmaceutically R1, R2, R4, R5, R6and R7are as defined herein.

[0172] In some embodiments of Formula I, the compound is of Formula IB:or a pharmaceutically acceptable salt thereof, where R1, R2, R4, R6and R7are as defined herein.

[0173] In some embodiments of Formula I, the compound is of Formula IC:or a pharmaceutically acceptable salt thereof, where R1- R7are as defined herein.

[0174] In some embodiments of Formula I, the is of Formula ID:(ID) or a pharmaceutically acceptable salt thereof, where R1- R4, R6and R7are as defined herein.Atty. Docket No.: 39953-58778 (002WO)

[0175] In some embodiments of Formula I, the compound is of Formula IE: or a pharmaceuticallyR2- R7are as defined herein.

[0176] In some embodiments of Formula I, the compound is of Formula IF:or a pharmaceutically acceptable salt thereof, where R2- R4, R6and R7are as defined herein.

[0177] In some embodiments of Formula I, the compound is of Formula IG:or a pharmaceutically acceptable salt thereof, where R2, R4, R5, R6and R7are as defined herein.

[0178] In some embodiments of Formula I, the compound is of Formula IH:or a pharmaceutically acceptable salt thereof, where R2, R4, R6and R7are as defined herein.Atty. Docket No.: 39953-58778 (002WO)

[0179] In some embodiments of Formula I, the compound is of Formula IJ: or a pharmaceuticallyR1, R4, R5, R6and R7are as defined herein.

[0180] In some embodiments of Formula I, the compound is of Formula IK:or a pharmaceutically acceptable salt thereof, where R1, R4, R6and R7are as defined herein.

[0181] In some embodiments of Formula I, the compound is of Formula IL:or a pharmaceutically acceptable salt thereof, where R1, R3, R4, R5, R6and R7are as defined herein.

[0182] In some embodiments of Formula I, the compound is of Formula IM:or a pharmaceutically acceptable salt thereof, where R1, R3, R4, R6and R7are as defined herein.

[0183] In some embodiments of Formula I, the compound is of Formula IA.

[0184] In some embodiments of Formula I, the compound is of Formula IB.Atty. Docket No.: 39953-58778 (002WO)

[0185] In some embodiments of Formula I, or any one of Formulae IA-IM, ring A is as defined herein.

[0186] In some embodiments of Formula I, or any one of Formulae IC-IF or IL-IM, R3is CN. In some embodiments of any one of Formula I, or any one of Formulae IC-IF or IL-IM, R3is H.

[0187] In some embodiments of Formula I, IA, or IC, R1, R2, R5and R7are each H.

[0188] In some embodiments of any one of Formula I or Formulae IA-IM, R6is selected from:wherein: R8is optionally substituted (C1-6)alkyl, optionally substituted (C2-6)alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; R9is H or optionally substituted (C1-6)alkyl; R10is a sulfone or a thiolactone; R52is H, optionally substituted (C1-6)alkyl, or optionally substituted heterocyclyl; R55is H, optionally substituted (C1-6)alkyl; and m is an integer from 0 to 2.

[0189] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6C. In some embodiments of 6C, R8is optionally substituted (C1-6)alkyl. In some embodiments, R8is -CH3 or -CH2-R13, and R13is optionally substituted (C1-6)alkyl. In some embodiments of 6C, R8is optionally substituted (C2-6)alkenyl. In some embodiments of 6C, R8is -CH=CH2 or -CH=CH-R14, and R14is optionally substituted (C1-6)alkyl. In some embodiments of 6C, R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of 6C, R8is (C3-4)cycloalkyl. In some embodiments of 6D, R8is optionally substituted (C2-6)heterocyclyl. In some embodiments of 6C, R8is (C2-4)heterocyclyl.

[0190] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6D. In some embodiments of 6D, R8is optionally substituted (C1-6)alkyl. In someAtty. Docket No.: 39953-58778 (002WO) embodiments, R8is -CH3 or -CH2-R13, and R13is optionally substituted (C1-6)alkyl. In some embodiments of 6D, R8is optionally substituted (C2-6)alkenyl. In some embodiments of 6D, R8is -CH=CH2or -CH=CH-R14, and R14is optionally substituted (C1-6)alkyl. In some embodiments of 6D, R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of 6D, R8is (C3-4)cycloalkyl. In some embodiments of 6D, R8is optionally substituted (C2-6)heterocyclyl. In some embodiments of 6D, R8is (C2-4)heterocyclyl.

[0191] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6E. In some embodiments of 6E, R9is H, and R55is H, or optionally substituted (C1-6)alkyl.

[0192] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6F. In some embodiments of 6F, R9is H, and R55is H, or optionally substituted (C1-6)alkyl.

[0193] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6G. In some embodiments of 6G, R9is H, and R10is sulfone or a thiolactone.

[0194] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6H. In some embodiments of 6H, m is 1. In some embodiments of 6H, m is 0. In some embodiments of 6H, m is 2.

[0195] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6I. In some embodiments of 6I, R52is H. In some embodiments of 6I, R52is optionally substituted (C1-6)alkyl. In some embodiments, R52is -CH3or -CH2-R13, and R13is optionally substituted (C1-6)alkyl. In some embodiments of 6I, R52is optionally substituted (C2-6)heterocyclyl. In some embodiments of 6I, R52is (C2-4)heterocyclyl.

[0196] In some embodiments of any one of 6C-6I, the A ring is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4-piperidinyl, and optionally substituted cyclohexyl. In some embodiments of any one of 6C-6I, the A ring is phenyl. In some embodiments of 6C-6I, the A ring is pyridyl. In some embodiments of 6C- 6I, the A ring is 4-piperidinyl. In some embodiments of 6C-6I, the A ring is cyclohexyl.

[0197] In some embodiments of any one of Formula I or Formulae IA-IM, R4is selected 4A-(4A), (4B), (4C), (4D),Atty. Docket No.: 39953-58778 (002WO) ,X1is O, or C(R26)2; X12is C(R15)2, O, or NR25; X14is O, or NR43; X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, X7and X8are each independently selected from N and CR26; each R15-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R21and R22are each independently optionally substituted C1-6 alkyl; R23is H, optionally substituted C1-6alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R25is H, or optionally substituted C1-6alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R27and R28are each independently H, or optionally substituted (C1-6)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group;Atty. Docket No.: 39953-58778 (002WO) R29and R30are each independently H, or optionally substituted C1-6 alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., optionally substituted spirocyclopropyl or spirocyclobutyl); k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently an integer from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; and R6is selected from:, wherein: Y11is selected from O, S, CH2, C(R11)2, and NR9; R9is H, optionally substituted (C1-6)alkyl, -L2-Z, or Z; each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; k is 0 or 1; n is an integer from 0 to 9. Y6-Y10groups are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; and each R12is independently selected from H, optionally substituted alkyl, halogen, and CN.

[0198] In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4A, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4B, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4C, and R6is of Formula 6A. InAtty. Docket No.: 39953-58778 (002WO) some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4D, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4E, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4F, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4G, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4H, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4I, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4J, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4K, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4L, and R6is of Formula 6A. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4M, and R6is of Formula 6A.

[0199] In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4A, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4B, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4C, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4D, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4E, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4F, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4G, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4H, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4I, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4J, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4K, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4L, and R6is of Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4M, and R6is of Formula 6B.

[0200] In some embodiments of any one of Formula I or Formulae IA-IM, R4is selected from Table 1Atty. Docket No.: 39953-58778 (002WO) Table 1: Example R4groups C A A A, , ,Atty. Docket No.: 39953-58778 (002WO), ,Atty. Docket No.: 39953-58778 (002WO) ,, , , , ,Atty. Docket No.: 39953-58778 (002WO) , , , , , ,, , , , ,Atty. Docket No.: 39953-58778 (002WO) , , , , ,Atty. Docket No.: 39953-58778 (002WO) aryl

[0201] In some embodiments of any one of Formula I or Formulae IA-IM, R6is selected from Table 2 T C A, , , ,Atty. Docket No.: 39953-58778 (002WO) O H, ,Atty. Docket No.: 39953-58778 (002WO) h h

[0202] In some embodiments of Formula I, or any one of Formulae IA-IM, the compound is of Formula IIA:, wherein, Y1-Y3, Y5, R4and Z are as defined herein; each R11is an optional substituent selected from optionally substituted alkyl, halogen, and nitrile; and n is 0 to 9.Atty. Docket No.: 39953-58778 (002WO)

[0203] In some embodiments, of Formula IIA, one or more of Y1-Y3is N. In some embodiments, Y3is N. In some embodiments, Y2is N. In some embodiments Y1is N. In some embodiments Y1and Y3are N. In some embodiments Y2and Y3are N. In some embodiments Y1and Y2are N.

[0204] In some embodiments of the compound of Formula IIA, two or more of Y1-Y3are CR1, CR2and CR3respectively. In some embodiments of the compound of Formula IIA, Y1- Y3are CR1, CR2and CR3respectively. In some embodiments, each of R1-R3are H. In some embodiments, at least one of R1-R3is not H. In some embodiments, Y2is CR2, and R2is not H. In some embodiments R2is selected from optionally substituted alkyl, alkyl halide, or - COR30, where R30is H or C1-6alkyl.

[0205] In some embodiments of the compound of Formula IIA, Y3is N and Y1and Y2are each CR1and CR2respectively. In some embodiments of the compound of Formula IIA, Y1is N and Y2and Y3are each CR2and CR3respectively. In some embodiments of the compound of Formula IIA, Y2is N and Y1and Y3are each CR1and CR3respectively.

[0206] In some embodiments of Formula IIA, Y5is CR5. In some embodiments, R5is H.

[0207] In some embodiments of Formula IIA, Y5is N.

[0208] In some embodiments of Formula IIA, n is 1-9, such that the piperidine ring includes one or more R11substituents. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments n is 4. In some embodiments, n is 5. In some embodiments, R11is selected from C1-3alkyl, halogen, and nitrile. In some embodiments, R11is methyl. In some embodiments R11is Cl or F. In some embodiments, R11is nitrile.

[0209] In Some embodiments of Formula IIA, n is 0, such that the piperidine ring does not include any R11substituents.

[0210] In some embodiments of Formula IIA, the compound is of the Formula IIIA:wherein R1, R2, Y5, R4and Z are as defined herein.

[0211] In some embodiments of Formula IIIA, Y5is CR5. In some embodiments, R5is H. In some embodiments of Formula IIIA, Y5is N.Atty. Docket No.: 39953-58778 (002WO)

[0212] In some embodiments of Formula IIA-IIIA, R4is of any one of Formulae 4A-4M. In some embodiments, R4is selected from Table 1.

[0213] In some embodiments of Formula IIA-IIIA, Z is of any one of Formulae Z1-Z6.

[0214] In some embodiments of Formula I, or any one of Formulae IA-IM, the compound is of Formula IIB:wherein: Z is attached to one of Y6-Y10, and the remaining Y6-Y10groups are independently selected from CR12or N, wherein each R12is independently selected from H, optionally substituted alkyl, halogen, and nitrile.

[0215] In some embodiments of Formula IIB, Z is attached to Y8. In some embodiments, Z is attached to Y6or Y10. In some embodiments, Z is attached to Y7or Y9.

[0216] In some embodiments of Formula IIB, Z is attached to Y8, and Y6, Y7, Y9and Y10are each CR12. In some embodiments, each R12is H. In some embodiments, at least one R12is not H. In some embodiments, at least one R12is selected from C1-3alkyl, halogen, and nitrile. In some embodiments, R12is methyl. In some embodiments R12is Cl or F. In some embodiments, R12is nitrile.

[0217] In some embodiments of formula IIB, at least one of Y6-Y10is N. In some cases, Y6or Y10is N. In some cases, both Y6and Y10are N. In some cases, Y7or Y9is N. In some cases, both Y7and Y9are N. In some cases, Y8is N.

[0218] In some embodiments, of Formula IIB, one or more of Y1-Y3is N. In some embodiments, Y3is N. In some embodiments, Y2is N. In some embodiments Y1is N. In some embodiments Y1and Y3are N. In some embodiments Y2and Y3are N. In some embodiments Y1and Y2are N.

[0219] In some embodiments of the compound of Formula IIB, two or more of Y1-Y3are CR1, CR2and CR3respectively. In some embodiments of the compound of Formula IIB, Y1- Y3are CR1, CR2and CR3respectively. In some embodiments, each of R1-R3are H. In some embodiments, at least one of R1-R3is not H. In some embodiments, Y2is CR2, and R2is notAtty. Docket No.: 39953-58778 (002WO) H. In some embodiments R2is selected from optionally substituted alkyl, alkyl halide, or - COR30, where R30is H or C1-6 alkyl.

[0220] In some embodiments of the compound of Formula IIB, Y3is N and Y1and Y2are each CR1and CR2respectively. In some embodiments of the compound of Formula IIB, Y1is N and Y2and Y3are each CR2and CR3respectively. In some embodiments of the compound of Formula IIB, Y2is N and Y1and Y3are each CR1and CR3respectively.

[0221] In some embodiments of Formula IIB, Y5is CR5. In some embodiments, R5is H.

[0222] In some embodiments of Formula IIB, Y5is N.

[0223] In some embodiments of Formula IIB, the compound is of the Formula IIIB:(IIIB), wherein R1, R2, Y5, R4and Z are as defined herein.

[0224] In some embodiments of Formula IIIB, Y5is CR5. In some embodiments, R5is H. In some embodiments of Formula IIIB, Y5is N.

[0225] In some embodiments of Formula IIB-IIIB, R4is of any one of Formulae 4A-4M. In some embodiments, R4is selected from Table 1.

[0226] In some embodiments of Formula IIB-IIIB, Z is of any one of Formulae Z1-Z6.

[0227] In some embodiments of Formula I, the compound is of Formula IA, or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments of Formula IA, the compound is of Formula IV:, or a pharmaceutically acceptable salt thereof, wherein: Y6, Y7, Y9, and Y10are independently selected from CR12and N, wherein at least two of Y6, Y7, Y9, and Y10are CR12; each R12is independently selected from H, optionally substituted (C1-6)alkyl, hydroxyl, halogen, and CN; and R1, R2, R4, R5, R7, and Z are as defined herein.Atty. Docket No.: 39953-58778 (002WO)

[0229] In some embodiments of Formula IV, Y6, Y7, Y9and Y10are each CR12. In some embodiments, each R12is H. In some embodiments, at least one R12is not H. In some embodiments, at least one R12is selected from C1-3alkyl, halogen, and nitrile. In some embodiments, at least one R12is methyl. In some embodiments, at least one R12is Cl or F. In some embodiments, at least one R12is nitrile.

[0230] In some embodiments of formula IV, at least one of Y6, Y7, Y9or Y10is N. In some cases, Y6or Y10is N. In some cases, both Y6and Y10are N. In some cases, Y7or Y9is N. In some cases, both Y7and Y9are N.

[0231] In some embodiments of Formula IV, Y6, Y7, Y9, and Y10are each independently CH or CR12and the compound is of the formula V:, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

[0232] In some embodiments of Formula IV-V, R4is of any one of Formulae 4A-4M. In some embodiments, R4is selected from Table 1.

[0233] In some embodiments, the compound of Formula V is of the Formula VIA:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5, R7, R12, R18, X2, X3, X4, Z, m, and v are as defined herein.

[0234] In some embodiments of Formula VIA, X2is C(R26)2. In some embodiments each R26is H. In some embodiments, at least one R26group is optionally substituted alkyl. In some embodiments of Formula VIA, X2is O. In some embodiments of Formula VIA, X2is NR25. In some embodiments, R25is H. In some embodiments, R25is (C1-C3)alkyl. In some embodiments of Formula VIA, X2is S. In some embodiments of Formula VIA, X2is C=O.Atty. Docket No.: 39953-58778 (002WO)

[0235] In some embodiments of Formula VIA, X3is N. In some embodiments of Formula VIA, X3is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0236] In some embodiments of Formula VIA, X4is N. In some embodiments of Formula VIA, X4is CR26. In some embodiments, R26is H. In some embodiments, R26is optionally substituted alkyl.

[0237] In some embodiments of Formula VIA, X2is NR25, X3is CR26and X4is CR26. In some embodiments of Formula VIA, X2is NR25, X3is N and X4is CR26. In some embodiments of Formula VIA, X2is O, X3is CR26and X4is N.

[0238] In some embodiments of Formula VIA, R4is selected from one of the following structures:.

[0239] In some embodiments of Formula VIA, R4is selected from:

[0240] In some embodiments of Formula VIA, R4is selected from :or wherein R25, R18and v are as defined herein.

[0241] In some from:or wherein R25, R18and v are as defined herein.Atty. Docket No.: 39953-58778 (002WO)

[0242] In some embodiments of any one of Formulae IV-VIA, Z is of any one of Formulae Z1-Z6.

[0243] In some embodiments of any one of Formulae IV-VIA, Z is of Formulae ZIB or Z1C , wherein X11, R8, R9, andR8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.

[0244] In some embodiments of Formula VIA, Z is Z1C, and X11is O. In some embodiments of Formula VIA, Z is Z1C, and X11is NH. In some embodiments of Formula VIA, Z is Z1C, and R9is H. In some embodiments of Formula VIA, Z is Z1C, and R9is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1C, and R10is H. In some embodiments of Formula VIA, Z is Z1C, and R10is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1C, and R10is optionally substituted cycloalkyl. In some embodiments of Formula VIA, Z is Z1C, and R10is optionally substituted heterocyclyl. In some embodiments of Formula VIA, Z is Z1C, R9is H, and R10is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1C, R9is H, and R10H.

[0245] In some embodiments of Formula VIA, Z is Z1C, X11is NH, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Formula VIA, Z is Z1C, X11is NH, R9is H and R10is ethyl.

[0246] In some embodiments of Formula VIA, Z is Z1C, X11is O, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Formula VIA, Z is Z1C, X11is O, R9is H and R10is ethyl.

[0247] In some embodiments of Formula VIA, Z is of Formula Z1B, and X11is O. In some embodiments of Formula VIA, Z is Z1B, and X11is NH. In some embodiments of Formula VIA, Z is Z1B, and R8is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1B, and R8is methyl. In some embodiments of Formula VIA, Z is Z1B, and R8is (C2-Atty. Docket No.: 39953-58778 (002WO) 6)alkenyl. In some embodiments of Formula VIA, Z is Z1B, and R8is -CH=CH2 or - C(CH3)=CH2. In some embodiments of Formula VIA, Z is Z1B, and R8is (C2-6)alkynyl. In some embodiments of Formula VIA, Z is Z1B, and R8is -CCH or -CC-CH3. In some embodiments of Formula VIA, Z is Z1B, and R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Formula VIA, Z is Z1B, and R8is optionally substituted (C3-7)heterocyclyl. In some embodiments of Formula VIA, Z is Z1B, and R8is (C3-4)cycloalkyl. In some embodiments of Formula VIA, Z is Z1B, and R8is (C2-4)heterocyclyl.

[0248] In some embodiments of Formula VIA, Z is Z1B, X11is NH, and R8is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Formula VIA, Z is Z1B, X11is NH, and R8is heterocyclyl.

[0249] In some embodiments of Formula VIA, Z is Z1B, X11is O, and R8is (C1-6)alkyl. In some embodiments of Formula VIA, Z is Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Formula VIA, Z is Z1B, X11is O, and R8is heterocyclyl.

[0250] In some embodiments, the compound of Formula VIA is of the Formula VIIA:or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl or optionally substituted -C(=O)C1-6 alkyl; X11is O or NH; R41is R8or N(R9)R10; R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; and R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and wherein R1, R2, R5, R7, R12, R18, m, and v are as defined herein.

[0251] In some embodiments of any one of Formulae V, VIA, or VIIA, each R12is H (or m is 0). In some embodiments, m is 1, 2, 3, or 4, and at least one R12is not H. In some embodiments, at least one R12is selected from C1-3alkyl, halogen, and nitrile. In someAtty. Docket No.: 39953-58778 (002WO) embodiments, at least one R12is methyl. In some embodiments, at least one R12is Cl or F. In some embodiments, at least one R12is nitrile.

[0252] In some embodiments of Formula VIA, or VIIA, v is 0, such that there are no R18substituents. In some embodiments, v is 1-3, and each R18substituent is independently selected from (C1-3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, v is 1 and R18is (C1-3)alkyl. In some embodiments, v is 1 and R18is halogen. In some embodiments the halogen is Cl or F.

[0253] In some embodiments, the compound of Formula VIIA is of the Formula VIIIA:or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl; R18is H, halogen, optionally substituted (C1-6)alkyl, or optionally substituted (C1- 6)alkoxyl; and R12is H, halogen, optionally substituted (C1-6)alkyl or optionally substituted (C1-6)alkoxyl; wherein X11, and R41are as defined herein.

[0254] In some embodiments of any one of Formulae VIIA, or VIIIA, R25is of structure:wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen, and / or any two of R33– R37(e.g., R33and R34, and / or R36and R37) can be cyclically linked and together with the carbon atom(s) to which they are attached provide a C3-C7 carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, R33and R34together with the carbon atom to which they are attached is a C3- C7 carbocyclic ring (e.g., cyclopropyl, or cyclobutyl). In some embodiments, R36and R37together with the carbon atom to which they are attached is a C3-C7 carbocyclic ring (e.g., cyclopropyl, or cyclobutyl). In some embodiments, at least one of R33-R37is a halogen. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In someAtty. Docket No.: 39953-58778 (002WO) embodiments, one or two of R33-R35are CF3. In some embodiments, one of R33-R35is CF3. In some embodiments, two of R33-R35are CF3. In some embodiments, one or two of R33-R35are OH. In some embodiments, one of R33-R35is OH. In some embodiments, two of R33-R35are OH. In some embodiments, one or both of R36-R37are H. In some embodiments, R36is H, and R37is selected from CF3, CHF2, CH2F, OH, OCH3, and halogen. In some embodiments, both R36and R37are H .

[0255] In some embodiments of any one of Formulae VIIA, or VIIIA, R25is of structure: .

[0256] In some embodiments of any one of Formulae VIIA, or VIIIA, R25is of structure:.

[0257] In some embodiments of any one of Formulae V, VIA, VIIA, or VIIIA, R12is H. In some embodiments, R12is (C1-6)alkyl. In some embodiments, R12is methyl. In some embodiments, R12is ethyl. In some embodiments, R12is propyl. In some embodiments, R12is halogen. In some embodiments, R12is F. In some embodiments, R12is Cl. In some embodiments, R12is (C1-6)alkoxyl. In some embodiments, R12is methoxy.

[0258] In some embodiments of any one of Formulae VIA, VIIA, or VIIIA, R18is H. In some embodiments, R18is (C1-6)alkyl. In some embodiments, R18is methyl. In some embodiments, R18is ethyl. In some embodiments, R18is propyl. In some embodiments, R18is halogen. In some embodiments, R18is F. In some embodiments, R18is Cl. In some embodiments, R18is (C1-6)alkoxyl. In some embodiments, R18is methoxy.

[0259] In some embodiments of Formula VIIA or VIIIA, R41is R8(as defined herein). In some embodiments, R41is (C1-6)alkyl. In some embodiments, R41is selected from methyl, ethyl or propyl. In some embodiments, R41is methyl. In some embodiments, R41is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl. In some embodiments, R41is (C3-4)cycloalkyl or (C2-4)heterocyclyl. In some embodiments, R41is N(R9)R10. In some embodiments, R41is NH2. In some embodiments, R41is -NH(C1-6)alkyl. In some embodiments of Formula VIIA or VIIIA, X11is NH. In some embodiments, X11is O.Atty. Docket No.: 39953-58778 (002WO)

[0260] In some embodiments of Formula VIIA or VIIIA, X11is NH, and R41is (C1- 6)alkyl. In some embodiments of Formula VIIA or VIIIA, X11is NH, and R41is cycloalkyl. In some embodiments of Formula VIIA or VIIIA, X11is NH, and R41is heterocyclyl.

[0261] In some embodiments of Formula VIIA or VIIIA, X11is O, R41is (C1-6)alkyl. In some embodiments of Formula VIIA or VIIIA, X11is O, and R41is cycloalkyl. In some embodiments of Formula VIIA or VIIIA, X11is O, and R41is heterocyclyl.

[0262] In some embodiments, the compound of Formula V is of the Formula VIB:or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R5, R7, R12, R23, Z, and m are as defined herein.

[0263] In some embodiments of Formula VIB, R23is H. In some embodiments of Formula VIB, R23is optionally substituted (C1-6)alkyl. In some embodiments, R23is methyl, ethyl or propyl. In some embodiments, R23is optionally substituted cycloalkyl. In some embodiments the cycloalkyl selected from cyclobutene, cyclopentane or cyclohexane. In some embodiments, R23is optionally substituted cycloalkene. In some embodiments, R23is optionally substituted heterocyclyl. In some embodiments, R23is optionally substituted heteroaryl. In some embodiments, R23is and optionally substituted aryl.

[0264] In some embodiments of Formula VIB, R23is selected from:, , , , wherein: X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, and X7are each independently selected from N and CR26; each R18-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy,Atty. Docket No.: 39953-58778 (002WO) carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R25is H, or optionally substituted (C1-6)alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0265] In some embodiments of Formula VIB, R23is of Formula 4F.

[0266] In some embodiments of Formula VIB, R23is selected from one of the following structures:, , , wherein R24, R25, R29, R30, and y are as defined herein.

[0267] In some embodiments of Formula VIB, Z is of Formulae ZIB or Z1Cor , wherein X11, R8, R9, and R10are as defined herein. R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl;Atty. Docket No.: 39953-58778 (002WO) R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.

[0268] In some embodiments of Formula VIB, Z is Z1C, and X11is O. In some embodiments of Formula VIB, Z is Z1C, and X11is NH. In some embodiments of Formula VIB, Z is Z1C, and R9is H. In some embodiments of Formula VIB, Z is Z1C, and R9is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1C, and R10is H. In some embodiments of Formula VIB, Z is Z1C, and R10is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1C, and R10is optionally substituted cycloalkyl. In some embodiments of Formula VIB, Z is Z1C, and R10is optionally substituted heterocyclyl. In some embodiments of Formula VIB, Z is Z1C, R9is H, and R10is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1C, R9is H, and R10H.

[0269] In some embodiments of Formula VIB, Z is Z1C, X11is NH, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Formula VIB, Z is Z1C, X11is NH, R9is H and R10is ethyl.

[0270] In some embodiments of Formula VIB, Z is Z1C, X11is O, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Formula VIB, Z is Z1C, X11is O, R9is H and R10is ethyl.

[0271] In some embodiments of Formula VIB, Z is of Formula Z1B, and X11is O. In some embodiments of Formula VIB, Z is Z1B, and X11is NH. In some embodiments of Formula VIB, Z is Z1B, and R8is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1B, and R8is methyl. In some embodiments of Formula VIB, Z is Z1B, and R8is (C2-6)alkenyl. In some embodiments of Formula VIB, Z is Z1B, and R8is -CH=CH2 or - C(CH3)=CH2. In some embodiments of Formula VIB, Z is Z1B, and R8is (C2-6)alkynyl. In some embodiments of Formula VIB, Z is Z1B, and R8is -CCH or -CC-CH3. In some embodiments of Formula VIB, Z is Z1B, and R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Formula VIB, Z is Z1B, and R8is optionally substituted (C3-7)heterocyclyl. In some embodiments of Formula VIB, Z is Z1B, and R8is (C3-4)cycloalkyl. In some embodiments of Formula VIB, Z is Z1B, and R8is (C2-4)heterocyclyl.

[0272] In some embodiments of Formula VIB, Z is Z1B, X11is NH, and R8is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Formula VIB, Z is Z1B, X11is NH, and R8is heterocyclyl.Atty. Docket No.: 39953-58778 (002WO)

[0273] In some embodiments of Formula VIB, Z is Z1B, X11is O, and R8is (C1-6)alkyl. In some embodiments of Formula VIB, Z is Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Formula VIB, Z is Z1B, X11is O, and R8is heterocyclyl.

[0274] In some embodiments, the compound of Formula VIB is of the Formula VIIB:or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R5, R7, R12, R24, R25, R29, R30, X11, R41, y and m are as defined herein.

[0275] In some embodiments, the compound of Formula VIIB is of the Formula VIIIB:or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R5, R7, R12, R24, R25, R29, R30, X11, R41, y and m are as defined herein.

[0276] In some embodiments, the compound of Formula VIIIB is of the Formula IX:(IX) or a pharmaceutically acceptable salt thereof, wherein: R12, R29, R30, X11, and R41are as defined herein.Atty. Docket No.: 39953-58778 (002WO)

[0277] In some embodiments of any one of Formulae VIB, VIIB, VIIIB, or IX R12is H. In some embodiments, R12is (C1-6)alkyl. In some embodiments, R12is methyl. In some embodiments, R12is ethyl. In some embodiments, R12is propyl. In some embodiments, R12is halogen. In some embodiments, R12is F. In some embodiments, R12is Cl. In some embodiments, R12is (C1-6)alkoxyl. In some embodiments, R12is methoxy.

[0278] In some embodiments of any one of Formulae VIIB, VIIIB, or IX, R29and R30are each independently optionally substituted (C1-6)alkyl. In some embodiments, R29and R30are each independently (C1-3)alkyl. In some embodiments, R29and R30are each methyl. In some embodiments, R29and R30are each ethyl.

[0279] In some embodiments of any one of Formulae VIIB, VIIIB, or IX, R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group. In some embodiments, the spirocyclic group is spirocyclopropyl or spirocyclobutyl.

[0280] In some embodiments of any one of Formulae VIIB, VIIIB, or IX, R41is R8(as defined herein). In some embodiments, R41is (C1-6)alkyl. In some embodiments, R41is selected from methyl, ethyl or propyl. In some embodiments, R41is methyl. In some embodiments, R41is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl. In some embodiments, R41is (C3-4)cycloalkyl or (C2-4)heterocyclyl. In some embodiments, R41is N(R9)R10. In some embodiments, R41is NH2. In some embodiments, R41is -NH(C1-6)alkyl. In some embodiments of Formula VIIB, VIIIB, or IX, X11is NH. In some embodiments, X11is O.

[0281] In some embodiments of any one of Formulae VIIB, VIIIB, or IX, X11is NH, and R41is (C1-6)alkyl. In some embodiments of any one of Formulae VIIB, VIIIB, or IX, X11is NH, and R41is cycloalkyl. In some embodiments of Formula VIIB, VIIIB, or IX, X11is NH, and R41is heterocyclyl.

[0282] In some embodiments of any one of Formulae VIIB, VIIIB, or IX, X11is O, R41is (C1-6)alkyl. In some embodiments of any one of Formulae VIIB, VIIIB, or IX, X11is O, and R41is cycloalkyl. In some embodiments of any one of Formulae VIIB, VIIIB, or IX, X11is O, and R41is heterocyclyl.Atty. Docket No.: 39953-58778 (002WO)

[0283] In some embodiments of Formula IA, the compound is of Formula X: or a pharmaceutically acceptableeach R11is independently selected from optionally substituted alkyl, optionally substituted alkoxyl, halogen, OH, and CN; and n is an integer from 0 to 9; wherein: R1, R2, R4, R5, R7, and Z are as defined herein.

[0284] In some embodiments of Formula X, R4is of any one of Formulae 4A-4M. In some embodiments, R4is selected from Table 1.

[0285] In some embodiments of Formula X, R4is of Formulae 4A, 4E, 4F, or 4I:, wherein: X2, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, and X4are each independently selected from N and CR26; X12is C(R42)2 or NR43; each R15, R18, and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile;Atty. Docket No.: 39953-58778 (002WO) R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., optionally substituted spirocyclopropyl or spirocyclobutyl); R42is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R43is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 r is 0 or 1; and v and y are each independently an integer from 0 to 3.

[0286] In Some embodiments of Formula X, R4is of Formula 4E, and X2, X3, X4, R18and v are as defined herein.

[0287] In some embodiments of Formula X, R4is of Formula 4F, and X9, X10, R24, R29, R30, and y are as defined herein.

[0288] In some embodiments of Formula X, R4is of Formula 4I, and R23is as defined herein.

[0289] In some embodiments of Formula X, R4is of Formula 4A, and the compound is of the Formula XI:or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R5, R7, R11, R15, X12, Z, n and q are as defined herein.

[0290] In some embodiments of the compound of Formula XI: X12is CHR42; and R42is selected from H, optionally substituted (C1-6)alkyl, acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.Atty. Docket No.: 39953-58778 (002WO)

[0291] In some embodiments of the compound of Formula XI, X12is CHR42; and R42is -C(=O)R42a, -C(=O)NHR42a, -NHC(=O)R42a, wherein R42ais H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, or optionally substituted aryl. In some embodiments, X12is CHR42; and R42is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl. In some embodiments, X12is CHR42; and R42is optionally substituted –(CH2)zcycloalkyl, optionally substituted –(CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted –(CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

[0292] In some embodiments of the compound of Formula XI: X12is NR43; and

[0293] R43is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

[0294] In some embodiments of the compound of Formula XI, X12is NR43; and

[0295] R43is optionally substituted -C(=O)C1-6 alkyl, optionally substituted - C(=O)cycloalkyl, optionally substituted -C(=O)heterocycle, optionally substituted - C(=O)heteroaryl or optionally substituted -C(=O)aryl. In some embodiments, X12is NR43; and R43is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl. In some embodiments, X12is NR43; and R43is optionally substituted –(CH2)zcycloalkyl, optionally substituted –(CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted –(CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

[0296] In some embodiments of Formula X or XI, Z is of Formulae ZIB or Z1C, wherein X11, R8, R9, and R10are as defined herein.

[0297] In some embodiments of Formula X or XI, Z is Z1C, and X11is O. In some embodiments of Formula X or XI, Z is Z1C, and X11is NH. In some embodiments of Formula X or XI, Z is Z1C, and R9is H. In some embodiments of Formula X or XI, Z is Z1C, and R9is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1C, and R10is H. In some embodiments of Formula X or XI, Z is Z1C, and R10is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1C, and R10is optionally substituted cycloalkyl. In some embodiments of Formula X or XI, Z is Z1C, and R10is optionally substitutedAtty. Docket No.: 39953-58778 (002WO) heterocyclyl. In some embodiments of Formula X or XI, Z is Z1C, R9is H, and R10is (C1- 6)alkyl. In some embodiments of Formula X or XI, Z is Z1C, R9is H, and R10H.

[0298] In some embodiments of Formula X or XI, Z is Z1C, X11is NH, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Formula X or XI, Z is Z1C, X11is NH, R9is H and R10is ethyl.

[0299] In some embodiments of Formula X or XI, Z is Z1C, X11is O, R9is H and R10is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Formula X or XI, Z is Z1C, X11is O, R9is H and R10is ethyl.

[0300] In some embodiments of Formula X or XI, Z is of Formula Z1B, and X11is O. In some embodiments of Formula X or XI, Z is Z1B, and X11is NH. In some embodiments of Formula X or XI, Z is Z1B, and R8is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is methyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is (C2-6)alkenyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is -CH=CH2 or - C(CH3)=CH2. In some embodiments of Formula X or XI, Z is Z1B, and R8is (C2-6)alkynyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is -CCH or -CC-CH3. In some embodiments of Formula X or XI, Z is Z1B, and R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is optionally substituted (C3-7)heterocyclyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is (C3-4)cycloalkyl. In some embodiments of Formula X or XI, Z is Z1B, and R8is (C2-4)heterocyclyl.

[0301] In some embodiments of Formula X or XI, Z is Z1B, X11is NH, and R8is (C1-6)alkyl. In some embodiments of Formula X or XI, Z is Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Formula X or XI, Z is Z1B, X11is NH, and R8is heterocyclyl.

[0302] In some embodiments of Formula X or XI, Z is Z1B, X11is O, and R8is (C1- 6)alkyl. In some embodiments of Formula X or XI, Z is Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Formula X or XI, Z is Z1B, X11is O, and R8is heterocyclyl.

[0303] In some embodiments of Formula I, or any one of Formulae IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, or XI, the compound is selected from one of Tables 3 to 15, or is any one of compounds 1-965, or a pharmaceutically acceptable salt thereof.Atty. Docket No.: 39953-58778 (002WO)

[0304] In some embodiments of any one of Formula I, Y5is CR5. In some embodiments, R5is selected from H, CH3, CF3, and halogen. In some cases, R5is H. In some cases, R5is CH3. In some cases, R5is CF3. In some cases, R5is halogen. In some cases, the halogen is F or Cl.

[0305] In some embodiments of any one of Formula I, or any one of Formulae IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, or XI , R7is selected from H, CH3, CF3, and halogen. In some embodiments of Formula I, or any one of Formulae IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, or XI , R7is H.

[0306] In some embodiments of Formula I, Y1is CR1. In some embodiments, R1is selected from H, CH3, CF3, and halogen. In some cases, R1is H. In some cases, R1is CH3. In some cases, R1is CF3. In some cases, R1is halogen. In some cases, the halogen is F or Cl.

[0307] In some embodiments of Formula I, Y2is CR2. In some embodiments, R2is selected from H, CH3, CF3, - CH(F)2, -CH2Cl, halogen, -C(O)H, and -(CH2)zOH, where z is 1 to 3. In some embodiments, R2is H. In some embodiments, R2is CH3. In some embodiments, R2is CF3. In some embodiments, R2is - CH(F)2. In some embodiments, R2is -CH2Cl. In some embodiments, R2is halogen. In some embodiments, R2is -C(O)H. In some embodiments, R2is -(CH2)zOH, where z is 1 to 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0308] In some embodiments, the compound is of Formula XII:wherein: R4is selected from:, , ,Atty. Docket No.: 39953-58778 (002WO), , , , ,Atty. Docket No.: 39953-58778 (002WO) , ,

[0309] Example CDK inhibitor compounds of this disclosure are shown in the Examples section under the “Methods of Preparation” section, and Tables 5-6.

[0310] In some embodiments, the compound of Formula I is a compound listed or illustrated in any one of Tables 3-15. In some embodiments, the compound of Formula I is a compound listed in Table 3. In some embodiments, the compound of Formula I is a compound listed in Table 4. In some embodiments, the compound of Formula I is a compound of number 1-965. In some embodiments, the compound of Formula I is a compound of number 1-188, 193-217, or 220-946. In some embodiments, the compound of Formula I is a compound of number 189-192, 218-219, or 947-965.

[0311] In some embodiments of Formula I, R6is a (methylsulfonyl)piperidine group, and the compound is of number 1-2, 4-8, 11-12, 17-19, 21-22, 25-98, 102, 111, 115-119, 212, 251, or 260-262.Atty. Docket No.: 39953-58778 (002WO)

[0312] In some embodiments of Formula I, R6is a (vinylsulfonyl)piperidine group, and the compound is of number 3, 10, 15, 20, 24, or 103-109.

[0313] In some embodiments of Formula I, R4is a cyclohexene group, and the compound is of number 20, 99-102, 113-114, 127, 253, or 254.

[0314] In some embodiments of Formula I, R6is a (methylsulfonyl)phenyl group, and the compound is of number 23, 120-121, 124-127, 129-130, 135, 138-139, 142, 144, 146, 147- 148, 150-155, 158-159, 163-184, 186, 189, 193-204, 206-208, 213-216, 220, 223-240, 242- 244, 246-248, 250, 252, 259, 267.

[0315] In some embodiments of Formula I, R6is a (vinylsulfonyl)phenyl group, and the compound is of number 122-123, 131, 136-137, 141, 145, 149, 156-157, 160-162, 185, 205, 209, 188, 211, 217, 241, or 245.

[0316] In some embodiments of Formula I, R6includes an electrophilic reactive hydrophilic Z group, such as compound 9, 13-14, 16, 110, 112-114, 128, 140, 249, 253-254, or 258.

[0317] In some embodiments of Formula I, R6includes a non-electrophilic hydrophilic Z group, such as compound 23, 99-101, 16, 110, 132-134, 143, 187, 210, 221, or 222.

[0318] In some embodiments of Formula I, the compound is 16, or 110-114

[0319] In some embodiments of Formula I, R6is an aryl group, and the compound is a compound listed in Table 12.

[0320] In some embodiments of Formula I, R4comprises an indazole, and the compound is a compound listed in Table 13.

[0321] In some embodiments of Formula I, R4comprises a substituted alkyne, and the compound is a compound listed in Table 14.

[0322] In some embodiments of Formula I, the compound is of Formula IA, such as compound 1-188, 193-217, or 220-946.

[0323] In some embodiments of Formula I, the compound comprises an alternative core to Formula IA (e.g., a core of any one of Formulae IB-IM), such as a compound of Table 15, or a compound of Table 4.

[0324] In some embodiments of Formula I, the compound is of Formula IB, such as compound 219, 956, 958, 963, or 965.

[0325] In some embodiments of Formula I, the compound is of Formula IC, such as compound 190, or 192.

[0326] In some embodiments of Formula I, the compound is of Formula ID, such as compound 189, 191, 955, 957, 961, 962, or 964.Atty. Docket No.: 39953-58778 (002WO)

[0327] In some embodiments of Formula I, the compound is of Formula IE, such as compound 959.

[0328] In some embodiments of Formula I, the compound is of Formula IG, such as compound 218, or 960.

[0329] In certain embodiments, the compound is described by the structure of one of the compounds illustrated in the Examples section under the heading “Methods of Preparation,” or in Tables 5-6. It is understood that any of the compounds shown herein may be present in a salt form. In some cases, the salt form of the compound is a pharmaceutically acceptable salt.

[0330] “Pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically-acceptable salts include the acid addition salts (e.g., formed with the free amino groups of the compound) and which are formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.

[0331] The term "prodrug" refers to an agent which is converted into the drug in vivo by some physiological or chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). It is understood that any of the compounds shown in in the Examples section under the heading “Methods of Preparation,” or illustrated in Tables 5-6may be present in a prodrug form.

[0332] The present disclosure includes compounds (e.g., as described herein) with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.

[0333] Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as2H,3H,11C,13C,14C,15N,18F31P,32P,35S,36Cl, and125I respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emissionAtty. Docket No.: 39953-58778 (002WO) computed tomography (SPECT) including drug or substrate tissue distribution assays, or in treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0334] Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.

[0335] In some embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of Formulas I, IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA- VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, XI, or XII, or exemplary compounds 1-965. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32,any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain other embodiments, when two substituents are combined to form a cycle or ring system the unsubstituted carbons may be deuterated. 4.2 Pharmaceutical Compositions

[0336] Also provided herein is a pharmaceutical composition comprising the subject CDK2 inhibitor compounds and a pharmaceutically acceptable carrier or excipient.

[0337] A "pharmaceutical composition" is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general, a “pharmaceutical composition” is sterile, and preferably free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of differentAtty. Docket No.: 39953-58778 (002WO) routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like.

[0338] In general, the compositions of the disclosure will include and be administered in a therapeutically effective amount by the desired mode of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.

[0339] The terms "effective amount," "pharmaceutically effective amount," or "therapeutically effective amount" as used herein mean a sufficient amount of the composition to provide the desired utility when administered to a subject having a particular condition. The term "therapeutically effective amount" therefore refers to an amount of therapeutic cells or a composition having therapeutic cells that is sufficient to promote a particular effect when administered to a subject in need of treatment. An effective amount would also include an amount sufficient to prevent or delay the development of a symptom of the disease, alter the course of a symptom of the disease (for example but not limited to, slow the progression of a symptom of the disease), or reverse a symptom of the disease. It is understood that for any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using routine experimentation.

[0340] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable carrier or excipient" can encompass substances referred to as pharmaceutically acceptable diluents, pharmaceutically acceptable additives, and pharmaceutically acceptable carriers.

[0341] A pharmaceutically acceptable carrier, diluent or excipient for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990), and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent,Atty. Docket No.: 39953-58778 (002WO) diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Carriers include excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the disclosed compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound, as described in more detail herein. 4.3 Methods of Use

[0342] Also provided herein are methods for using the subject CDK inhibitor compounds and pharmaceutical compositions in research and as therapeutics. 4.4.1 Methods of Inhibiting CDK

[0343] As illustrated in the working examples the subject compounds can inhibit cyclin- dependent kinases such as CDK2 or CDK4. By inhibiting a CDK it is meant that the activity of the enzyme, e.g., in a sample or biological system, is decreased by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, e.g., relative to a control in any convenient in vitro inhibition assay. In some cases, inhibiting a CDK means decreasing the activity of the enzyme by a factor of 2 or more, such as 3 or more, 5 or more, 10 or more, 100 or more, or 1000 or more, relative to its normal activity (e.g., relative to a control as measured by any convenient assay).

[0344] In some cases, the method is a method of inhibiting CDK in a sample. The term "sample" as used herein relates to a material or mixture of materials, typically, although not necessarily, in fluid form, containing one or more components of interest.

[0345] Accordingly, in some embodiments there is provided a method of inhibiting cyclin-dependent kinase (e.g., CDK2 or CDK4), the method including contacting a biological sample containing CDK with an effective amount of a subject compound or a pharmaceutical composition, as described herein, to inhibit the CDK.

[0346] In some embodiments, there is provided a method of inhibiting CDK2, the method comprising contacting a sample with a CDK2 inhibitor to inhibit activity of CDK2. In some embodiments, there is provided a method of inhibiting CDK4, the method comprisingAtty. Docket No.: 39953-58778 (002WO) contacting a sample with a CDK2 inhibitor to inhibit activity of CDK4. In some cases, the sample is a cellular sample.

[0347] In certain embodiments the CDK (e.g., CDK2 or CDK4) inhibitor is a compound as defined herein. In some embodiments, the CDK (e.g., CDK2 or CDK4) inhibitor is an inhibitor according to any one of Formulas I, IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, XI, or XII, or exemplary compounds 1-965, or a pharmaceutically acceptable salt thereof. In some cases, the CDK inhibitor is any compound illustrated in Tables 3-15, or a pharmaceutically acceptable salt thereof. In some cases, the CDK2 inhibitor is any one of compounds 1-965.

[0348] In some embodiments the CDK inhibitor is a covalent inhibitor. In some embodiments, there is provided a method of inhibiting CDK, the method comprising contacting a sample with a CDK inhibitor that covalently binds to CDK to inhibit CDK. In some embodiments, the CDK inhibitor covalently binds to a lysine residue of CDK to inhibit CDK.

[0349] In some embodiments the CDK inhibitor is a classic inhibitor. In some embodiments, there is provided a method of inhibiting CDK, the method comprising contacting a sample with a CDK inhibitor that associates with CDK to inhibit CDK.

[0350] In some embodiments the CDK inhibitor is a covalent reversible inhibitor. In some embodiments, there is provided a method of inhibiting CDK, the method comprising contacting a sample with a CDK inhibitor that reversibly covalently binds to CDK to inhibit CDK.

[0351] In some embodiments, the subject compounds have a CDK inhibition profile that reflects activity against additional enzymes. In some embodiments, the subject compounds selectively inhibit CDK2 without significant inhibition of one or more other enzymes. In some embodiments, the subject compounds specifically inhibit CDK2 without undesired inhibition of CDK1. In some embodiments, the subject compounds selectively inhibit CDK2 over CDK4, and / or CDK6. In some embodiments, the subject compounds selectively inhibit CDK4 over CDK1. In some embodiments, the subject compounds selectively inhibit CDK4 over CDK2, and / or CDK6.

[0352] In some embodiments, the subject compounds inhibit CDK (e.g., CDK2 or CDK4), as determined by an inhibition assay, e.g., by an assay that determines the level of activity of the enzyme either in a cell-free system or in a cell after treatment with a subject compound, relative to a control, by measuring the IC50or EC50value, respectively. In certain embodiments, the subject compounds have an IC50 value (or EC50 value) of 10 μΜ or less,Atty. Docket No.: 39953-58778 (002WO) such as 3 μΜ or less, 1 μΜ or less, 500 nM or less, 300 nM or less, 200nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower.

[0353] As summarized above, aspects of the disclosure include methods of inhibiting CDK (e.g., CDK2 or CDK4). A subject compound (e.g., as described herein) may inhibit at activity of CDK (e.g., CDK2 or CDK4) in the range of 10% to 100%, e.g., by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more. In certain assays, a subject compound may inhibit its target with an IC50of 1 x 10"6M or less (e.g., 1 x 10"6M or less, 1 x 10"7M or less, 1 x 10"8M or less, 1 x 10-9M or less, 1 x 1010M or less, or 1 x 1011M or less).

[0354] The protocols that may be employed in determining CDK activity are numerous, and include but are not limited to cell-free assays, e.g., binding assays; assays using purified enzymes, cellular assays in which a cellular phenotype is measured, e.g., gene expression assays; and in vivo assays that involve a particular animal (which, in certain embodiments may be an animal model for a condition related to the target pathogen).

[0355] In some embodiments, the subject method is an in vitro method that includes contacting a sample with a subject compound that specifically inhibits CDK. In certain embodiments, the sample is suspected of containing CDK and the subject method further comprises evaluating whether the compound inhibits CDK.

[0356] In certain embodiments, the subject compound is a modified compound that includes a label, e.g., a fluorescent label, and the subject method further includes detecting the label, if present, in the sample, e.g., using optical detection.

[0357] In certain embodiments, the compound is modified with a support or with affinity groups that bind to a support (e.g., biotin), such that any sample that does not bind to the compound may be removed (e.g., by washing). The specifically bound CDK, if present, may then be detected using any convenient means, such as, using the binding of a labeled target specific probe, or using a fluorescent protein reactive reagent.

[0358] In another embodiment of the subject method, the sample is known to contain the CDK(s) of interest.

[0359] In some embodiments, the method is a method of reducing cancer cell proliferation, where the method includes contacting the cell with an effective amount of a subject CDK (e.g., CDK2 or CDK4) inhibitor compound (e.g., as described herein) to reduce cancer cell proliferation. The method can be performed in combination with a chemotherapeutic agent (e.g., as described herein). The cancer cells can be in vitro or in vivo.Atty. Docket No.: 39953-58778 (002WO) In certain instances, the method includes contacting the cell with a CDK (e.g., CDK2 or CDK4) inhibitor compound (e.g., as described herein) and contacting the cell with a chemotherapeutic agent. Any convenient cancer cells can be targeted.

[0360] In some embodiments, there is provided a method of inhibiting CDK (e.g., CDK2 or CDK4) in a subject, comprising administering to the subject a compound or a pharmaceutical composition, as described herein, to inhibit CDK (e.g., CDK2 or CDK4) in the subject. 4.4.2 Methods of Treatment

[0361] Compounds of the present disclosure can inhibit CDK (e.g., CDK2 or CDK4) and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by the CDK. Accordingly, provided herein is a method of treating a disease or disorder associated with a CDK (e.g., CDK2 or CDK4) in a subject, including administering to the subject suffering from a disease or disorder associated with the CDK a therapeutically effective amount of a compound, or a pharmaceutical composition as described herein.

[0362] Such diseases or disorders associated with CDK (e.g., CDK2 or CDK4) include cancer and other diseases of proliferation disorders. In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a subject compound (e.g., a compound of Formula (I) or a salt or stereoisomer thereof) such that growth of cancerous tumors is inhibited. A subject CDK (e.g., CDK2 or CDK4) inhibitor compound can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK kinase activity. These include, but are not limited to, disease (e.g., cancers) that are characterized by amplification or overexpression of CCNE1, or cyclin D (CCND).

[0363] In certain embodiments the CDK (e.g., CDK2 or CDK4) inhibitor is an inhibitor as defined herein. In some embodiments, the CDK inhibitor is an inhibitor according to any one of Formulas I, IA-IM, IIA-IIB, IIIA- IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, XI, or XII. In some cases, the CDK inhibitor is a compound illustrated in any of Tables 3-15, or a pharmaceutically acceptable salt thereof. In some cases, the CDK inhibitor is any one of compounds 1-965, or a pharmaceutically acceptable salt thereof.

[0364] Accordingly, in some embodiments of the methods, the patient has been previously determined to have an amplification of the cyclin El (CCNE1) gene and / or an expression level of CCNE1 in a biological sample obtained from the human subject that isAtty. Docket No.: 39953-58778 (002WO) higher than a control expression level of CCNE1. Alternatively, a subject CDK2 inhibitor compound can be used in conjunction with other agents or standard cancer treatments.

[0365] In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a subject compound. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with CCNE1 amplification and overexpression in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a subject compound.

[0366] In some embodiments, provided herein is a method of inhibiting CDK, comprising contacting the CDK with a subject CDK inhibitor compound. In some embodiments, provided herein is a method of inhibiting CDK in a patient, comprising administering to the patient a compound of Formula (I) or any of the Formulae as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.

[0367] In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient (in need thereof), a therapeutically effective amount of a subject CDK inhibitor compound. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1.

[0368] In some embodiments, the disease or disorder is associated with CDK4. In some embodiments, the disease or disorder associated with CDK4 is associated with an amplification and / or overexpression of the cyclin D (CCND) axis.

[0369] In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK in a patient, comprising administering to the patient a therapeutically effective amount of a subject CDK2 inhibitor compound. In some embodiments, the disease or disorder associated with CDK2 is associated with an amplification of the cyclin El (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells, K-Ras mutant lung cancers, and cancers with FBXW7 mutation and CCNE1 overexpression. 4.4 Utility

[0370] The subject methods and compositions, e.g., as described above, can be used in any application where CDK inhibition is desired. Applications of interest include both research and therapeutic applications. Applications of interest include, but are not limited to: research applications, diagnostic applications and therapeutic applications.Atty. Docket No.: 39953-58778 (002WO)

[0371] In some instances, the application of interest is a therapeutic application, for example, in the treatment of a disease. For example, the compositions and methods of the present application may be used to deliver a subject CDK inhibitor to a cell to treat a disease or condition where the underlying pathology is, wholly or partially, mediated by CDK. As one nonlimiting example, compositions of the present application may be used in the treatment of diseases or disorders associated with CDK such as cancer and other diseases with proliferation disorder. 4.5 Definitions

[0372] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated

[0373] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction isAtty. Docket No.: 39953-58778 (002WO) intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0374] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0375] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0376] Compounds are described using standard nomenclature. The compounds in any of the formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.Atty. Docket No.: 39953-58778 (002WO)

[0377] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0378] The abbreviations used herein have their conventional meaning without the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0379] As used herein, the phrase "having the formula" or "having the structure" is not intended to be limiting and is used in the same way that the term "comprising" is commonly used. The term "independently selected from" is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different.

[0380] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0381] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, orAtty. Docket No.: 39953-58778 (002WO) silicon; the quaternized form of any basic nitrogen or; a substituted nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N- substituted pyrrolidinyl)).

[0382] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0383] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0384] As used herein, the term “cyclopropylenyl” refers to a divalent cyclopropyl group of the following structure:

[0385] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:Atty. Docket No.: 39953-58778 (002WO).

[0386] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom.

[0387] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, “C1-C6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0388] The term “acyl” as used herein refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a C1-10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[0389] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 28 carbon atoms, referred to herein as (C2-C8)alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)- pentenyl.

[0390] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to hereinAtty. Docket No.: 39953-58778 (002WO) as C1-8 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3 methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3 methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[0391] The term “alkoxy” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t- butoxy, or pentoxy groups.

[0392] The term “alkylene” as used herein refers to a divalent alkyl radical. Representative examples of C1-10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n- pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n- decylene.

[0393] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-C8)alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4 butyl 2 hexynyl.

[0394] The term “aryl” herein refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0395] For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclicAtty. Docket No.: 39953-58778 (002WO) ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0396] The term “heteroaryl” refers to a group having 5 to 10 ring atoms, 5, 6, or 9 ring atoms; having 6, 10, or 14π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term “heteroaryl”, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydrquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0397] The term “cyano” as used herein refers to CN.

[0398] The term “cycloalkyl” as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(C3-C8)cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups canAtty. Docket No.: 39953-58778 (002WO) be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.

[0399] The terms “halo” or “halogen” as used herein refer to -F, -Cl, -Br, and / or -I.

[0400] “Haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0401] A “heterocyclyl” or “heterocyclic” group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic, or a bridged ring system. The heterocyclic group is independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1H)-oxide, tetrahydro- 2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0402] A “spirocycle”, “spirocyclyl”, or “spirocyclylene” refers to a chemical entity having two heterocyclyl or two cycloalkyl moieties as defined herein, or to a combination of one or more heterocyclyl and one or more cycloalkyl moiety, having one ring atom in common, i.e., the two rings are connected via one common ring atom. Some exemplary spirocyclic ring systems, yet non-limiting examples of spirocyclic ring systems, includeAtty. Docket No.: 39953-58778 (002WO) , ,a includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0404] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a divalent group. Thus, any of the terms above can be modified with the suffix “- ene” to describe a divalent version of that moiety. For example, a divalent carbocycle is “carbocyclylene”, a divalent aryl ring is “arylene”, a divalent benzene ring is “phenylene”, a divalent heterocycle is “heterocyclylene”, a divalent heteroaryl ring is “heteroarylene”, a divalent alkyl chain is “alkylene”, a divalent alkenyl chain is “alkylene”, a divalent alkynyl chain is “alkynylene”, and so forth.

[0405] As described herein, compounds of the disclosure may, when specified, contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g., refers to at ; and, , , . addition, in a polycyclic ring substituents unless otherwise replace ahydrogen on any individual ring (e.g., refers to at least ,Atty. Docket No.: 39953-58778 (002WO) Unless otherwise indicated, an “optionallyat each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. For example, when the term "substituted" appears prior or after a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase "substituted alkyl and aryl" is to be interpreted as "substituted alkyl and substituted aryl."

[0406] Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their purification, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0407] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°; - O(CH2)0-4C(O)OR°; -O(CH2)0-4OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted with R°, - CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)N(R°)2; -N(R°)C(S)N(R°)2; -(CH2)0-4N(R°)C(S)N(R°)2; - (CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)N(R°)2; - N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; - (CH2)0-4C(O)OSi(R°)3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR°; -SC(S)SR°; -(CH2)0- 4SC(O)R°; -(CH2)0-4C(O)N(R°)2; -C(S)N(R°)2; -C(S)SR°; -SC(S)SR°; -(CH2)0-4OC(O)N(R°)2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°; -(CH2)0- 4S(O)R°; -N(R°)S(O)2N(R°)2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)N(R°)2; -P(OR°)2; - P(O)(R°)2; -OP(O)(R°)2; -OP(O)(OR°)2; -SiR°3; -(C1-4straight or branched alkylene)O- N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, - O(CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated,Atty. Docket No.: 39953-58778 (002WO) partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atoms(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[0408] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen; -(CH2)0-2R●; -(haloR●), -(CH2)0-2OH; -(CH2)0-2OR●; -(CH2)0-2CH(OR●)2; - O(haloR●); -CN; -N3; -(CH2)0-2C(O)R●; -(CH2)0-2C(O)OH; -(CH2)0-2C(O)OR●; -(CH2)0-2SR●; -(CH2)0-2SH; -(CH2)0-2NH2; -(CH2)0-2NHR●; -(CH2)0-2NR●2; -NO2, -SiR●3; -OSiR●3; - C(O)SR●; -(C1-4 straight or branched alkylene)C(O)OR●, or -SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-memebered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0409] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O; =S; =NNR#2; =NNHC(O)R#2; =NNHC(O)OR#2; =NNHS(O)2R#2; =NR#; =NOR#; -O(C(R#2))2-3O-; or -S(C(R#2))2-3S-; wherein each independent occurrence of R#is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR#2)2-3O-, wherein each independent occurrence of R#is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0410] Suitable substituents on the aliphatic group of R#include halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-memberedAtty. Docket No.: 39953-58778 (002WO) saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0411] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, - S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†2; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences or R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0412] Suitable substituents on the aliphatic group of R†are independently halogen, -R●, - (haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0413] Those skilled in the art will appreciate that a bond designated as in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. Forthe structure: is intended to encompass both and.

[0414] The term “oxo”, as used herein, means an oxygen that is double bonded to a carbon atom thereby forming a carbonyl.

[0415] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH.

[0416] Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl - CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)-Atty. Docket No.: 39953-58778 (002WO) groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0417] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0418] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain, in some embodiments, a meso moiety, be a meso compound, or have meso isomerism.

[0419] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0420] “Stereoisomer” or “optical isomer” means a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds areAtty. Docket No.: 39953-58778 (002WO) prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0421] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0422] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos.5,114,946 and 4,818,541.

[0423] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greaterAtty. Docket No.: 39953-58778 (002WO) than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5% or more.

[0424] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral- phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0425] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.

[0426] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents forAtty. Docket No.: 39953-58778 (002WO) pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0427] Additionally, as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.

[0428] The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0429] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.Atty. Docket No.: 39953-58778 (002WO)

[0430] A compound of this disclosure may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the present disclosure includes a solvated form of the compound. The term “solvate” refers to a molecular complex of a compound (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. A solvate can be in a liquid or solid form.

[0431] Salts, solvates, hydrates, and prodrug forms of a compound are of interest. All such forms are embraced by the present disclosure. Thus, the compounds described herein include salts, solvates, hydrates, prodrug and isomer forms thereof, including the pharmaceutically acceptable salts, solvates, hydrates, prodrugs and isomers thereof. In certain embodiments, a compound may be a metabolized into a pharmaceutically active derivative.

[0432] Chemical names were generated using PerkinElmer ChemDraw® Professional, version 17.

[0433] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0434] As used herein, “cancer” refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0435] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows,Atty. Docket No.: 39953-58778 (002WO) sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0436] As used herein, the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0437] A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.

[0438] As will be understood from context, a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison. In some embodiments, information about a reference compound is obtained simultaneously with information about a particular compound. In some embodiments, comparison of a particular compound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.

[0439] As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect, when administered to a subject.

[0440] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0441] As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.Atty. Docket No.: 39953-58778 (002WO)

[0442] Definitions of other terms and concepts appear throughout the detailed description.

[0443] The following example(s) is / are offered by way of illustration and not by way of limitation. 5. ADDITIONAL EMBODIMENTS

[0444] This disclosure is further described by the following non-limiting clauses:

[0445] Clause 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: Y1is N or CR1; Y2is N or CR2; Y3is N or CR3; Y5is N or CR5; R6is of the formula, wherein: A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; Z is an optional hydrophilic group; L1and L2are optional linkers; and * represents the point of attachment of R6to the adjacent nitrogen atom; R4is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl; R1-R3, R5and R7are independently selected from H, optionally substituted (C1-6)alkyl, halo(C1-6)alkyl, -COR30, -OR30, halogen, and CN; and R30is H or optionally substituted (C1-6)alkyl.Atty. Docket No.: 39953-58778 (002WO)

[0446] Clause 2. The compound of clause 1, wherein A is optionally substituted aryl or optionally substituted heteroaryl.

[0447] Clause 3. The compound of clause 2, wherein R6comprises the structure 6A: wherein:Y6-Y10are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; and each R12is independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, halogen, and CN.

[0448] Clause 4. The compound of clause 3, wherein Y8is C-Z.

[0449] Clause 5. The compound of clause 3 or 4, wherein at least one of Y6-Y10is N.

[0450] Clause 6. The compound of clause 5, wherein one and only one of Y6-Y10is N.

[0451] Clause 7. The compound of clause 5 or 6, wherein Y6is N.

[0452] Clause 8. The compound of clause 5 or 6, wherein Y7is N.

[0453] Clause 9. The compound of clause 4, wherein R6is of the structure 6A1:wherein m is 0, 1, 2, 3 or 4.

[0454] Clause 10. The compound of clause 9, wherein R6is of the structure 6A2:wherein R12is selected from hydrogen, halogen, optionally substituted (C1-6)alkyl, and optionally substituted (C1-6)alkoxy.

[0455] Clause 11. The compound of clause 1, wherein A is optionally substituted cycloalkyl, or optionally substituted heterocyclyl (e.g., piperidinyl).Atty. Docket No.: 39953-58778 (002WO)

[0456] Clause 12. The compound of clause 11, wherein R6comprises the structure 6B: wherein:Y11is selected from O, S, CH2, CHR11, C(R11)2, and NR9; R9is H, optionally substituted alkyl, -L2-Z, or Z; each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; k is 0 or 1; and n is an integer from 0 to 9.

[0457] Clause 13. The compound of clause 12, wherein R6comprises the structure 6B1 or 6B3:.

[0458] Clause 14. The compound of clause 13, wherein: n is 0, 1, 2, 3 or 4; and each R11is independently selected from optionally substituted (C1-3)alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, and CN.

[0459] Clause 15. The compound of clause 14, wherein each R11is independently selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro.

[0460] Clause 16. The of clause 13, wherein R6is of the structure 6B2:.

[0461] Clause 17. The compound R6is of the structure 6B4:(6B4).Atty. Docket No.: 39953-58778 (002WO)

[0462] Clause 18. The compound of any one of clauses 1 to 17, wherein R4is selected from substituted amine, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.

[0463] Clause 19. The compound of any one of clauses 1 to 18, wherein R4is optionally substituted alkynyl.

[0464] Clause 20. The compound of any one of clauses 1 to 18, wherein R4is optionally substituted cycloalkyl.

[0465] Clause 21. The compound of any one of clauses 1 to 18, wherein R4is optionally substituted cycloalkene.

[0466] Clause 22. The compound of any one of clauses 1 to 18, wherein R4is optionally substituted heterocyclyl.

[0467] Clause 23. The compound of any one of clauses 1 to 18, wherein R4is optionally substituted aryl.

[0468] Clause 24. The compound of any one of clauses 1 to 18, wherein R4is an optionally substituted heteroaryl.

[0469] Clause 25. The compound of any one of clauses 20 to 24, wherein R4is an optionally substituted monocyclic group.

[0470] Clause 26. The compound of any one of clauses 20 to 24, wherein R4is an optionally substituted bicyclic group.

[0471] Clause 27. The compound of clause 26, wherein R4is an optionally substituted spirocyclic group.

[0472] Clause 28. The compound of clause 26, wherein R4is an optionally substituted fused bicyclic group.

[0473] Clause 29. The compound of any one of clauses 18 to 28, wherein R4is selected from substituted amine, (C2-6)alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrazole, azetidine, azepane, pyridyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, oxindole, triazole, oxadiazole, cyclohexanone, and optionally substituted versions thereof.

[0474] Clause 30. The compound of any one of clauses 18 to 29, wherein R4is selected from any one of Formulae 4A-4M:Atty. Docket No.: 39953-58778 (002WO), wherein, X1is O, CH2, or C(R26)2; X12is CH2, C(R15)2, O, NCOR25, or NR25; X14is O, NCOR25, or NR25; X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, X7and X8are each independently selected from N and CR26; each R15-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R21and R22are each independently optionally substituted (C1-6)alkyl; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R25is H, optionally substituted (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionallyAtty. Docket No.: 39953-58778 (002WO) substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R27and R28are each independently H, or optionally substituted (C1-6)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0475] Clause 31. The compound of clause 30, wherein R4is of Formula 4A.

[0476] Clause 32. The compound of clause 31, wherein R4is of Formula 4A1 or 4A2:, , wherein: r is 0, 1 or 2; and R25is H, or optionally substituted (C1-6)alkyl.

[0477] Clause 33. The compound of clause 30, wherein R4is of Formula 4B.

[0478] Clause 34. The compound of clause 33, wherein X1is CH2.

[0479] Clause 35. The compound of clause 30, wherein R4is of Formula 4C or 4D.

[0480] Clause 36. The compound of clause 35, wherein R4is of Formula 4C wherein u is 2.

[0481] Clause 37. The compound of clause 30, wherein R4is of Formula 4E:Atty. Docket No.: 39953-58778 (002WO)

[0482] Clause 38. The compoundR4is selected from one of the following structures: .

[0483] Clause 39. The compound of clause 38, wherein R4is selected from one of the following structures:.

[0484] Clause 40. The compound of clause 38 or 39, wherein R25is of structure:wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen, and / or any two of R33– R37(e.g., R33and R34, and / or R36and R37) can be cyclically linked and together with the carbon atom(s) to which they are attached provide a C3-C7 carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0485] 4J-4L:(4J), (4K), or (4L).

[0486] Clause 42. The compound of clause 41, wherein X5is CR26.

[0487] Clause 43. The compound of clause 41, wherein X5is N.Atty. Docket No.: 39953-58778 (002WO)

[0488] Clause 44. The compound of clause 30, wherein R4is of Formula 4M:

[0489] Clause 45. The compoundR4is: .

[0490] Clause 46. The is of Formula 4G: .

[0491] Clause 47. The compound of clause 46, wherein X8is N

[0492] Clause 48. The compound of clause 46, wherein X8is CH.

[0493] Clause 49. The compound of clause 30, wherein R4is of Formula 4I:.

[0494] Clause 50. The compound of clause 49, wherein R23is selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

[0495] Clause 51. The compound of clause 50, wherein R23is selected from:, , , , wherein: X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, and X7are each independently selected from N and CR26; each R18-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R25is H, or optionally substituted C1-6 alkyl;Atty. Docket No.: 39953-58778 (002WO) each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0496] Clause 52. The compound of clause 51, wherein R23is of Formula 4F.

[0497] Clause 53. The compound of clause 52, wherein R23is selected from one of the following structures:.

[0498] Clause 54. The compound of clause 30, wherein R4is of Formula 4F:.

[0499] Clause 55. The compound of clause 54, wherein R4is selected from one of the structures:R25, , , and .Atty. Docket No.: 39953-58778 (002WO)

[0500] Clause 56. The compound of clause 30, wherein R4is of Formula 4H: .

[0501] Clause 57. The compoundR27and R28together with the nitrogen atom to which they are attached are cyclically linked to provide an optionally substituted piperidinyl.

[0502] Clause 58. The compound of any one of clauses 1 to 57, wherein Z comprises a hydrophilic moiety that is substantially biologically inert.

[0503] Clause 59. The compound of any one of clauses 1 to 57, wherein Z comprises an electrophilic reactive moiety capable of covalently conjugating a biological target.

[0504] Clause 60. The compound of any one of clauses 1 to 59, wherein Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.

[0505] Clause 61. The compound of clause 60, wherein Z is alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl or heterocyclylsulfonyl.

[0506] Clause 62. The compound of clause 60, wherein Z is alkylsulfoximine, cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, or alkylsulfonamide.

[0507] Clause 63. The compound of any one of clauses 1 to 62, wherein L1and L2are independently absent, or optionally substituted (C1-6)alkylene (e.g., CH2, (CH2)2, or (CH2)3).

[0508] Clause 64. The compound of any one of clauses 1 to 63, wherein -L2-Z or Z is of one of Z1-Z6:(Z4), (Z5), or (Z6), wherein: Y9is absent, -O-, -NR9-, -(C1-6)alkylene-O-, -(C1-6)alkylene-NR9-;Atty. Docket No.: 39953-58778 (002WO) X11is O, or NH; R51is selected from halogen, R8, -NR9R10; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone (e.g., SO2alkyl, or SO2NHalkyl), or a thiolactone; and R52is H, optionally substituted (C1-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; m is 0, 1 or 2; and p, q, s and t are independently 0, 1, 2, 3, 4, 5 or 6.

[0509] Clause 65. The compound of clause 64, wherein -L2-Z or Z is of formula Z1 and is of one of the following structures: ,wherein: R51is halogen; R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; and R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, or optionally substituted heterocyclyl.

[0510] Clause 66. The compound of clause 65, wherein -L2-Z or Z is and R8is (C1-C6)alkyl.

[0511] Clause 67. The compound of clause 66, wherein R8is methyl.Atty. Docket No.: 39953-58778 (002WO) X11O

[0512] Clause 68. The compound of clause 65, wherein -L2-Z or Z and R8is C -C alk2 6 enyl.

[0513] Clause 69. The compound of clause 68, wherein R8is -CH=CH2or -C(CH3)=CH2. X11

[0514] Clause 70. The compound of clause 65, wherein -L2-Z or Z and R8isC2-C6 alkynyl.

[0515] Clause 71. The compound of clause 70, wherein R8is -CCH or -CC-CH3. X11O S8

[0516] Clause 72. The compound of clause 65, wherein -L2-Z or Z is R and R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

[0517] Clause 73. The compound of clause 72, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.

[0518] Clause 74. The compound of clause 65, wherein -L2-Z or Z is , R9is H, and R10is H, or optionally substituted (C1-6)alkyl.

[0519] Clause 75. The compound of any one of clauses 65-74, wherein X11is O.

[0520] Clause 76. The compound of any one of clauses 65-74, wherein X11is NH.

[0521] Clause 77. The compound of clause 65, wherein -L2-Z or Z is of the formula:, wherein R51is halogen.

[0522] Clause 78. The compound of clause 64, wherein -L2-Z or Z is of Formula Z4 wherein s is 0:wherein; R9is H; and R10is -SO2R38; and R38is optionally substituted alkyl, or amino.Atty. Docket No.: 39953-58778 (002WO)

[0523] Clause 79. The compound of clause 64, wherein -L2-Z or Z is of Formula Z4 wherein s is 0: ,wherein; R9is H; and R10is -SO2R38wherein R38is optionally substituted alkenyl, or R10is optionally substituted thiolactone.

[0524] Clause 80. The compound of clause 79, wherein -L2-Z is of Formula Z4C:wherein m is 0, 1 or 2.

[0525] Clause 81. The compound of clause 64, wherein -L2-Z or Z is of Formula Z2:wherein m is 0, 1 or 2.

[0526] Clause 82. The compound of clause 64, wherein -L2-Z or Z is of Formula Z3:wherein: R52is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and t is 0, 1, or 2.

[0527] Clause 83. The compound of wherein R52is:.Atty. Docket No.: 39953-58778 (002WO)

[0528] Clause 84. The compound of clause 64, wherein -L2-Z or Z is of Formula Z3A wherein t is 0, (Z3A) wherein R52is H.

[0529] Clause 85. The compound of clause 64, wherein -L2-Z or Z is of Formula Z5.wherein q is 0, 1, or 2.

[0530] Clause 86. The compound of clause 64, wherein-L2-Z or Z is of Formula Z6,wherein p is 0, 1, or 2.

[0531] Clause 87. The compound of any one of clauses 1 to 86, wherein R5is selected from H, CH3, CF3, and halogen.

[0532] Clause 88. The compound of clause 87, wherein R5is H.

[0533] Clause 89. The compound of any one of clauses 1 to 88, wherein R7is selected from H, CH3, CF3, and halogen.

[0534] Clause 90. The compound of clause 89, wherein R7is H.

[0535] Clause 91. The compound of any one of clauses 1 to 90, wherein R1is selected from H, CH3, CF3, and halogen.

[0536] Clause 92. The compound of clause 91, wherein R1is H.

[0537] Clause 93. The compound of any one of clauses 1 to 92, wherein R2is selected from H, CH3, CF3, - CHF2, -CH2Cl, halogen, -C(=O)H, and -(CH2)zOH, where z is 1, 2 or 3.

[0538] Clause 94. The compound of clause 93, wherein R2is H.

[0539] Clause 95. The compound of any one of clauses 1 to 94, wherein the compound is of any one of Formulae IA-IM:Atty. Docket No.: 39953-58778 (002WO)or a pharmaceutically acceptable salt thereof.

[0540] Clause 96. The compound of clause 95, wherein R3is CN.

[0541] Clause 97. The compound of clause 95, wherein R3is H.

[0542] Clause 98. The compound of any one of clauses 95 to 97, wherein R1, R2, R5and R7are each H.

[0543] Clause 99. The compound of any one of clauses 95 to 98, wherein R6is selected from:wherein:Atty. Docket No.: 39953-58778 (002WO) A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; R8is optionally substituted (C1-6)alkyl, optionally substituted (C2-6)alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; R9is H, or optionally substituted (C1-6)alkyl; R10is a sulfone or a thiolactone; R52is H, optionally substituted (C1-6)alkyl, or optionally substituted heterocyclyl; R55is H, or optionally substituted (C1-6)alkyl; and m is an integer from 0 to 2.

[0544] Clause 100. The compound of clause 99, wherein R6is of Formula:

[0545] Clause 101. The compound of clause 99, wherein R6is of Formula:

[0546] Clause 102. The compound of any one of clauses 100 to 101, wherein:

[0547] R8is -CH3 or -CH2-R13, and

[0548] R13is optionally substituted (C1-6)alkyl.

[0549] Clause 103. The compound of any one of clauses 100 to 101, wherein:

[0550] R8is -CH=CH2 or -CH=CH-R14, and

[0551] R14is optionally substituted (C1-6)alkyl.

[0552] Clause 104. The compound of any one of clauses 100 to 101, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

[0553] Clause 105. The compound of any one of clauses 100 to 101, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl. The compound of clause 99, wherein R6is of Formula:.

[0555] Clause 107. The compound of clause 99, wherein R6is of Formula:Atty. Docket No.: 39953-58778 (002WO)The compound of any one of clauses 106 to 107, wherein R9is H, and R10is H, or optionally substituted (C1-6)alkyl.

[0557] Clause 109. The compound of any one of clauses 99 to 108, wherein the A ring is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4-piperidinyl, and optionally substituted cyclohexyl.

[0558] Clause 110. The compound of any one of clauses 95 to 109, wherein: R4is selected from any one of Formulae 4A-4M:, , , , wherein, X1is O, CH2, or C(R26)2; X12is CH2, C(R15)2, O, NCOR25, or NR25; X14is O, NCOR43, or NR43; X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, X7and X8are each independently selected from N and CR26; each R15-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN;Atty. Docket No.: 39953-58778 (002WO) R21and R22are each independently optionally substituted C1-6 alkyl; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R25is H, or optionally substituted (C1-6)alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R27and R28are each independently H, or optionally substituted (C1-6)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently an integer from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; and R6is selected from:and , wherein: Y11is selected from O, S, CH2, CHR11, C(R11)2, and NR9; R9is H, optionally substituted (C1-6)alkyl, -L2-Z, or Z;Atty. Docket No.: 39953-58778 (002WO) each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; k is 0 or 1; n is an integer from 0 to 9. Y6-Y10groups are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; and each R12is independently selected from H, optionally substituted alkyl, halogen, and CN.

[0559] Clause 111. The compound of clause 110, wherein R4is selected from Table 1.

[0560] Clause 112. The compound of clause 110, wherein R6is selected from Table 2.

[0561] Clause 113. The compound of any one of clauses 95 to 112, wherein the compound is of Formula (IA):, or a pharmaceutically acceptable salt thereof.

[0562] Clause 114. The compound of clause 113, wherein the compound is of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: Y6, Y7, Y9, and Y10are independently selected from CR12and N, wherein at least two of Y6, Y7, Y9, and Y10are CR12; and each R12is independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxy, hydroxyl, halogen, and CN.

[0563] Clause 115. The compound of clause 114, wherein Y6, Y7, Y9, and Y10are each independently CH or CR12and the compound is of Formula V:Atty. Docket No.: 39953-58778 (002WO) or a pharmaceuticallywherein m is an integer from 0 to 4.

[0564] Clause 116. The compound of clause 115, wherein the compound is of Formula VIA: 2or a pharmaceutically acceptable salt thereof.

[0565] Clause 117. The compound of any one of clauses 113 to 115, wherein Z is, wherein: R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.

[0566] Clause 118. The compound of clause 116 or 117, wherein the compound is of the formula (VIIA):(VIIA)Atty. Docket No.: 39953-58778 (002WO) or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl or optionally substituted -C(=O)C1-6 alkyl; X11is O or NH; R41is R8or N(R9)R10; R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; and R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

[0567] Clause 119. The compound of clause 118, wherein the compound is of Formula VIIIA:or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl; R18is H, halogen, optionally substituted (C1-6)alkyl, or optionally substituted (C1- 6)alkoxyl; and R12is H, halogen, optionally substituted (C1-6)alkyl or optionally substituted (C1-6)alkoxyl.

[0568] Clause 120. The compound of any one of clauses 118 to 119, wherein R25is selected from methyl, ethyl, propyl, isopropyl, isobutyl, isopentyl, and substituted versions thereof.

[0569] Clause 121. The compound of any one of clauses 118 to 120, wherein R25is of structure:wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen, and / or any two of R33– R37(e.g., R33and R34, and / or R36and R37) can beAtty. Docket No.: 39953-58778 (002WO) cyclically linked and together with the carbon atom(s) to which they are attached provide a C3-C7 carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0570] Clause 122. The compound of clause 121, wherein R35is OH.

[0571] Clause 123. The compound of clause 122, wherein R25is:

[0572] of any one of clauses 118 to 123, wherein R41is R8.

[0573] Clause 125. The compound of clause 124, wherein R8is (C1-6)alkyl.

[0574] Clause 126. The compound of clause 124, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

[0575] Clause 127. The compound of clause 126, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.

[0576] Clause 128. The compound of any one of clauses 118 to 123, wherein R41is N(R9)R10.

[0577] Clause 129. The compound of clause 128, wherein R41is NH2or -NH(C1-6)alkyl

[0578] Clause 130. The compound of any one of clauses 117 to 129, wherein X11is O.

[0579] Clause 131. The compound of any one of clauses 117 to 129, wherein X11is NH.

[0580] Clause 132. The compound of clause 115, wherein the compound is of Formula VIB:or a pharmaceutically acceptable salt thereof, wherein m is an integer from 0 to 4.Atty. Docket No.: 39953-58778 (002WO)

[0581] Clause 133. The compound of clause 132, wherein the compound is of Formula VIIB: .or a pharmaceutically each R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R25is H, or optionally substituted (C1-6)alkyl; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; and y is 0, 1, 2, or 3.

[0582] Clause 134. The compound of clause 133, wherein the compound is of Formula VIIIB:or a pharmaceutically acceptable salt thereof.

[0583] Clause 135. The compound of clause 133 or 134, wherein the compound is of Formula IX:Atty. Docket No.: 39953-58778 (002WO) or a pharmaceutically

[0584] Clause 136. The compound of any one of clauses 133 to 135 wherein R12is H, halogen, optionally substituted (C1-6)alkyl or optionally substituted (C1-6)alkoxyl.

[0585] Clause 137. The compound of clause 136, wherein R12is H.

[0586] Clause 138. The compound of clause 136, wherein R12is (C1-6)alkyl.

[0587] Clause 139. The compound of clause 138, wherein R12is methyl.

[0588] Clause 140. The compound of clause 136, wherein R12is halogen.

[0589] Clause 141. The compound of clause 136, wherein R12is (C1-6)alkoxyl.

[0590] Clause 142. The compound of clause 141, wherein R12is methoxy.

[0591] Clause 143. The compound of any one of clauses 133 to 142, wherein R29and R30are each independently optionally substituted (C1-6)alkyl.

[0592] Clause 144. The compound of clause 143, wherein R29and R30are each independently (C1-3)alkyl.

[0593] Clause 145. The compound of clause 144, wherein R29and R30are each methyl.

[0594] Clause 146. The compound of clause 144, wherein R29and R30are each ethyl.

[0595] Clause 147. The compound of any one of clauses 133 to 142, wherein R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group.

[0596] Clause 148. The compound of clause 147, wherein the optionally substituted spirocyclic group is spirocyclopropyl or spirocyclobutyl.

[0597] Clause 149. The compound of any one of clauses 133 to 148, wherein R41is R8.

[0598] Clause 150. The compound of clause 149, wherein R8is (C1-6)alkyl.

[0599] Clause 151. The compound of clause 149, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

[0600] Clause 152. The compound of clause 151, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.Atty. Docket No.: 39953-58778 (002WO)

[0601] Clause 153. The compound of any one of clauses 133 to 148, wherein R41is N(R9)R10.

[0602] Clause 154. The compound of clause 153, wherein R41is NH2or NH-(C1-6)alkyl.

[0603] Clause 155. The compound of any one of clauses 133 to 154, wherein X11is O.

[0604] Clause 156. The compound of any one of clauses 133 to 154, wherein X11is NH.

[0605] Clause 157. The compound of clause 113, wherein the compound is of Formula X:or a pharmaceutically acceptable salt thereof, wherein: each R11is independently selected from optionally substituted alkyl, optionally substituted alkoxyl, halogen, OH, and CN; and n is an integer from 0 to 9.

[0606] Clause 158. The compound of clause 157, wherein R4is selected from:, wherein: X2, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, and X4are each independently selected from N and CR26; X12is CH2, CHR42, C(R42)2, NCOR43, or NR43; each R15, R18, and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionallyAtty. Docket No.: 39953-58778 (002WO) substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., optionally substituted spirocyclopropyl or spirocyclobutyl); R42is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R43is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 r is 0 or 1; and v and y are each independently an integer from 0 to 3.

[0607] Clause 159. The compound of clause 157 or 158, wherein the compound is of Formula XI:or a pharmaceutically acceptable salt thereof.

[0608] Clause 160. The compound of clause 159, wherein: X12is CHR42; and R42is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

[0609] Clause 161. The compound of clause 160, wherein: R42is -C(=O)R42a, -C(=O)NHR42a, -NHC(=O)R42a, wherein R42ais H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, or optionally substituted aryl;Atty. Docket No.: 39953-58778 (002WO) R42is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; or R42is optionally substituted –(CH2)zcycloalkyl, optionally substituted – (CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted – (CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

[0610] Clause 162. The compound of clause 159, wherein: X12is NR43; and R43is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

[0611] Clause 163. The compound of clause 161, wherein: R43is optionally substituted -C(=O)C1-6 alkyl, optionally substituted - C(=O)cycloalkyl, optionally substituted -C(=O)heterocycle, optionally substituted - C(=O)heteroaryl or optionally substituted -C(=O)aryl; R43is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; or R43is optionally substituted –(CH2)zcycloalkyl, optionally substituted – (CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted – (CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

[0612] Clause 164. The compound of any one of clauses 157 to 163, wherein Z is of the formula:, wherein:R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof;R9is H or optionally substituted (C1-6)alkyl;R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.

[0613] Clause 165. The compound of any one of clauses 1-164, wherein the compound is selected from any one of compounds 1-965 and the compounds of Tables 3 to 15 (e.g., as described in the experimental section), or a pharmaceutically acceptable salt thereof.

[0614] Clause 166. A pharmaceutical composition comprising a compound of any one of clauses 1 to 165 and a pharmaceutically acceptable excipient.Atty. Docket No.: 39953-58778 (002WO)

[0615] Clause 167. A method of inhibiting cyclin-dependent kinase (CDK), the method comprising contacting a biological sample containing a CDK with an amount of a compound of any one of clauses 1 to 165 effective to inhibit the CDK.

[0616] Clause 168. A method of inhibiting CDK in a subject, comprising administering to a subject a compound of any one of clauses 1 to 165, or a pharmaceutical composition according to clause 166, to inhibit CDK in the subject.

[0617] Clause 169. The method of clause 167 or 168, wherein the CDK is CDK2.

[0618] Clause 170. The method of clause 167 or 168, wherein the CDK is CDK4.

[0619] Clause 171. A method of treating a disease or disorder associated with CDK2 in a subject, comprising administering to a subject in need thereof a dose of a compound of any one of clauses 1 to 165, or a pharmaceutical composition of clause 166.

[0620] Clause 172. The method of clause 171, wherein the disease or disorder associated with CDK2 is cancer. 6. EXAMPLES

[0621] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

[0622] General methods in molecular and cellular biochemistry can be found in such standard textbooks as Molecular Cloning: A Laboratory Manual, 3rd Ed. (Sambrook et al., HaRBor Laboratory Press 2001); Short Protocols in Molecular Biology, 4th Ed. (Ausubel et al. eds., John Wiley & Sons 1999); Protein Methods (Bollag et al., John Wiley & Sons 1996); Nonviral Vectors for Gene Therapy (Wagner et al. eds., Academic Press 1999); Viral Vectors (Kaplift & Loewy eds., Academic Press 1995); Immunology Methods Manual (I. Lefkovits ed., Academic Press 1997); and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle & Griffiths, John Wiley & Sons 1998), the disclosures of which are incorporated herein by reference. Reagents, cloning vectors, cells, and kits for methods referred to in, or related to, this disclosure are available from commercial vendors such asAtty. Docket No.: 39953-58778 (002WO) BioRad, Agilent Technologies, Thermo Fisher Scientific, Sigma-Aldrich, New England Biolabs (NEB), Takara Bio USA, Inc., and the like, as well as repositories such as e.g., Addgene, Inc., American Type Culture Collection (ATCC), and the like.

[0623] CDK2 Assay

[0624] A CDK homogeneous time-resolved fluorescence (HTRF) assay was used to assess the potency of the compounds described herein.

[0625] To an untreated 384-well microtiter plate (ProxiPlate) was added 100 nL 100 x test compound in DMSO and 5 μL 2 x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01 % Tween 20, 2mM DTT). The plate was centrifuged at 800 RPM for 1 min then incubated for 20 min at 23 °C.2.5 μL per well of 4 x ATP and 2.5 μL 4 x ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate were added to all wells. After addition, the plates were centrifuged at 800 RPM for 1 min. The plates were incubated at 23 °C for 60 min.5 μL per well 4 x EDTA solution were added to each well to stop the reaction.5 μL 4 x LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46) antibody were added to each well and the plate was centrifuged for 1 min at 800 RPM. The plate was incubated for 60 min at 23 °C. Fluorescence was read at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader. The final concentrations of reagents in the activity assay were 3 nM CDK2 / CCNE1, 1 mM ATP, 50 nM ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate, 1 % DMSO, 10 mM EDTA, and 2 nM LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46).

[0626] Dose-response titrations were conducted by using an 11-point, half-logarithmic serial dilution scheme typically starting at 10 μM. Signals were reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm / fluorescence units at 615 nm. Signals are referred to below as “Lance signals”. Compound potencies were determined by first calculating % inhibition at each compound concentration according to the following equation: % inhibition = (Lance signal DMSO control – Lance signal value of sample) * 100 / Lance DMSO control - Lance signal value of background), where Lance signal DMSO control represents an average of 8-16 replicates, Lance signal value of sample represents an average of 2 replicates, and Lance signal of background represents an average of 8-16 replicates.

[0627] CDK1 Assay

[0628] A CDK homogeneous time-resolved fluorescence (HTRF) assay was used to assess the potency of the compounds described herein.Atty. Docket No.: 39953-58778 (002WO)

[0629] To an untreated 384-well microtiter plate (ProxiPlate) was added 100 nL 100 x test compound in DMSO and 5 μL 2 x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01 % Tween 20, 2mM DTT). The plate was centrifuged at 800 RPM for 1 min then incubated for 20 min at 23 °C.2.5 μL per well of 4 x ATP and 2.5 μL 4 x ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate were added to all wells. After addition, the plates were centrifuged at 800 RPM for 1 min. The plates were incubated at 23 °C for 60 min.5 μL per well 4 x EDTA solution were added to each well to stop the reaction.5 μL 4 x LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46) antibody were added to each well and the plate was centrifuged for 1 min at 800 RPM. The plate was incubated for 60 min at 23 °C. Fluorescence was read at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader. The final concentrations of reagents in the activity assay were 0.5 nM CDK1 / CCNB1, 1 mM ATP, 50 nM ULight™-eIF4E- binding protein 1 (Thr37 / 46) Peptide substrate, 1 % DMSO, 10 mM EDTA, and 2 nM LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46).

[0630] Dose-response titrations were conducted by using an 11-point, half-logarithmic serial dilution scheme typically starting at 10 μM. Signals were reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm / fluorescence units at 615 nm. Signals are referred to below as “Lance signals”. Compound potencies were determined by first calculating % inhibition at each compound concentration according to the following equation: % inhibition = (Lance signal DMSO control – Lance signal value of sample) * 100 / Lance DMSO control - Lance signal value of background), where Lance signal DMSO control represents an average of 8-16 replicates, Lance signal value of sample represents an average of 2 replicates, and Lance signal of background represents an average of 8-16 replicates.

[0631] CDK4 Assay

[0632] A CDK homogeneous time-resolved fluorescence (HTRF) assay was used to assess the potency of the compounds described herein.

[0633] To an untreated 384-well microtiter plate (ProxiPlate) was added 100 nL 100 x test compound in DMSO and 5 μL 2 x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01 % Tween 20, 2mM DTT). The plate was centrifuged at 800 RPM for 1 min then incubated for 20 min at 23 °C.2.5 μL per well of 4 x ATP and 2.5 μL 4 x ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate were added to all wells. After addition, the plates were centrifuged at 800 RPM for 1 min. The plates were incubated at 23 °C for 60 min.5 μL per well 4 x EDTA solution were added to each well to stop theAtty. Docket No.: 39953-58778 (002WO) reaction.5 μL 4 x LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46) antibody were added to each well and the plate was centrifuged for 1 min at 800 RPM. The plate was incubated for 60 min at 23 °C. Fluorescence was read at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader. The final concentrations of reagents in the activity assay were 1.5 nM CDK4 / CCND3, 1 mM ATP, 50 nM ULight™-eIF4E- binding protein 1 (Thr37 / 46) Peptide substrate, 1 % DMSO, 10 mM EDTA, and 2 nM LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46).

[0634] Dose-response titrations were conducted by using an 11-point, half-logarithmic serial dilution scheme typically starting at 10 μM. Signals were reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm / fluorescence units at 615 nm. Signals are referred to below as “Lance signals”. Compound potencies were determined by first calculating % inhibition at each compound concentration according to the following equation: % inhibition = (Lance signal DMSO control – Lance signal value of sample) * 100 / Lance DMSO control - Lance signal value of background), where Lance signal DMSO control represents an average of 8-16 replicates, Lance signal value of sample represents an average of 2 replicates, and Lance signal of background represents an average of 8-16 replicates.

[0635] CDK6 Assay

[0636] A CDK homogeneous time-resolved fluorescence (HTRF) assay was used to assess the potency of the compounds described herein.

[0637] To an untreated 384-well microtiter plate (ProxiPlate) was added 100 nL 100 x test compound in DMSO and 5 μL 2 x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01 % Tween 20, 2mM DTT). The plate was centrifuged at 800 RPM for 1 min then incubated for 20 min at 23 °C.2.5 μL per well of 4 x ATP and 2.5 μL 4 x ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate were added to all wells. After addition, the plates were centrifuged at 800 RPM for 1 min. The plates were incubated at 23 °C for 60 min.5 μL per well 4 x EDTA solution were added to each well to stop the reaction.5 μL 4 x LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46) antibody were added to each well and the plate was centrifuged for 1 min at 800 RPM. The plate was incubated for 60 min at 23 °C. Fluorescence was read at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader. The final concentrations of reagents in the activity assay were 1 nM CDK6 / CCND1, 1 mM ATP, 50 nM ULight™-eIF4E-binding protein 1 (Thr37 / 46) Peptide substrate, 1 % DMSO, 10 mM EDTA, and 2 nM LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37 / 46).Atty. Docket No.: 39953-58778 (002WO)

[0638] Dose-response titrations were conducted by using an 11-point, half-logarithmic serial dilution scheme typically starting at 10 μM. Signals were reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm / fluorescence units at 615 nm. Signals are referred to below as “Lance signals”. Compound potencies were determined by first calculating % inhibition at each compound concentration according to the following equation: % inhibition = (Lance signal DMSO control – Lance signal value of sample) * 100 / Lance DMSO control - Lance signal value of background), where Lance signal DMSO control represents an average of 8-16 replicates, Lance signal value of sample represents an average of 2 replicates, and Lance signal of background represents an average of 8-16 replicates.

[0639] Using this assay, the IC50 values of example compounds were determined. Table 3 illustrates the IC50 for various Example compounds of Formula IA. Table 4 illustrates the IC50for various other Example compounds of Formula I. ND = not determined. Table 3: IC50for Example Compounds of Formula IA. 021 x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x ND ND ND ND ND NDAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x ND ND ND ND ND NDAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500x x x xAtty. Docket No.: 39953-58778 (002WO) CDK2 / CCNE IC50CDK1 / CCNB IC50CDK4 / CCND IC50CDK6 / CCND IC500Table 4: IC50for other Compounds of Formula I 0965 x x x x a. Methods of Preparation

[0640] Synthetic schemes for preparing intermediates and compounds of the disclosure are described below. The illustrative schemes described are not intended to limit the methodsAtty. Docket No.: 39953-58778 (002WO) available to prepare the compounds or imply a specific ordering of steps is required, nor are any of the R groups intended to limit any of the claims described herein. Unless specified otherwise, compounds were prepared as racemic mixtures. Chirally pure materials could be obtained by chiral preparative HPLC separation, chiral SFC separation of the racemic mixtures or by employing homochiral starting materials. MeOH Methanol [1,1’-bis(diphenylphosphino)- PdCl2(dppf) ferrocene]dichloropalladium(II) Me Methyl Et Ethyl Pr Propyl iPr Isopropyl Bu Butyl tBu tert-butyl Ar Aryl group Ph Phenyl PTSA para-toluenesulfonic acid PhMe Toluene (benzotriazol-1-yloxy)tripyrrolidinophosphonium PyBOP hexafluorophosphate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-diisopropylethylamine Tf2O triflic anhydride Py Pyridine PdCl2(PPh3)2bis(triphenylphosphine)palladium(II) dichloride THF Tetrahydrofuran KOtBu potassium tert-butoxide ACN Acetonitrile TFA trifluoroacetic acid EtOAc ethyl acetate DMF N,N-dimethylformamide NMP N-methyl-2-pyrrolidoneAtty. Docket No.: 39953-58778 (002WO) dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2- Pd-PEPPSI-iHeptCl ylidene](3-chloropyridyl)palladium(II) DCM dichloromethane Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) TEA, Et3N triethylamine O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- HATU tetramethyluronium hexafluorophosphate AISF [4-(acetylamino)phenyl]imidodisulfuryl difluoride EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide HOBt 1-hydroxybenzotriazole DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide Dess-Martin periodinane, 1,1,1-Tris(acetyloxy)-1,1- DMP dihydro-1,2-benziodoxol-3-(1H)-one TMSCl trimethylsilyl chloride TfOH trifluoromethanesulfonic acid BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl nBuLi n-butyllithium NH4OAc Ammonium acetate MeMgBr Methyl magnesium bromide [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- Pd-PEPPSI-IPr chloropyridyl)palladium(II) dichloride EtOH ethanol mCPBA Meta-chloroperoxybenzoic acid 2-(Di-tert-butylphosphino)-2′,4′,6′- triisopropyl-3,6- tBuBrettPhos dimethoxy-1,1′-biphenyl AcCl Acetyl chloride SEMCl 2-(trimethylsilyl)ethoxymethyl chloride tBuONa Sodium tert-butoxide IPA isopropanolAtty. Docket No.: 39953-58778 (002WO) DTBPF 1,1′-Bis(di-tert-butylphosphino)ferrocene Pd(OAc)2 Palladium(II) acetate MTBE Methyl tert-butyl ether SFC Supercritical fluid chromatography Boc2O di-tert-butyl dicarbonate DME dimethoxyethane Ni(cod)2Bis(1,5-cyclooctadiene)nickel(0) DMA dimethylacetamide MeNH2methylamine AcOH Acetic acid NCS N-chlorosuccinimide TBSCl Tert-butyldimethylsilyl chloride TBAF Tetrabutylammonium fluoride Cu(OAc)2 Copper acetate MeI iodomethane [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- BrettPhos Pd G3 triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ - biphenyl)]palladium(II) methanesulfonate (SP-4-3)-[Dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1- methylethyl)[1,1′-biphenyl]-2-yl]phosphine- BrettPhos Pd G4 κP](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′- biphenyl]-2-yl-κC] Bromo[Dicyclohexyl[3-(1,1-dimethylethoxy)-6- methoxy-2',6'-bis(1-methylethyl)[1,1'-biphenyl]-2- GPhos Pd G6 TES yl]phosphine](4-((2- (trimethylsilyl)ethoxy)carbonyl)benzen-1- ide)palladium(II) [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′- tBuXPhos Pd G3 biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate Selectfluor, F-TEDA, 1-chloromethyl-4-fluoro-1,4- Select F diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)Atty. Docket No.: 39953-58778 (002WO) [Dicyclohexyl(2′,6′-diisopropoxy-2- RuPhos Pd G4 biphenylyl)phosphine-κP](methanesulfonatato-κO)[2′- (methylamino-κN)-2-biphenylyl-κC2]palladium Burgess reagent Methyl N-(triethylammoniumsulfonyl)carbamate 2-MeTHF 2-methyltetrahydrofuran KOTMS Potassium trimethylsilanoate B2pin2Bis(pinacolato)diboron AsPh3 Triphenylarsine KOAc Potassium acetate BF3-Et2O Boron trifluoride diethyletherate Dppf 1,1’-bis(diphenylphosphino)ferrocene DIAD Diisopropyl azodicarboxylate TFE trifluoroethanol EtI Ethyl iodide BAIB (diacetoxyiodo)benzene Sn2Me6hexamethylditin oxone Potassium peroxymonosulfate MsCl Methanesulfonyl chloride, mesyl chloride [(Tricyclohexylphosphine)-2-(2′- Cy3P Pd G3 aminobiphenyl)]palladium(II) methanesulfonate 1,1'-Bis(di-tert- PdCl2(dtbpf) butylphosphino)ferrocene]dichloropalladium(II) T3P Propanephosphonic acid anhydride LDA Lithium diisopropylamide 1 x Once 2 x Twice 3 x Thrice °C degrees Celsius eq Equivalents g gram, grams mg milligram, milligrams L liter, liters mL milliliter, millilitersAtty. Docket No.: 39953-58778 (002WO) μL microliter, microliters N Normal M Molar mmol millimole, millimoles μmol micromole, micromoles rt room temperature RT retention time min Minutes h Hours ON Overnight atm Atmosphere psi pounds per square inch conc Concentrated sat Saturated MS mass spectrometry ESI electrospray ionization LCMS liquid chromatography mass spectrometry HPLC high-pressure liquid chromatography Prep-HPLC preparative high-pressure liquid chromatography TLC thin layer chromatography NMR nuclear magnetic resonance spectroscopy1H Proton δ Delta s Singlet d Doublet t Triplet q Quartet m Multiplet br Broad MHz Megahertz ppm parts per millionAtty. Docket No.: 39953-58778 (002WO)

[0641] Scheme 1 illustrates the approach to access compounds of the type exemplified by 1-8. Generation of the naphthyridine core (1-5) is accessible in 4 steps from carboxylic acid 1-1. Methyl ester 1-2 can be treated with an appropriate boronic acid or boronate ester to generate 1-3. After conversion of the ester to the amide (1-4), an acid-mediated cyclization provides compounds similar to 1-5. Activation of 1-5 can be done with PyBOP, followed by coupling with an appropriate amine to generate compounds characterized by 1-7. This two- step sequence can be done via other methods known to those skilled in the art. An additional Pd-mediated coupling reaction can provide compounds similar to 1-8. Further modification of R groups can occur to generate additional analogs of 1-8 using methods known to those skilled in the art. Scheme 1 2 R Cl

[0642] Scheme 2 provides an alternative order to installation of the peripheral groups. Pd-mediated coupling on 1-5 provides intermediates similar to 2-9. Conversion to the triflate 2-10 provides an opportunity to generate compounds similar to 2-11. Alternatives to the triflate as a coupling partner are available to those skilled in the art. Use of R4-X is one potential coupling partner. Use of an amine coupling partner would represent an alternative method to access compounds exemplified by 1-8. Scheme 2Atty. Docket No.: 39953-58778 (002WO)

[0643] Scheme 3 illustrates a related method in which alkylation of 1-5 can yield intermediate 3-12. A Pd-mediated coupling reaction with an amine can produce compounds similar to 3-13. Scheme 3

[0644] Scheme 4 illustrates an alternative synthesis of the core enabling access to additional points of substitution. Starting with 1-2, a Sonogashira coupling followed by conversion to an amide can yield intermediates like 4-15. Base-mediated cyclization can yield compounds similar to 4-16 which can be further elaborated by the methods described in the other schemes. Scheme 4

[0645] Scheme 5 illustrates a potential synthetic route to install an alkyne moiety on the napthyridine core. Starting with 4-16, a Buchwald-Hartwig coupling can be utilized to install an aryl or heteroaryl amine. This chemistry could also be implemented on a non-aromatic amine. Conversion to triflate 5-18 can be followed by a Sonogashira reaction with an alkyne under standard conditions to yield 5-19. In addition to the triflate, this chemistry can also be implemented with an appropriately substituted halogen. A second Sonogashira reaction can be performed to yield adducts similar to 5-20. While conditions listed involve in situ deprotection of the alkyne, this can also be done over a two-step process. Alternative metals to palladium, such as nickel, can also be employed.Atty. Docket No.: 39953-58778 (002WO) Scheme 5

[0646] Scheme 6 details an alternate route to access final compounds similar to 5-20. In this scheme, 4-16 can initially be converted to the triflate 6-21 prior to the Sonogashira coupling to access 6-22. The triflate can also be a halogen. In situ deprotection followed by a second Sonogashira reaction can yield compounds similar to 6-23. Similar to Scheme 5, the deprotection can occur in situ or as a separate synthetic step. To access compounds like 5-20, a Buchwald-Hartwig coupling can be utilized to install an arylamine as shown. Heteroaryl, alkyl and cycloalkyl amines can also be coupled in this fashion or by related reactions known to those in the art. Further substitution of the aryl group can occur after isolation of compounds like 5-20. Scheme 6

[0647] While Scheme 5 and Scheme 6 detail methods to install an alkyne over several steps, Scheme 7 provides a convergent method to access compounds similar to 7-25.Atty. Docket No.: 39953-58778 (002WO) Compounds similar to 5-18 and 7-24 can undergo a Sonogashira coupling reaction to install a more fully functionalized alkyne in one step. In some cases, synthesis of the alkyne may require several steps and after the Sonogashira coupling, additional deprotection steps may be required to get a final product. Scheme 7

[0648] Indazole-containing analogs similar to 8-29 and 8-30 can be made by several different methods described in the next few schemes. In scheme 8, epoxide opening with 8- 26 can lead to both isomers of 8-27. While epoxides are shown as the electrophile, alkyl halides are also suitable coupling partners in this transformation. Conversion of the halides in 8-27 to boronate esters or boronic acids can undergo Suzuki couplings with 5-18 to produce compounds similar to 8-29 and 8-30. The regioisomers can be individually isolated by use of chiral separation methods such as chiral SFC or chiral HPLC.Atty. Docket No.: 39953-58778 (002WO) Scheme 8

[0649] An alternative method to install indazoles is shown in Scheme 9. An indazole boronate can be coupled with 7-24 under Suzuki conditions to yield 9-31. Ring opening of the epoxide under basic conditions can yield 8-29 and 8-30. In order to access the individual regioisomers, chiral purification is required. Although an epoxide is shown as the electrophile, any alkyl halide could be utilized as an electrophile in this scheme.Atty. Docket No.: 39953-58778 (002WO) Scheme 9

[0650] Separation of indazole regioisomers can be avoided by following the route outlined in Scheme 10. Addition of a substituted hydrazine to an ortho-fluorobenzaldehyde similar to 10-32 can yield the regioisomerically pure indazoles such as 10-33. While the tertiary alcohol is shown for example, any alkyl hydrazine would work. Reduction of the nitro group led to 10-34 which could undergo further transformation to yield the boronate ester exemplified by 10-35. Suzuki coupling with the napthyridine core shown or with 7-24 can yield the penultimate compound in the sequence. Buchwald-Hartwig coupling with an aniline can yield the final compounds exemplified by 8-29. In addition to the arylamine, heteroaryl, alkyl, cycloalkyl and heterocyclic amines will all work in the coupling reaction.Atty. Docket No.: 39953-58778 (002WO) Scheme 10

[0651] Schemes 11 through 16 detail syntheses of alternative cores to the napthyridine. Heck coupling of 1-2 followed by treatment with base to induce cyclization provides the core 11-38. Buchwald-Hartwig coupling can be utilized to install an amine for compounds exemplified by 11-39. Conversion to the triflate precedes another coupling that can be mediated by palladium to install groups like an alkyne, indazole or other groups that can be represented by 11-41. Conversion to the cyano compounds exemplified by 11-44 occurs by initial hydrolysis of methyl ester 11-41, followed by conversion to amide 11-43. Dehydration with a reagent such as Burgess reagent forms cyano 11-44.Atty. Docket No.: 39953-58778 (002WO) Scheme 11

[0652] Scheme 12 can be initiated with displacement of the 12-45 chloride with an amine to yield 12-46. Palladium-mediated cyanation, followed by triflation can provide 12-48. A variety of palladium couplings can install R1 to produce analogs similar to 12-49. Scheme 12

[0653] Scheme 13 can begin with an oxidation of the sulfide to sulfone 13-51. Coupling of the amine can occur under basic conditions to yield compounds represented by 13-52. AAtty. Docket No.: 39953-58778 (002WO) variety of palladium-mediated reactions can be utilized to install additional functionality and produce compounds such as that exemplified by 13-53. Scheme 13conversion to chloride 14-55, palladium-mediated coupling can be utilized to install a variety of functionality for R1. Subsequent Buchwald-Harwig coupling can install an amine and complete the synthesis. Scheme 14

[0655] The core exemplified in Scheme 15 can be accessed with initial Buchwald- Hartwig coupling to yield compounds like 15-59. After conversion to triflate 15-60, palladium-mediated coupling can install further functionality to yield compounds similar to 15-61. Scheme 15

[0656] Scheme 16 describes a two step process to access compounds exemplified by 16- 63. Installation of the amine can occur via acid-mediated displacement to yield 16-62. A variety of functionality can be installed via palladium-mediated reactions to yield the final compounds.Atty. Docket No.: 39953-58778 (002WO) Scheme 16were used to assist in characterization of intermediates. Instruments utilized and methods employed are listed below:

[0658] Instrument names: Shimadzu LC2020 Nexera Series; Shimadzu MS2020 N- Series; Agilent 1290; Agilent 1260 & 6125B.

[0659] Method A: Mobile Phase: A: 0.1 % HCOOH in water, B: ACN; Column: ZORBAX ECLIPSE PLUS C18 (50 x 2.1 mm), 1.8 mm.

[0660] Method B: Mobile Phase: A: 10 mM NH4HCO3 in water, B: ACN; Column: Phenomenex Kinetex EVO C18 (50 x 3.0 mm), 2.5 mm.

[0661] Method C: Mobile Phase: A: 0.1 % TFA in water, B: ACN; Column: XBRIGDE C8 (4.6 x 50 mm), 3.5 μm.

[0662] Method D: Mobile Phase: A: 10 mM NH4HCO3in Water, B: ACN; Column: Phenomenex Kinetex EVOC18 (3.0 x 50 mm), 2.6 μm.

[0663] Method E: Mobile Phase: A: 10 mM NH4HCO3 in Water, B: ACN; Column: Xbridge C18 (2.1 x 50mm), 5 μm.

[0664] Method F: Mobile Phase: A: 0.04 % TFA in water, B: 0.02 % TFA in ACN; Column: Luna-C18(2) (2.0 x 50mm), 5 μm.

[0665] Purification of intermediates and final compounds could be accomplished by normal or reverse phase chromatography. Conditions for normal phase chromatography are listed in the experimental section. Methods and instruments utilized for preparative HPLC purification are listed below:

[0666] Instrument names: Shimadzu LC; Prominence-I series instruments as followed using % with UV detection (Maxplot).

[0667] Method A: Mobile Phase: A- 0.1 % formic acid in water, B: ACN; flow rate: 2.0 mL / min; Column: X-Select CSH C18 (4.6 x 150 mm, 5 μm).

[0668] Method B: Mobile Phase: A- 10 mM ammonium bicarbonate in water, B: ACN; flow rate: 2.0 mL / min; Column: X-Bridge C8 (4.6 x 150 mm,5 μm).Atty. Docket No.: 39953-58778 (002WO)

[0669] Method C: Mobile Phase: A- 0.1 % TFA in water, B: ACN; Column: Phenomenex Luna C18 (75 x 30 mm, 3 μm; flow rate: 25.0 mL / min) (100 x 40 mm, 3 μm; flow rate: 25.0 mL / min) (150 x 25 mm, 10 μm; flow rate: 60.0 mL / min) (250 x 150mm, 15 μm; flow rate: 60.0 mL / min).

[0670] Method D: Mobile Phase: A- 10 mM ammonium bicarbonate in water, B: ACN; flow rate: 60 mL / min; Column: Welch Xtimate C18 (180 x 70 mm, 10 μm)

[0671] Method E: Mobile Phase: A- 10 mM ammonium bicarbonate in water, B: ACN; Column: Waters Xbridge BEH C18 (100 x 25 mm, 10 μm; flow rate: 25.0 mL / min) (100 x 30 mm, 10 μm; flow rate: 25.0 mL / min) (250 x 50 mm, 10 μm; flow rate: 60.0 mL / min) (250 x 70 mm, 10 μm; flow rate: 60.0 mL / min).

[0672]

[0673] NMR data was acquired in Bruker Avance Neo nano bay 400 MHz NMR Spectrometer. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvent as indicated in NMR spectral data. A small amount (1-5 mg) of sample is dissolved in an appropriate deuterated solvent (0.6 mL).

[0674] Final compound characterization and purity was assessed by and determined using orthogonal HPLC runs, LCMS and NMR. Example 1: 1-(7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1- yl)piperidin-4-ol

[0675] 1A: Methyl 5-bromo-2-chloroisonicotinate: To a solution of 5-bromo-2- chloroisonicotinic acid (100 g, 423 mmol) in MeOH (400 mL) was added SOCl2(30.9 mL, 423 mmol) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 60 °C for 16 h. Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated in vacuo to afford crude material as a colorless liquid. The crude was diluted with water, basified with 10 % aqueous NaHCO3 solution and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resultingAtty. Docket No.: 39953-58778 (002WO) crude product (130 g) was purified by Biotage Isolera (60-120 silica gel, using 10 % EtOAc in hexanes as an eluent) to obtain the desired product, methyl 5-bromo-2-chloroisonicotinate (100 g, 94 % yield) as a colorless liquid.

[0676] 1H-NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 7.69 (s, 1H), 4.00 (s, 3H).

[0677] LCMS: RT: 2.30 min, m / z: 250.0 (M+H)+

[0678] 1B: Methyl (E)-2-chloro-5-(2-ethoxyvinyl) isonicotinate: In a 5 liter pressure reactor methyl 5-bromo-2-chloroisonicotinate (100 g, 399 mmol), (E)-2-(2-ethoxyvinyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 g, 479 mmol) and Cs2CO3 (390 g, 120 mmol) were charged followed by the addition of 1,4-dioxane (1800 mL) and water (200 mL). The reaction mixture was degassed for 10 min before addition of PdCl2(dppf) (14.6 g, 20.0 mmol). Then the reaction mixture was heated at 80 °C for 24 h. Reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was evaporated in vacuo. The resulting crude was treated with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give crude product, which was purified by Biotage Isolera (60-120 silica gel, eluted in 10 % EtOAc in hexanes) to provide the desired product, methyl (E)-2- chloro-5-(2-ethoxyvinyl) isonicotinate (58 g, 59 % yield) as a yellow solid.

[0679] 1H-NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 7.69 (s, 1H), 7.40 (d, J = 12.8 Hz, 1H), 6.29 (d, J = 13.2 Hz, 1H), 3.96 (q, J = 6.8 Hz, 2H), 3.88 (s, 3H), 1.28 (t, J = 6.8 Hz, 3H).

[0680] LCMS: RT: 2.53 min, m / z: 242.0 (M+H)+

[0681] 1C: (E)-2-chloro-5-(2-ethoxyvinyl) isonicotinamide: In a 2-liter pressure reactor, methyl (E)-2-chloro-5-(2-ethoxyvinyl) isonicotinate (58 g, 240 mmol) was dissolved in 7 M NH3 in MeOH (1.0 L) and stirred at 60 °C for 20 h. Reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated in vacuo to afford the desired product (E)-2-chloro-5-(2-ethoxyvinyl) nicotinamide (52.0 g, 230 mmol, 96 % yield) as a yellow solid.

[0682] 1H-NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.39 (s, 1H), 7.35 (d, J = 12.8 Hz, 1H), 5.95 (d, J = 13.2 Hz, 1H), 3.91 (q, J = 6.8 Hz, 2H), 1.26 (t, J = 6.8 Hz, 3H).

[0683] LCMS: RT: 1.73 min, m / z: 227.1 (M+H)+

[0684] 1D: 7-chloro-2,6-naphthyridin-1-ol: To a suspension of (E)-2-chloro-5-(2- ethoxyvinyl) isonicotinamide (52 g, 229 mmol) in toluene (550 mL) was added PTSA monohydrate (21.8 g, 115 mmol) at rt. The resulting reaction mixture was stirred at 80 °C forAtty. Docket No.: 39953-58778 (002WO) 16 h under nitrogen atmosphere. Reaction progress was monitored by TLC. The reaction mixture was evaporated in vacuo. To the resulting crude was added 10 % aqueous NaHCO3 solution, and the solid precipitated was filtered, washed with water, and dried to give the desired product, 7-chloro-2,6-naphthyridin-1-ol (40 g, 95 % yield) as a brown solid.

[0685] 1H-NMR (400 MHz, DMSO- d6): δ 11.77 (s, 1H), 8.96 (s, 1H), 7.99 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 7.2 Hz, 1H).

[0686] LCMS: RT: 1.12 min, m / z: 181.1 (M+H)+

[0687] 1E: 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine: To a solution of 7-chloro-2,6-naphthyridin-1-ol (5.0 g, 27.7 mmol) in DMF (50 mL) were added PyBOP (14.4 g, 27.7 mmol) and DBU (12.7 g, 83 mmol) and stirred at rt for 4 h under nitrogen atmosphere. Reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water (100 mL) and the solid precipitate was filtered through a Büchner funnel, washed with water and dried to give the desired product, 1-((1H-benzo[d][1,2,3] triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine (7.0 g crude) as a brown solid. This was used in the next reaction without purification.

[0688] 1H-NMR (400 MHz, DMSO- d6): δ 9.49 (s, 1H), 8.57 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 6.4 Hz, 2H), 7.84-7.81 (m, 1H), 7.67 -7.63 (m, 1H), 7.58-7.54 (m, 1H).

[0689] LCMS: RT: 2.49 min, m / z: 298.1 (M+H)+

[0690] 1F: 1-(7-chloro-2,6-naphthyridin-1-yl) piperidin-4-ol: To a solution of 1-((1H- benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine (3.0 g, 10.08 mmol) in ACN (100 mL) were added DIPEA (6.51 g, 50.4 mmol) and piperidin-4-ol (2.55 g, 25.2 mmol) at rt. The reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. Reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated in vacuo to afford crude, which was purified by Biotage Isolera (100-200 silica gel, using 35 % EtOAc in hexanes as an eluent) to obtain desired product, 1-(7-chloro-2,6- naphthyridin-1-yl)piperidin-4-ol (1.70 g, 6.46 mmol, 64 % yield) as a yellow solid.

[0691] 1H-NMR (400 MHz, DMSO- d6): δ 9.20 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J = 5.6 Hz, 1H), 4.77 (d, J = 4.0 Hz, 1H), 3.78-3.65 (m, 3H), 3.16-3.09 (m, 2H), 1.99-1.92 (m, 2H), 1.69-1.62 (m, 2H).

[0692] LCMS: RT: 1.60 min, m / z: 264.2 (M+H)+

[0693] 1: To a solution of 1-(7-chloro-2,6-naphthyridin-1-yl) piperidin-4-ol (500 mg, 1.90 mmol) and 1-(methyl sulfonyl) piperidin-4-amine (676 mg, 3.79 mmol) in NMP (10 mL) was added Cs2CO3 (1.85 g, 5.69 mmol) at rt and degassed the reaction mixture withAtty. Docket No.: 39953-58778 (002WO) nitrogen for 5 min. To the reaction mixture was added Pd-PEPPSI-iHeptCl (184 mg, 0.190 mmol) and stirred at 120 °C for 16 h under nitrogen atmosphere. After completion of reaction, reaction mixture was concentrated in vacuo to get crude product, which was purified by reverse phase chromatography using Biotage Isolera (C18 mesh, 30 % aqueous ammonium bicarbonate and ACN as eluting solvents) and fractions were lyophilized to afford the desired compound, 1-(7-((1-(methyl sulfonyl) piperidin-4-yl) amino)-2,6-naphthyridin-1- yl) piperidin-4-ol (345 mg, 45 % yield) as pale-yellow solid.

[0694] 1H-NMR (400 MHz, DMSO- d6): δ 8.84 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.19 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 4.75 (d, J = 4.0 Hz, 1H), 3.89 (t, J = 7.2 Hz, 1H), 3.74-3.68 (m, 1H), 3.58-3.55 (m, 4H), 2.97-2.91 (m, 4H), 2.90 (s, 3H), 2.06- 2.04 (m, 2H), 1.94-1.92 (m, 2H), 1.70-1.61 (m, 2H), 1.58-1.48 (m, 2H).

[0695] LCMS: RT: 1.84 min, m / z: 406.4 (M+H)+Example 2: N-(1-(methylsulfonyl)piperidin-4-yl)-5-(pyrrolidin-1-yl)-2,6-naphthyridin-3- amine

[0696] 2A: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-ol: To a solution of 7-chloro-2,6-naphthyridin-1-ol (1D) (500 mg, 2.77 mmol) in NMP (5 mL) were added 1-(methylsulfonyl)piperidin-4-amine (987 mg, 5.54 mmol) and Cs2CO3(2.71 g, 8.31 mmol) at rt under nitrogen atmosphere and degassed with argon for 5 min. To this reaction mixture was added Pd-PEPPSI-iHeptCl (269 mg, 0.277 mmol) and stirred at 120 °C for 16 h. Reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL) The combined organic layer was dried over sodium sulfate and concentrated to give crude product, which was purified by Biotage Isolera (100-200 silica gel, using 10 % MeOH in DCM as an eluent) to obtain desired product, 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-ol (80 mg, 0.244 mmol, 9 % yield) as a pale-yellow solid.

[0697] LCMS: RT: 1.48 min, m / z: 323.2 (M+H)+

[0698] 2B: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate: To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-Atty. Docket No.: 39953-58778 (002WO) naphthyridin-1-ol (70 mg, 0.217 mmol) in DCM (5 mL) were added pyridine (172 mg, 2.171 mmol) and triflic anhydride (184 mg, 0.651 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at rt for 6 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (3 x 20 mL), and the combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Biotage Isolera using (100-200 silica gel, 60 % EtOAc in pet ether as eluent) to obtain the desired product, 7-((1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (76 mg, 0.134 mmol, 62 % yield) as a pale green gummy solid.

[0699] LCMS: RT: 2.66 min, m / z: 455.0 (M+H)+

[0700] 2: To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin- 1-yl trifluoromethanesulfonate (70 mg, 0.154 mmol) in 1,4-dioxane (5 mL) were added pyrrolidine (0.03 mL, 0.308 mmol) and Cs2CO3 (151 mg, 0.462 mmol). Reaction mixture was degassed with nitrogen then Xantphos (8.91 mg, 0.015 mmol) and Pd2(dba)3(14.1 mg, 0.015 mmol) were added at 25 °C under nitrogen atmosphere. Reaction mixture was stirred at 120 °C for 16 h under nitrogen atmosphere and reaction progress was monitored by TLC and LCMS analysis. After completion of reaction, reaction mixture was quenched with water, extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over sodium sulfate and concentrated to get crude product. Crude product was purified by prep-HPLC by using formic acid as buffer and pure fractions were lyophilized to obtain desired compound N-(1-(methylsulfonyl)piperidin-4-yl)-5-(pyrrolidin-1-yl)-2,6-naphthyridin-3-amine, formate salt (4.3 mg, 0.011 mmol, 7.3 % yield) as a yellow solid.

[0701] 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.34 (s, 1H), 7.63 (d, J = 5.7 Hz, 1H), 7.08 (s, 1H), 6.89 (d, J = 5.7 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 3.87 (d, J = 10.9 Hz, 1H), 3.74 – 3.69 (m, 4H), 2.98 – 2.92 (m, 1H), 2.89 (s, 3H), 2.04 (d, J = 12.6 Hz, 2H), 1.97 – 1.90 (m, 4H), 1.56 – 1.45 (m, 2H).

[0702] LCMS: RT: 1.50 min, m / z: 376.4 (M+H)+Example 3: Synthesis of 5-(piperidin-1-yl)-N-(1-(vinylsulfonyl)piperidin-4-yl)-2,6- naphthyridin-3-amine(3)Atty. Docket No.: 39953-58778 (002WO)

[0703] 3A: 7-chloro-1-(piperidin-1-yl)-2,6-naphthyridine: To a solution of 1-((1H- benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine (1E) (350 mg, 1.18 mmol) in ACN (10 mL) were added DIPEA (0.61 mL, 3.53 mmol) and piperidine (0.23 mL, 2.35 mmol) at rt. The reaction mixture was stirred at 80 °C for 16 h and reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude product was purified by Biotage Isolera (60-120 silica gel, using 15 % EtOAc in hexanes as an eluent) to obtain desired product 7-chloro-1-(piperidin-1-yl)-2,6- naphthyridine (110 mg, 0.443 mmol, 38 % yield) as a yellow solid.

[0704] LCMS: RT: 2.45 min, m / z: 248.2 (M+H)+

[0705] 3B: tert-butyl 4-((5-(piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)piperidine-1- carboxylate: To a solution of 7-chloro-1-(piperidin-1-yl)-2,6-naphthyridine (110 mg, 0.444 mmol) in NMP (5 mL) were added Cs2CO3 (434 mg, 1.33 mmol) and tert-butyl 4- aminopiperidine-1-carboxylate (178 mg, 0.888 mmol) at rt. Reaction mixture was degassed with nitrogen for 5 min followed by addition of Pd-PEPPSI-iHeptCl (43.2 mg, 0.044 mmol) and the reaction mixture was stirred at 120 °C for 16 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). Combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by Biotage Isolera (60-120 silica gel, using 30 % EtOAc in hexanes as an eluent) to obtain the desired product, tert-butyl 4-((5-(piperidin-1-yl)-2,6-naphthyridin-3- yl)amino)piperidine-1-carboxylate (110 mg, 0.258 mmol, 58 % yield) as a yellow solid.

[0706] LCMS: RT: 2.09 min, m / z: 412.2 (M+H)+

[0707] 3C: 5-(piperidin-1-yl)-N-(piperidin-4-yl)-2,6-naphthyridin-3-amine: To a solution of tert-butyl 4-((5-(piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)piperidine-1-carboxylate (100 mg, 0.243 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1 mL, 0.243 mmol) at rt. The reaction mixture was stirred at 25 °C for 2 h, concentrated in vacuo, diluted with water (20 mL) and washed with EtOAc (2 x 20 mL). The aqueous phase was basified with 10 % aqueous sodium hydroxide solution (pH ~10), then extracted with DCM (2 x 20 mL). Organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the desired product, 5-(piperidin-1-yl)-N- (piperidin-4-yl)-2,6-naphthyridin-3-amine (60 mg, 0.153 mmol, 63 % yield) as a yellow solid.Atty. Docket No.: 39953-58778 (002WO)

[0708] LCMS: RT: 1.15 min, m / z: 312.2 (M+H)+

[0709] 3: To a solution of 5-(piperidin-1-yl)-N-(piperidin-4-yl)-2,6-naphthyridin-3-amine (30 mg, 0.096 mmol) in DCM (2 mL) were added ethenesulfonyl chloride (12 mg, 0.096 mmol) and TEA (97 mg, 0.963 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 0 °C for 30 min. Reaction progress was monitored by TLC. After completion, reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). Combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Crude product was purified by prep-HPLC and fractions were lyophilized to obtain desired product, 5-(piperidin-1-yl)-N-(1- (vinylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (5.6 mg, 0.013mmol, 14 % yield) as a pale yellow solid.

[0710] 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.77 (d, J = 5.7 Hz, 1H), 7.19 (dd, J = 5.8, 0.8 Hz, 1H), 6.90 – 6.70 (m, 3H), 6.23 – 6.08 (m, 2H), 3.91 – 3.80 (m, 1H), 3.53 (d, J = 12.5 Hz, 2H), 3.21 (t, J = 5.1 Hz, 4H), 2.92 – 2.77 (m, 2H), 2.04 (dd, J = 13.3, 3.7 Hz, 2H), 1.75 (m, 4H), 1.65 (d, J = 5.5 Hz, 2H), 1.58 – 1.48 (m, 2H).

[0711] LCMS: RT: 1.93 min, m / z: 402.1 (M+H)+Example 4: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6- naphthyridin-3-amine

[0712] To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1- yl trifluoromethanesulfonate (2B) (25 mg, 0.055 mmol) in 1,4-dioxane (1.8 mL) and water (0.2 mL) were added Cs2CO3(25 mg, 0.077 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.6 mg, 0.061 mmol) at rt and degassed with nitrogen for 5 min. To the resultant solution was added Pd(PPh3)4 (25 mg, 0.022 mmol) and reaction mixture was stirred at 85 °C for 16 h under nitrogen atmosphere. Reaction progress was monitored by TLC and LCMS. After completion of reaction, reaction mixture was concentrated in vacuo to get crude product which was purified by Prep-HPLC. Collected fractions were concentrated followed by lyophilization to get the desired product, 5-(1-Atty. Docket No.: 39953-58778 (002WO) methyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (5 mg, 0.013 mmol, 23 % yield) as a yellow solid.

[0713] 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.14 (s, 1H), 6.86 (d, J = 7.7 Hz, 1H), 3.97 – 3.94 (m, 4H), 3.55 (d, J = 11.7 Hz, 2H), 2.97 (d, J = 11.1 Hz, 2H), 2.90 (s, 3H), 2.06 (d, J = 13.5 Hz, 2H), 1.54 (d, J = 11.5 Hz, 2H).

[0714] LCMS: RT: 1.59 min, m / z: 387.4 (M+H)+Example 5: 5-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine

[0715] To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1- yl trifluoromethanesulfonate (2B) (4 g, 8.80 mmol) in DMF (35 mL) and MeOH (35 mL)was added TEA (3.7 mL, 26.4 mmol) at 25 °C. Reaction mixture was degassed for 10 min followed by addition of palladium(II) acetate (790 mg, 3.52 mmol) and dppf (2 mg, 3.52 mmol) at rt. Reaction mixture was stirred at 80 °C under CO atmosphere for 16 h and reaction progress was monitored by TLC and LCMS. Reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). Combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude (liquid). Crude product (50 mg) was purified by Biotage Isolera (100- 200 silica using 20 % EtOAc- hexanes as an eluent) to obtain methyl 7-((1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridine-1-carboxylate (250 mg, 0.686 mmol, 7.8 % yield) as minor product and 5-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- 2,6-naphthyridin-3-amine (1.2 g, 3.57 mmol, 41 % yield) as a major product.

[0716] 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 7.67 (d, J = 5.9 Hz, 1H), 7.24 (dd, J = 5.9, 0.9 Hz, 1H), 6.85 (d, J = 14.1 Hz, 2H), 4.01 (s, 3H), 3.95 – 3.77 (m, 1H), 3.54 (d, J = 12.2 Hz, 2H), 3.01 – 2.83 (m, 5H), 2.07 – 1.91 (m, 2H), 1.64 – 1.43 (m, 2H).

[0717] LCMS: RT: 1.95 min, m / z 337.2 (M+H)+Atty. Docket No.: 39953-58778 (002WO) Example 6: 5-isopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine

[0718] 6A: N-(1-(methylsulfonyl)1-en-2-yl)-2,6-naphthyridin-3- amine: A procedure similar to that disclosed in Example 4 was used here starting with 7-((1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (2B) (300 mg, 0.660 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (111 mg, 0.660 mmol), tetrakis(triphenylphosphine)palladium(0) (153 mg, 0.132 mmol) and Cs2CO3 (645 mg, 1.98 mmol) to yield N-(1-(methylsulfonyl)piperidin-4-yl)-5-(prop-1-en-2-yl)-2,6- naphthyridin-3-amine (62 mg, 0.178 mmol, 27 % yield).

[0719] LCMS: RT: 1.66 min, m / z 347.2 (M+H)+

[0720] 6: To a solution of N-(1-(methylsulfonyl)piperidin-4-yl)-5-(prop-1-en-2-yl)-2,6- naphthyridin-3-amine (61 mg, 0.176 mmol) in methanol (6 mL) was added Pd / C (19 mg, 0.176 mmol). The resulting reaction mixture was stirred at rt under a hydrogen bladder for 1 h. The reaction progress was monitored by LCMS. After completion, reaction mixture was diluted with methanol (20 mL) and filtered. Filtrate was concentrated in vacuo to afford crude which was purified by Prep-HPLC and fractions obtained were lyophilized to obtain the desired product, 5-isopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (11 mg, 0.030 mmol, 17 % yield).

[0721] 1H-NMR (400 MHz, DMSO- d6): δ 8.95 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.50 (dd, J = 5.7, 0.9 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 3.98 – 3.87 (m, 1H), 3.69 (h, J = 6.8 Hz, 1H), 3.56 (dd, J = 12.0, 4.5 Hz, 2H), 3.00 – 2.88 (m, 5H), 2.05 (dt, J = 13.3, 3.9 Hz, 2H), 1.55 (dtd, J = 14.3, 10.7, 4.0 Hz, 2H), 1.30 (d, J = 6.7 Hz, 6H).

[0722] LCMS: RT: 1.86 min, m / z 349.2 (M+H)+Example 7: N-(4-(methylsulfonyl) - -2,6-naphthyridin-3-amine(7)

[0723] 7A:7-((4-(methylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate: A procedure similar to that disclosed in Example 2B was usedAtty. Docket No.: 39953-58778 (002WO) here starting with 7-((4-(methylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-ol (1.20 g, 3.81 mmol), trifluoromethanesulfonic anhydride (3.22 g, 11.4 mmol) and pyridine (3.01 g, 38.1 mmol) to yield 7-((4-(methylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (1.01 g, 2.24 mmol, 59% yield).

[0724] 7: To a solution of 7-((4-(methylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (400 mg, 0.894 mmol) in 1,4-dioxane (2 mL) was added TEA (1.2 mL, 8.94 mmol) and purged with N2for 10 min. To the resulting solution, copper(I) iodide (17.0 mg, 0.089 mmol) and PdCl2(PPh3)2 (31.5 mg, 0.045 mmol) were added at rt and again purged with N2for 5 min. To this reaction mixture was added propyne (860 mg, 1.07 mmol, 5% solution in THF) and stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was diluted with EtOAc (50 mL) and passed through a pad of Celite and washed with EtOAc (50 mL). Filtrate was concentrated in vacuo to afford residue which was purified by Biotage Isolera (60-120 silica gel, using 5 % EtOAc in hexanes as an eluent) to afford the desired product, N-(4-(methylsulfonyl)phenyl)- 5-(prop-1-yn-1-yl)-2,6-naphthyridin-3-amine (190 mg, 0.552 mmol, 62 % yield).

[0725] 1H-NMR (400 MHz, DMSO- d6): δ 10.10 (s, 1H), 9.28 (d, J = 1.0 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.92 – 7.76 (m, 5H), 7.59 (s, 1H), 3.16 (s, 3H), 2.29 (s, 3H).

[0726] LCMS: RT: 1.60 min, m / z: 338.2 (M+H)+Example 8: N-(1-(methylsulfonyl)piperidin-4-yl)-5-(pyridin-2-yl)-2,6-naphthyridin-3- amine

[0727] A solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (2B) (150 mg, 0.33 mmol) and 2-(tributylstannyl)pyridine (243 mg, 0.660 mmol) in 1,4-dioxane (4.0 mL) was degassed for 10 min. To the reaction mixture, Pd(dppf)Cl2(48.3 mg, 0.066 mmol) was added at rt under nitrogen atmosphere and the reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was filtered on Celite bed and washed with EtOAc (100 mL). Filtrate was concentrated in vacuo to afford crude as yellow solid which was purified by Prep-HPLC. The product fractions were lyophilized to obtain the desired compound, N-(1-(methylsulfonyl)piperidin-4-yl)-5-Atty. Docket No.: 39953-58778 (002WO) (pyridin-2-yl)-2,6-naphthyridin-3-amine (12.5 mg, 0.031 mmol, 9.4 % yield) as a pale yellow solid.

[0728] 1H-NMR (400 MHz, DMSO- d6): δ 9.07 (s, 1H), 8.77 (dt, J = 4.8, 1.5 Hz, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.07 – 7.96 (m, 2H), 7.77 (d, J = 5.4 Hz, 1H), 7.63 (s, 1H), 7.54 (ddd, J = 6.8, 4.9, 2.0 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 3.89 (s, 1H), 3.55 (d, J = 12.2 Hz, 2H), 2.89 (s, 5H), 2.03 (d, J = 12.9 Hz, 2H), 1.54 (q, J = 10.1 Hz, 2H).

[0729] LCMS: RT: 1.87 min, m / z: 384.3 (M+H)+Example 9: 5-(piperidin-1-yl)-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-2,6-naphthyridin-3- amine

[0730] 9A: tert-butyl3-((5-(piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)pyrrolidine-1- carboxylate:

[0731] To a solution of 7-chloro-1-(piperidin-1-yl)-2,6-naphthyridine (3A) (400 mg, 1.62 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (601 mg, 3.23 mmol) in 1,4-dioxane (10 mL) was added Cs2CO3(1.58 g, 4.84 mmol) under continuous bubbling of nitrogen. To the resulting solution was added Pd-PEPPSI-iHeptCl (157 mg, 0.161 mmol) and reaction mixture was stirred at 110 °C for 16 h. Reaction progress was monitored by TLC. After completion, reaction mixture was concentrated in vacuo to afford crude which was purified by Biotage Isolera (100-200 mesh size silica gel, using 35 % EtOAc in hexanes as an eluent) to obtain desired product, tert-butyl 3-((5-(piperidin-1-yl)-2,6-naphthyridin-3- yl)amino)pyrrolidine-1-carboxylate (500 mg, 1.22 mmol, 76 % yield) as a brown solid.

[0732] LCMS: RT: 2.01 min, m / z: 398.2 (M+H)+

[0733] 9B: 5-(piperidin-1-yl)-N-(pyrrolidin-3-yl)-2,6-naphthyridin-3-amine, HCl: To a solution of tert-butyl 3-((5-(piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)pyrrolidine-1- carboxylate (500 mg, 1.26 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (4.7 mL, 18.9 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 1 h and reaction progress mixture was monitored by TLC. Reaction mixture was concentrated in vacuo to afford crude as a pale brown gum. The crude was triturated with MTBE (20 mL) and solid precipitate obtained was dried to get the desired product, 5-Atty. Docket No.: 39953-58778 (002WO) (piperidin-1-yl)-N-(pyrrolidin-3-yl)-2,6-naphthyridin-3-amine, HCL (500 mg, 1.29 mmol, 103 % yield) as a pale yellow solid.

[0734] LCMS: RT: 1.37 min, m / z: 298.3 (M+H)+

[0735] 9: To a solution of 5-(piperidin-1-yl)-N-(pyrrolidin-3-yl)-2,6-naphthyridin-3- amine (150 mg, 0.504 mmol) in DCM (10 mL) were added TEA (0.7 mL, 5.04 mmol) and 2- chloroethane-1-sulfonyl chloride (82 mg, 0.504 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was concentrated in vacuo to afford crude as a brown solid. Crude compound was purified by Prep-HPLC and fractions were lyophilized to obtain desired product, 5-(piperidin-1-yl)-N-(1-(vinylsulfonyl)pyrrolidin- 3-yl)-2,6-naphthyridin-3-amine (8.7 mg, 0.022 mmol, 4.3 % yield) as a brown solid.

[0736] 1H-NMR (400 MHz, DMSO- d6): δ 8.87 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.21 (dd, J = 5.8, 0.8 Hz, 1H), 7.05 (d, J = 6.1 Hz, 1H), 6.88 (dd, J = 16.5, 10.0 Hz, 1H), 6.77 (t, J = 1.0 Hz, 1H), 6.10 (dd, J = 13.3, 3.3 Hz, 2H), 4.40 (p, J = 5.8 Hz, 1H), 3.55 (dd, J = 10.2, 6.1 Hz, 1H), 3.44 (dt, J = 10.1, 7.2 Hz, 1H), 3.36 – 3.33 (m, 1H), 3.22 (t, J = 5.3 Hz, 4H), 3.12 (dd, J = 10.2, 4.6 Hz, 1H), 2.22 (ddd, J = 14.3, 12.8, 6.9 Hz, 1H), 1.92 (dq, J = 12.9, 6.2 Hz, 1H), 1.75 (d, J = 7.1 Hz, 4H), 1.65 (d, J = 5.6 Hz, 2H).

[0737] LCMS: RT: 1.68 min, m / z: 388.3 (M+H)+Example 10: 5-(4,4-difluoropiperidin-1-yl)-N-(1-(vinylsulfonyl)piperidin-4-yl)-2,6- naphthyridin-3-amine

[0738] 10A: 7-chloro-1-(4,4-difluoropiperidin-1-yl)-2,6-naphthyridine: A procedure similar to that disclosed in Example 1F was used here starting with 1-((1H- benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine (1E) (600 mg, 2.02 mmol) and 4,4-difluoropiperidine (488 mg, 4.03 mmol) to yield 7-chloro-1-(4,4-difluoropiperidin-1-yl)- 2,6-naphthyridine (300 mg, 1.06 mmol, 52 % yield).

[0739] LCMS: RT: 2.62 min, m / z: 284.2 (M+H)+

[0740] 10B: tert-butyl 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthyridin-3- yl)amino)piperidine-1-carboxylate: To a solution of 7-chloro-1-(4,4-difluoropiperidin-1-yl)-Atty. Docket No.: 39953-58778 (002WO) 2,6-naphthyridine (300 mg, 1.06 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (424 mg, 2.12 mmol) in NMP (5 mL) was added Cs2CO3 (1.03 g, 3.17 mmol) under continuous bubbling of nitrogen. To the resultant solution was added Pd-PEPPSI-iHeptCl (103 mg, 0.106 mmol) under nitrogen atmosphere and reaction mixture was stirred at 110 °C for 16 h. Reaction progress mixture was monitored by TLC. After completion, reaction mixture concentrated in vacuo to afford crude as a brown liquid which was purified by Biotage Isolera (100-200 mesh size silica-gel, using 15 % EtOAc- hexanes as an eluent) to obtain desired product, tert-butyl 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthyridin-3- yl)amino)piperidine-1-carboxylate (450 mg, 0.941 mmol, 89 % yield) as a green solid.

[0741] LCMS: RT: 2.58 min, m / z: 448.4 (M+H)+

[0742] 10C: 5-(4,4-difluoropiperidin-1-yl)-N-(piperidin-4-yl)-2,6-naphthyridin-3-amine: To a solution of tert-butyl 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthyridin-3- yl)amino)piperidine-1-carboxylate (450 mg, 1.01 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (3.8 mL, 15.1 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 1 h under nitrogen atmosphere and reaction progress was monitored by TLC. After completion, reaction mixture was concentrated in vacuo to afford crude as a green gum. Reaction mixture was diluted with 10 % NaHCO3solution (20 mL) and extracted with 10 % MeOH in DCM (3 x 40 mL). Combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford desired product, 5-(4,4-difluoropiperidin-1-yl)-N-(piperidin-4-yl)-2,6-naphthyridin- 3-amine (250 mg, 0.703 mmol, 70 % yield) as a green solid.

[0743] LCMS: RT: 1.37 min, m / z: 348.3 (M+H)+

[0744] 10: To a solution of 5-(4,4-difluoropiperidin-1-yl)-N-(piperidin-4-yl)-2,6- naphthyridin-3-amine (250 mg, 0.720 mmol) was dissolved in DCM (10 mL) were added TEA (1 mL, 7.20 mmol) and 2-chloroethane-1-sulfonyl chloride (82 mg, 0.504 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 4 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was concentrated in vacuo to afford crude as off-white solid. Crude product was purified by Prep-HPLC. Fractions were lyophilized to obtain desired product, 5-(4,4-difluoropiperidin-1- yl)-N-(1-(vinylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (35.2 mg, 0.079 mmol, 11 % yield) as a yellow solid.

[0745] 1H-NMR (400 MHz, DMSO- d6): δ 8.88 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.27 (d, J = 5.7 Hz, 1H), 6.89 – 6.72 (m, 3H), 6.24 – 6.07 (m, 2H), 3.90 (d, J = 10.1 Hz, 1H), 3.53Atty. Docket No.: 39953-58778 (002WO) (d, J = 12.4 Hz, 2H), 3.40 (t, J = 5.7 Hz, 4H), 2.88 (t, J = 10.9 Hz, 2H), 2.24 (d, J = 14.7 Hz, 4H), 2.09 – 1.99 (m, 2H), 1.53 (q, J = 9.8 Hz, 2H).

[0746] MSI ESI: RT: 2.25 min, m / z: 438.2 (M+H)+Example 11: 5-(benzyloxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3- amine

[0747] 11A: 1-(benzyloxy)-7-chloro-2,6-naphthyridine: To a solution of 7-chloro-2,6- naphthyridin-1-ol (1D) (1.00 g, 5.54 mmol) in toluene was added (10 mL) silver carbonate (3.05g, 11.1 mmol). To this reaction mixture was added benzyl bromide (0.8 mL, 7.20 mmol) and the resultant reaction mixture was stirred at rt for 16 h. Reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice cold water and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (3 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by Biotage Isolera (100-200 mesh size silica gel using 4 % EtOAc in hexanes as eluent) to afford the desired product, 1-(benzyloxy)-7-chloro-2,6-naphthyridine (370 mg, 1.23 mmol, 22 % yield) as a pale yellow solid.

[0748] LCMS: RT: 2.27 min, m / z: 270.1 (M+H)+

[0749] 11: To a solution of 1-(benzyloxy)-7-chloro-2,6-naphthyridine (30 mg, 0.111 mmol), 1-(methylsulfonyl)piperidin-4-amine (19.8 mg, 0.111 mmol) in 1,4-dioxane (3 mL) was added Cs2CO3(108 mg, 0.332 mmol) under continuous bubbling of nitrogen. To the resulting solution was added Pd-PEPPSI-iHeptCl (8.77 mg, 0.011 mmol) and reaction mixture was stirred at 120 °C for 16 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was concentrated in vacuo to afford crude. Crude product was purified by Prep-HPLC. Fractions were lyophilized to obtain desired product 5- (benzyloxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (35 mg, 0.083 mmol, 75 % yield) as a pale yellow solid.

[0750] 1H-NMR (400 MHz, DMSO- d6): δ 8.87 (s, 1H), 7.67 (d, J = 5.8 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.48 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 7.26 (dd, J = 5.9, 0.9 Hz, 1H), 6.95Atty. Docket No.: 39953-58778 (002WO) (t, J = 1.0 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.50 (s, 2H), 3.93 (s, 1H), 3.58 – 3.46 (m, 2H), 3.02 – 2.90 (m, 2H), 2.88 (s, 3H), 2.01 (dd, J = 13.3, 3.9 Hz, 2H), 1.60 – 1.42 (m, 2H).

[0751] LCMS: RT: 2.05 min, m / z: 413.2 (M+H)+Example 12: (4-hydroxypiperidin-1-yl)(7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6- naphthyridin-1-yl)methanone

[0752] 12A: Synthesis of methyl 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6- naphthyridine-1-carboxylate: To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)- 2,6-naphthyridin-1-yl trifluoromethanesulfonate (2B) (4.0 g, 8.80 mmol) in DMF (35 mL) and MeOH (35.0 mL)was added TEA (3.7 mL, 26.4 mmol) at 25 °C. Reaction mixture was degassed for 10 min followed by addition of palladium(II) acetate (790 mg, 3.52 mmol) and dppf (1.95 g, 3.52 mmol) at rt. Reaction mixture was stirred at 80 °C under CO atmosphere for 16 h and reaction progress was monitored by TLC and LCMS. Reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). Combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude (liquid). Crude product was purified by Biotage Isolera (100-200 silica using 20 % EtOAc-Hexanes as an eluent) to obtain the desired compound, 5- methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (1.20 g, 3.57 mmol, 41 % yield) as white solid.

[0753] LCMS: RT: 1.90 min, m / z: 365.2 (M+H)+.

[0754] 12B: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridine-1-carboxylic acid: To a solution of methyl 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridine- 1-carboxylate (300 mg, 0.823 mmol) in water (0.6 mL) and THF (3 mL) was added LiOH (59.1 mg, 2.47 mmol) at 0 °C and the reaction mixture was stirred at rt for 30 h. Reaction progress was monitored by TLC and LCMS. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (50 mL), acidified with citric acid and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product, 7-((1-Atty. Docket No.: 39953-58778 (002WO) (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridine-1-carboxylic acid (250 mg, 0.700 mmol, 85 % yield) as a yellow solid.

[0755] LCMS: RT: 1.48 min, m / z: 351.1 (M+H)+

[0756] 12: To a solution of 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6- naphthyridine-1-carboxylic acid (25 mg, 0.071 mmol) in DMF (1.5 mL) were added HATU (40.7 mg, 0.107 mmol), DIPEA (23 mg, 0.178 mmol) and piperidin-4-ol (7.2 mg, 0.071 mmol) at rt under nitrogen atmosphere. Reaction mixture was stirred at rt for 16 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion of reaction, reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). Combined organic layer was dried over sodium sulfate and concentrated in vacuo to get crude product. Crude product was purified by Prep-HPLC and fractions were lyophilized to afford the desired product, (4-hydroxypiperidin-1-yl)(7-((1-(methylsulfonyl)piperidin-4- yl)amino)-2,6-naphthyridin-1-yl)methanone (16 mg, 0.037 mmol, 51 % yield) as a pale yellow solid.

[0757] 1H-NMR (400 MHz, DMSO- d6): δ 9.06 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.73 (d, J = 5.7 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.58 (s, 1H), 4.84 (d, J = 3.9 Hz, 1H), 4.15 (d, J = 12.3 Hz, 1H), 3.92 (s, 1H), 3.77 (s, 1H), 3.54 (d, J = 12.5 Hz, 1H), 2.92-2.84 (m, 6H), 2.08 – 1.77 (m, 4H), 1.74 – 1.31 (m, 5H), 1.26 (d, J = 14.4 Hz, 2H).

[0758] LCMS: RT: 1.64 min, m / z: 434.2 (M+H)+Example 13: 3-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)phenyl sulfurofluoridate

[0759] 13A: 1-(7-chloro-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile: To a solution of 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyridine (1E) (2.000 g, 6.72 mmol) in NMP (10 mL) were added DIPEA (3.51 mL, 20.2 mmol) and piperidine-4- carbonitrile (1.11 g, 10.08 mmol) at rt under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h and monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product (2.5 g) was purified by Biotage Isolera using (100-200 silica gel, 25Atty. Docket No.: 39953-58778 (002WO) % EtOAc in hexanes as eluent) to provide the desired compound, 1-(7-chloro-2,6- naphthyridin-1-yl)piperidine-4-carbonitrile (1.03 g, 3.70 mmol, 55 % yield) as a yellow solid.

[0760] LCMS: RT: 2.25 min, m / z: 273.2 (M+H)+

[0761] 13B: 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthyridin-1-yl)piperidine-4- carbonitrile: To a solution of 1-(7-chloro-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile (150 mg, 0.550 mmol) in NMP (10 mL) were added 3-aminophenol (90 mg, 0.825 mmol) and Cs2CO3 (538 mg, 1.65 mmol) and degassed the reaction mixture with nitrogen for 10 min. To the resultant solution was added Pd-PEPPSI-iHeptCl (53.5 mg, 0.055 mmol) at rt under nitrogen atmosphere and stirred at 120 °C for 16 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 40 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product. Crude product was purified by Biotage Isolera (60-120 silica gel, using 60 % EtOAc in hexanes as an eluent) to afford the desired compound, 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthyridin- 1-yl)piperidine-4-carbonitrile (190 mg, 0.546 mmol, 99 % yield) as yellow solid.

[0762] LCMS: RT: 2.25 min, m / z: 346.2 (M+H)+

[0763] 13: To a solution of 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthyridin-1- yl)piperidine-4-carbonitrile (190 mg, 0.550 mmol) in THF (25 mL). To this reaction mixture, AISF (182 mg, 0.578 mmol) and DBU (0.18 mL, 1.210 mmol) were added at 25 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product. Crude product was purified by Prep-HPLC to obtain the desired product, 3-((5-(4- cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)phenyl sulfurofluoridate (55 mg, 0.129 mmol, 23 % yield) as a pale yellow solid.

[0764] 1H-NMR (400 MHz, DMSO- d6): δ 9.73 (s, 1H), 9.11 (d, J = 0.9 Hz, 1H), 8.08 – 7.91 (m, 2H), 7.61 (ddd, J = 8.4, 2.0, 0.9 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 5.8, 0.9 Hz, 1H), 7.30 (t, J = 1.1 Hz, 1H), 7.08 (dd, J = 8.1, 2.5 Hz, 1H), 3.57 – 3.39 (m, 2H), 3.21 (ddd, J = 12.8, 8.6, 3.6 Hz, 3H), 2.14 (ddd, J = 13.4, 7.3, 2.7 Hz, 2H), 2.01 (ddt, J = 13.5, 9.0, 4.2 Hz, 2H).

[0765] LCMS: RT: 2.58 min, m / z: 428.2 (M+H)+Atty. Docket No.: 39953-58778 (002WO) Example 14: 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)phenyl sulfurofluoridate

[0766] 14A: 1-(7-((4-- 1-yl)piperidine-4- carbonitrile: To a solution of 1-(7-chloro-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile (13A) (150 mg, 0.550 mmol) in NMP (10 mL) were added 4-aminophenol (90 mg, 0.825 mmol) and Cs2CO3(538 mg, 1.65 mmol) and degassed the reaction mixture with nitrogen for 10 min. To the resultant solution was added Pd-PEPPSI-iHeptCl (53.5 mg, 0.055 mmol) at 25 °C under nitrogen atmosphere and reaction mixture was stirred at 120 °C for 16 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 40 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product. Crude product was purified by Biotage Isolera (60-120 silica gel, using 60 % EtOAc in hexanes as an eluent) to afford the desired product, 1-(7-((4- hydroxyphenyl)amino)-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile (190 mg, 0.528 mmol, 96 % yield).

[0767] LCMS: RT: 1.68 min, m / z: 346.2 (M+H)+

[0768] 14: To a solution of 1-(7-((4-hydroxyphenyl)amino)-2,6-naphthyridin-1- yl)piperidine-4-carbonitrile (190 mg, 0.550 mmol) in THF (25 mL) were added AISF (182 mg, 0.578 mmol) and DBU (0.18 mL, 1.21 mmol) at 25 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. Reaction progress was monitored by LCMS. After completion, reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product. Crude product was purified by Prep-HPLC and fractions were lyophilized to obtain the desired compound, 4-((5- (4-cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)phenyl sulfurofluoridate (32 mg, 0.075 mmol, 14 % yield) as a pale yellow solid.

[0769] 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 9.07 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.56 – 7.47 (m, 2H), 7.43 – 7.37 (m, 1H), 7.27 (s,Atty. Docket No.: 39953-58778 (002WO) 1H), 3.56 – 3.43 (m, 2H), 3.19 (dt, J = 13.1, 4.8 Hz, 3H), 2.20 – 2.06 (m, 2H), 2.00 (dtd, J = 12.2, 8.4, 3.2 Hz, 2H).

[0770] LCMS: RT: 2.59 min, m / z: 428.2 (M+H)+Example 15: 1-(7-((4-(vinylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-yl)piperidine-4- carbonitrile

[0771] 15A: 1-(7-((4-((2- -2,6-naphthyridin-1- yl)piperidine-4-carbonitrile: To a solution of 1-(7-chloro-2,6-naphthyridin-1-yl)piperidine-4- carbonitrile (13A) (400 mg, 1.47 mmol) in 1,4-dioxane (20 mL) were added Cs2CO3 (956 mg, 2.93 mmol) and 2-((4-aminophenyl)sulfonyl)ethan-1-ol (443 mg, 2.20 mmol) under continuous nitrogen bubbling. To the resulting solution was added Pd-PEPPSI-iHeptCl (143 mg, 0.147 mmol) at 25 °C and the reaction mixture was stirred at 100 °C for 16 h. Reaction progress was monitored by TLC and LCMS. After completion, the reaction was filtered over Celite bed and washed with EtOAc. Organic layer was evaporated to dryness to give the crude. Crude was purified by Prep-HPLC and fractions obtained were lyophilized to obtained the desired product, 1-(7-((4-((2-hydroxyethyl)sulfonyl)phenyl)amino)-2,6-naphthyridin-1- yl)piperidine-4-carbonitrile (70 mg, 0.157 mmol, 11 % yield).

[0772] LCMS: RT: 1.82 min, m / z: 438.2 (M+H)+

[0773] 15: To a solution of 1-(7-((4-((2-hydroxyethyl)sulfonyl)phenyl)amino)-2,6- naphthyridin-1-yl)piperidine-4-carbonitrile (50 mg, 0.114 mmol) in ACN (5 mL) were added TEA (0.16 mL, 1.14 mmol) and SOCl2(20.4 mg, 0.171 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 6 h under nitrogen atmosphere and reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). Combined organic extract was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude as a black liquid. Crude product (100 mg) was purified by Prep-HPLC and fractions were lyophilized to obtain desired product, 1-(7-((4- (vinylsulfonyl)phenyl)amino)-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile (4.38 mg, 10.3 µmol, 9.0 % yield) as a pale yellow solid.Atty. Docket No.: 39953-58778 (002WO)

[0774] 1H-NMR (400 MHz, DMSO- d6):) δ 9.92 (s, 1H), 9.13 (d, J = 0.8 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.90 – 7.81 (m, 2H), 7.81 – 7.68 (m, 2H), 7.49 – 7.32 (m, 2H), 7.05 (dd, J = 16.4, 9.8 Hz, 1H), 6.25 (d, J = 16.4 Hz, 1H), 6.11 (d, J = 9.9 Hz, 1H), 3.57 – 3.45 (m, 2H), 3.22 (ddt, J = 12.9, 8.1, 3.5 Hz, 3H), 2.14 (ddt, J = 9.8, 7.0, 3.5 Hz, 2H), 2.01 (dtd, J = 12.2, 8.5, 3.3 Hz, 2H).

[0775] LCMS: RT: 2.15 min, m / z: 420.2 (M+H)+Example 16: 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)-N-(2- oxotetrahydrothiophen-3-yl)benzamide

[0776] 16A: To a solution of 1-(7-chloro-2,6-naphthyridin-1-yl)piperidine-4-carbonitrile (13A) (250 mg, 0.917 mmol) in NMP (5 mL) were added 4-aminobenzoic acid (189 mg, 1.38 mmol) and Cs2CO3(1.49 g, 4.58 mmol) The reaction mixture was degassed with nitrogen for 10 min and Pd-PEPPSI-iHeptCl (89 mg, 0.092 mmol) was added at rt under nitrogen atmosphere. The reaction mixture was stirred at 120 °C for 16 h under nitrogen atmosphere. The reaction was monitored by TLC, and the reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase Biotage Isolera using 50% ACN and formic acid as eluent. The fractions were lyophilized to afford the desired product, 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)benzoic acid (201 mg, 0.499 mmol, 54 % yield) as a pale-yellow solid.

[0777] LCMS: RT: 1.92 min, m / z: 372.2 (M+H)+

[0778] 16: To a stirred solution of 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyridin-3- yl)amino)benzoic acid (200 mg, 0.536 mmol) in DMF (3 mL) were added EDC (154 mg, 0.803 mmol), 3-aminodihydrothiophen-2(3H)-one, HCl (82 mg, 0.536 mmol), HOBt (123 mg, 0.803 mmol) and DMAP (7 mg, 0.054 mmol) at 25 °C under nitrogen atmosphere. Reaction mixture was stirred at rt for 15 min and then added DIPEA (0.47 mL, 2.68 mmol). The resulting mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. Reaction progress was monitored by TLC. After completion, reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude compound was purified byAtty. Docket No.: 39953-58778 (002WO) Prep-HPLC and lyophilized to get the desired compound, 4-((5-(4-cyanopiperidin-1-yl)-2,6- naphthyridin-3-yl)amino)-N-(2-oxotetrahydrothiophen-3-yl)benzamide (86.8 mg, 0.181 mmol, 34 % yield) as pale yellow solid.

[0779] 1H-NMR (400 MHz, DMSO- d6):) δ 9.62 (s, 1H), 9.10 (d, J = 0.8 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.75 – 7.60 (m, 2H), 7.41 (dd, J = 5.9, 0.9 Hz, 1H), 7.33 (t, J = 1.0 Hz, 1H), 4.85 (ddd, J = 12.7, 8.4, 7.0 Hz, 1H), 3.57 – 3.41 (m, 3H), 3.39 – 3.35 (m, 1H), 3.21 (qd, J = 9.4, 5.4 Hz, 3H), 2.49 – 2.43 (m, 1H), 2.36 – 2.31 (m, 1H), 2.20 – 2.10 (m, 2H), 2.01 (dtd, J = 12.0, 8.3, 3.2 Hz, 2H).

[0780] LCMS: RT: 1.83 min, m / z: 473.2 (M+H)+Example 17: (7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1-(piperidin-1-yl)-2,6- naphthyridin-3-yl)methanol

[0781] 17A: methyl 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2- chloroisonicotinate: To a solution of 5-bromo-2-chloroisonicotinate (1A) (5.00 g, 20.0 mmol) in THF (50 mL) were added (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (4.42 g, 24.0 mmol) and TEA (27.8 mL, 200 mmol). Reaction mixture was purged with N2 for 10 min, followed by addition of copper(I) iodide (380 mg, 2.0 mmol) and PdCl2(PPh3)2(701 mg, 0.998 mmol) and again purged with N2for 5 min. After addition, reaction mixture was stirred at rt for 16 h and reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was passed through Celite pad, washed with EtOAc (100 mL), collected the filtrate and washed with water (100 mL) and brine solution (100 mL). Collected organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford residue. The crude material was purified by Biotage Isolera (60-120 silica gel, using 10 % EtOAc in hexanes as an eluent) to afford the desired product, methyl 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn- 1-yl)-2-chloroisonicotinate (4.20 g, 8.07 mmol, 40 % yield).

[0782] LCMS: RT: 3.45 min, m / z: 354.2 (M+H)+

[0783] 17B: 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-chloroisonicotinamide: A solution of methyl 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-chloroisonicotinate (1.70 g, 5.00 mmol) in 7M ammonia in methanol (20 mL) was stirred in pressure reactor at 80 °C for 6 h. Reaction progress was monitored by TLC and LCMS. After completion,Atty. Docket No.: 39953-58778 (002WO) reaction mixture was concentrated in vacuo to afford crude. Crude was purified by Biotage Isolera (60-120 silica gel, using 20 % EtOAc in hexanes as an eluent) to obtain the desired product, 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-chloroisonicotinamide (801 mg, 2.265 mmol, 45 % yield).

[0784] LCMS: RT: 2.18 min, m / z: 325.3 (M+H)+

[0785] 17C: 3-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-2,6-naphthyridin-1-ol: To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-chloroisonicotinamide (800 mg, 2.46 mmol) in THF (10 mL) at 0 °C was added KOtBu (691 mg, 6.16 mmol). After addition, reaction mixture was warmed to 25 °C and stirred for 1 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (2 mL), neutralized with aqueous HCl (2 mL), diluted with water (20 mL), extracted with EtOAc (2 x 20 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford residue. Residue was purified by Biotage Isolera (60-120 silica gel, using 20 % EtOAc in hexanes as an eluent) at 0 °C to afford the desired product, 3- (((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-2,6-naphthyridin-1-ol (151 mg, 0.392 mmol, 16 % yield).

[0786] LCMS: RT: 2.23 min, m / z: 325.2 (M+H)+

[0787] 17D: 1-( [d][1,2,3]triazol-1-yl)oxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-2,6-naphthyridine: To a solution of 3-(((tert- butyldimethylsilyl)oxy)methyl)-7-chloro-2,6-naphthyridin-1-ol (390 mg, 1.20 mmol) in DMF (10 mL) was added DBU (0.54 mL, 3.60 mmol) followed by addition of PyBOP (656 mg, 1.26 mmol) and then stirred at 25 °C for 1 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was cooled to 0°C, quenched with ice, and solid precipitate obtained was filtered, washed with water, and dried to afford the desired compound, 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)- 7-chloro-2,6-naphthyridine (501 mg, 1.08 mmol, 90 % yield) as green solid.

[0788] LCMS: RT: 2.70 min, m / z: 442.3 (M+H)+

[0789] 17E: 3-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-1-(piperidin-1-yl)-2,6- naphthyridine: To a solution of 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3-(((tert- butyldimethylsilyl)oxy)methyl)-7-chloro-2,6-naphthyridine (500 mg, 1.13 mmol) in ACN (10 mL) were added DIPEA (0.59 mL, 3.39 mmol) and piperidine (0.22 mL, 2.26 mmol) at rt and the reaction mixture was stirred at 80 °C for 16h. Reaction mixture was then concentrated in vacuo to afford residue. Residue was purified by Biotage Isolera (60-120 silica gel, using 10 % EtOAc in hexanes as an eluent) to afford the desired product, 3-(((tert-Atty. Docket No.: 39953-58778 (002WO) butyldimethylsilyl)oxy)methyl)-7-chloro-1-(piperidin-1-yl)-2,6-naphthyridine (130 mg, 0.330 mmol, 29 % yield) as green solid.

[0790] LCMS: RT: 3.93 min, m / z: 392.2 (M+H)+

[0791] 17F: 7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(piperidin-1-yl)-2,6-naphthyridin-3-amine: To a solution of 3-(((tert- butyldimethylsilyl)oxy)methyl)-7-chloro-1-(piperidin-1-yl)-2,6-naphthyridine (250 mg, 0.638 mmol) and 1-(methylsulfonyl)piperidin-4-amine (171 mg, 0.957 mmol) in 1,4-dioxane (5 mL) was added Cs2CO3 (623 mg, 1.91 mmol) at rt under nitrogen atmosphere. Reaction mixture was degassed for 5 min with N2followed by addition of Pd-PEPPSI-iHeptCl (62.1 mg, 0.064 mmol). Reaction mixture was then stirred at 120 °C for 16 h under nitrogen atmosphere and reaction progress was monitored by TLC and LCMS. Reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 25 mL). Combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude. Crude was purified by Biotage Isolera (60-120 silica gel, using 80 % EtOAc in hexanes as an eluent) to obtain the desired product, 7-(((tert-butyldimethylsilyl)oxy)methyl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-2,6-naphthyridin-3-amine (240 mg, 0.445 mmol, 70 % yield) as a brown solid.

[0792] LCMS: RT: 2.76 min, m / z: 534.4 (M+H)+

[0793] 17: To a solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-2,6-naphthyridin-3-amine (210 mg, 0.393 mmol) in DCM (0.5 mL) was added TFA (0.152 mL, 1.97 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 16 h under nitrogen atmosphere and reaction progress was monitored by TLC and LCMS. Reaction mixture was concentrated in vacuo and the residue was diluted with 10 % NaHCO3 solution (20 mL) and extracted with 10 % methanol in DCM (3 x 25 mL). Combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude compound was washed with MTBE (10 mL) and pentane (20 mL) and then dried to get desired product, (7- ((1-(methylsulfonyl)piperidin-4-yl)amino)-1-(piperidin-1-yl)-2,6-naphthyridin-3-yl)methanol (70 mg, 0.160 mmol, 41 % yield) as a yellow solid.

[0794] 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.21 (s, 1H), 6.72 (d, J = 17.1 Hz, 2H), 5.31 (d, J = 79.2 Hz, 1H), 4.48 (s, 2H), 3.86 (td, J = 9.0, 5.3 Hz, 1H), 3.56 (dt, J = 12.2, 4.0 Hz, 2H), 3.22 (t, J = 5.2 Hz, 4H), 3.02 – 2.80 (m, 5H), 2.06 (dt, J = 13.4, 3.6 Hz, 2H), 1.75 (q, J = 5.5 Hz, 4H), 1.68 – 1.43 (m, 4H).

[0795] LCMS: RT: 1.67 min, m / z: 420.2 (M+H)+Atty. Docket No.: 39953-58778 (002WO) Example 18: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1-(piperidin-1-yl)-2,6- naphthyridine-3-carbaldehyde

[0796] To a solution of (7-((1- -1-(piperidin-1-yl)- 2,6-naphthyridin-3-yl)methanol (17) (45 mg, 0.107 mmol) in DCM (5 mL) was added DMP (114 mg, 0.268 mmol). The resulting reaction mixture was stirred at rt for 16 h and the reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was diluted with DCM (30 mL) and filtered. The filtrate was washed with sodium bicarbonate (20 mL) and extracted with DCM (2 x 40 mL). Combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude. Crude was purified by Biotage Isolera (60-120 silica gel, using 60 % EtOAc in hexanes as an eluent) to obtain the desired product, 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1-(piperidin-1-yl)- 2,6-naphthyridine-3-carbaldehyde (21 mg, 0.047 mmol, 44 % yield).

[0797] 1H-NMR (400 MHz, DMSO- d6): δ 9.83 (s, 1H), 9.07 (s, 1H), 7.93 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 3.97 (s, 2H), 3.66 – 3.39 (m, 3H), 3.01 – 2.82 (m, 5H), 2.07 (d, J = 12.7 Hz, 2H), 1.91 – 1.10 (m, 10H)

[0798] LCMS: RT: 2.09 min, m / z: 418.2 (M+H)+Example 19: 2-(7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1-(piperidin-1-yl)-2,6- naphthyridin-3-yl)ethan-1-ol

[0799] 19A: methyl 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2- chloroisonicotinate: To a solution of 5-bromo-2-chloroisonicotinate (1A) (5.0 g, 20.0 mmol) in THF (50 mL) were added (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (4.42 g, 24.0 mmol) and TEA (27.8 mL, 200 mmol) at rt. Reaction mixture was purged with N2 for 10Atty. Docket No.: 39953-58778 (002WO) min, followed by addition of copper(I) iodide (380 mg, 2.0 mmol) and PdCl2(PPh3)2 (701 mg, 0.998 mmol) at rt and again purged with N2 for 5 min. Reaction mixture was then stirred at rt for 16 h and reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was passed through Celite pad, washed with EtOAc (100 mL), collected the filtrate and washed with water (100 mL) and brine solution (100 mL). Collected organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford residue. The crude material was purified by Biotage Isolera (60-120 silica gel, using 10 % EtOAc in hexanes as an eluent) to afford the desire product, methyl 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1- yl)-2-chloroisonicotinate (4.2 g, 8.07 mmol, 40 % yield) as an off-white solid.

[0800] LCMS: RT: 3.45 min, m / z: 354.2 (M+H)+

[0801] 19B: 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2-chloroisonicotinamide: A solution of methyl 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2-chloroisonicotinate (3.5 g, 9.89 mmol) in 7M ammonia in methanol (25 mL) at rt. Reaction mixture was stirred in pressure reactor at 80 °C for 6 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was concentrated in vacuo to afford residue which was purified by Biotage Isolera (60-120 mesh size silica gel, using 50 % EtOAc in hexanes as an eluent) to afford the desire product, 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2- chloroisonicotinamide (2.50 g, 7.30 mmol, 74 % yield).

[0802] LCMS: RT: 2.25 min, m / z: 339.2 (M+H)+

[0803] 19C: 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-2,6-naphthyridin-1-ol: To a solution of 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2-chloroisonicotinamide (1.00 g, 2.95 mmol) in THF (50 mL) at 0 °C was added NaH (248 mg, 6.20 mmol) and then stirred at 40 °C for 16 h. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (2 mL), neutralized with aqueous HCl (2 mL), diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford residue. Residue was purified by Biotage Isolera (60-120 silica gel, using 20 % EtOAc in hexanes as an eluent) to afford the desired product, 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)- 7-chloro-2,6-naphthyridin-1-ol (630 mg, 1.79 mmol, 61 % yield) as an off-white solid.

[0804] LCMS: min, m / z: 339.2 (M+H)+

[0805] 19D: 1-([d][1,2,3]triazol-1-yl)oxy)-3-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-2,6-naphthyridine: To a solution of 3-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-2,6-naphthyridin-1-ol (600 mg, 1.77 mmol) in DMF (10 mL) was added DBU (0.79 mL, 5.31 mmol) followed by addition of PyBOP (967 mg,Atty. Docket No.: 39953-58778 (002WO) 1.86 mmol). Reaction mixture was then stirred at rt for 1 h and reaction progress was monitored by TLC and LC.MS. After completion, reaction mixture was cooled to 0 °C, ice was added and solid precipitate obtained was filtered, washed with water, and dried to afford the desired compound, 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-2,6-naphthyridine (500 mg, 1.01 mmol, 57 % yield) as brown ...

Claims

Atty. Docket No.: 39953-58778 (002WO) WHAT IS CLAIMED IS:

1. A compound of Formula I: or a pharmaceutically acceptable saltwherein: Y1is N or CR1; Y2is N or CR2; Y3is N or CR3; Y5is N or CR5; R6is of the formula, wherein: A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; Z is an optional hydrophilic group; L1and L2are optional linkers; and * represents the point of attachment of R6to the adjacent nitrogen atom; R4is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl; R1-R3, R5and R7are independently selected from H, optionally substituted (C1-6)alkyl, halo(C1-6)alkyl, -COR30, -OR30, halogen, and CN; and R30is H or optionally substituted (C1-6)alkyl.

2. The compound of claim 1, wherein A is optionally substituted aryl or optionally substituted heteroaryl.Atty. Docket No.: 39953-58778 (002WO) 3. The compound of claim 2, wherein R6comprises the structure 6A: wherein:Y6-Y10are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; and each R12is independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, halogen, and CN.

4. The compound of claim 3, wherein Y8is C-Z.

5. The compound of claim 3 or 4, wherein at least one of Y6-Y10is N.

6. The compound of claim 5, wherein one and only one of Y6-Y10is N.

7. The compound of claim 5 or 6, wherein Y6is N.

8. The compound of claim 5 or 6, wherein Y7is N.

9. The compound of claim 4, wherein R6is of the structure 6A1:wherein m is 0, 1, 2, 3 or 4.

10. The compound of claim 9, wherein R6is of the structure 6A2:(6A2)Atty. Docket No.: 39953-58778 (002WO) wherein R12is selected from hydrogen, halogen, optionally substituted (C1-6)alkyl, and optionally substituted (C1-6)alkoxy.

11. The compound of claim 1, wherein A is optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

12. The compound of claim 11, wherein R6comprises the structure 6B:wherein: Y11is selected from O, S, CH2, CHR11, C(R11)2, and NR9; R9is H, optionally substituted alkyl, -L2-Z, or Z; each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; k is 0 or 1; and n is an integer from 0 to 9.

13. The compound of claim 12, wherein R6comprises the structure 6B1 or 6B3:.

14. The compound of claim 13, wherein: n is 0, 1, 2, 3, or 4; and each R11is independently selected from optionally substituted (C1-3)alkyl, optionally substituted (C1-3)alkoxy, hydroxyl, halogen, and CN.

15. The compound of claim 14, wherein each R11is independently selected from methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro.Atty. Docket No.: 39953-58778 (002WO) 16. The compound of claim 13, wherein R6is of the structure 6B2: .

17. The compound of claim 4, wherein R6is of the structure 6B4: .

18. The compound of any one of claims 1 to 17, wherein R4is selected from substituted amine, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.

19. The compound of any one of claims 1 to 18, wherein R4is optionally substituted alkynyl.

20. The compound of any one of claims 1 to 18, wherein R4is optionally substituted cycloalkyl.

21. The compound of any one of claims 1 to 18, wherein R4is optionally substituted cycloalkenyl.

22. The compound of any one of claims 1 to 18, wherein R4is optionally substituted heterocyclyl.

23. The compound of any one of claims 1 to 18, wherein R4is optionally substituted aryl.

24. The compound of any one of claims 1 to 18, wherein R4is an optionally substituted heteroaryl.Atty. Docket No.: 39953-58778 (002WO) 25. The compound of any one of claims 20 to 24, wherein R4is an optionally substituted monocyclic group.

26. The compound of any one of claims 20 to 24, wherein R4is an optionally substituted bicyclic group.

27. The compound of claim 26, wherein R4is an optionally substituted spirocyclic group.

28. The compound of claim 26, wherein R4is an optionally substituted fused bicyclic group.

29. The compound of any one of claims 18 to 28, wherein R4is selected from substituted amine, (C2-6)alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrazole, azetidine, azepane, pyridyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, oxindole, triazole, oxadiazole, cyclohexanone, and optionally substituted versions thereof.

30. The compound of any one of claims 18 to 29, wherein R4is selected from any one of Formulae 4A-4M:(4J), (4K), (4L), and (4M), wherein,Atty. Docket No.: 39953-58778 (002WO) X1is O, CH2, or C(R26)2; X12is CH2, C(R15)2, O, NCOR25, or NR25; X14is O, NCOR25, or NR25; X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, X7and X8are each independently selected from N and CR26; each R15-R20and R24is an optional substituent independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R21and R22are each independently optionally substituted (C1-6)alkyl; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R25is H, optionally substituted (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R27and R28are each independently H, or optionally substituted (C1-6)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently 0, 1, 2, or 3;Atty. Docket No.: 39953-58778 (002WO) w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

31. The compound of claim 30, wherein R4is of Formula 4A.

32. The compound of claim 31, wherein R4is of Formula 4A1 or 4A2: ,wherein: r is 0, 1 or 2; and R25is H, or optionally substituted (C1-6)alkyl.

33. The compound of claim 30, wherein R4is of Formula 4B.

34. The compound of claim 33, wherein X1is CH2.

35. The compound of claim 30, wherein R4is of Formula 4C or 4D.

36. The compound of claim 35, wherein R4is of Formula 4C wherein u is 2.

37. The compound of claim 30, wherein R4is of Formula 4E:.

38. The compound of claim 37, wherein R4is selected from one of the following structures:, , ,Atty. Docket No.: 39953-58778 (002WO) .

39. The compound of claim 38, wherein R4is selected from one of the following structures:.

40. The compound of claim 38 or 39, wherein R25is of structure:wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

41. The compound of claim 30, wherein R4is of one of Formula 4J-4L:, , .

42. The compound of claim 41, wherein X5is CR26.

43. The compound of claim 41, wherein X5is N.

44. The compound of claim 30, 4M:(4M).Atty. Docket No.: 39953-58778 (002WO) 45. The compound of claim 44, wherein R4is: .

46. The compound of claim 30, wherein R4is of Formula 4G: R21.

47. The compound of claim 46, wherein X8is N 48. The compound of claim 46, wherein X8is CH.

49. The compound of claim 30, wherein R4is of Formula 4I:.

50. The compound of claim 49, wherein R23is selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

51. The compound of claim 50, wherein R23is selected from: ,X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, and X7are each independently selected from N and CR26; each R18-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN;Atty. Docket No.: 39953-58778 (002WO) R25is H, or optionally substituted C1-6 alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

52. The compound of claim 51, wherein R23is of Formula 4F.

53. The compound of claim 52, wherein R23is selected from one of the following structures:, , , .

54. The compound of claim 30, wherein R4is of Formula 4F:.Atty. Docket No.: 39953-58778 (002WO) 55. The compound of claim 54, wherein R4is selected from one of the following structures: .

56. The compound of claim 30, wherein R4is of Formula 4H: .

57. The compound of claim 56, wherein R27and R28together with the nitrogen atom to which they are attached are cyclically linked to provide an optionally substituted piperidinyl.

58. The compound of any one of claims 1 to 57, wherein Z comprises a hydrophilic moiety that is substantially biologically inert.

59. The compound of any one of claims 1 to 57, wherein Z comprises an electrophilic reactive moiety capable of covalently conjugating a biological target.

60. The compound of any one of claims 1 to 59, wherein Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.

61. The compound of claim 60, wherein Z is alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl or heterocyclylsulfonyl.

62. The compound of claim 60, wherein Z is alkylsulfoximine, cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, or alkylsulfonamide.

63. The compound of any one of claims 1 to 62, wherein L1and L2are independently absent, or optionally substituted (C1-6)alkylene (e.g., CH2, (CH2)2, or (CH2)3).Atty. Docket No.: 39953-58778 (002WO) 64. The compound of any one of claims 1 to 63, wherein -L2-Z or Z is of one of Z1-Z6: ,wherein: Y9is absent, -O-, -NR9-, -(C1-6)alkylene-O-, -(C1-6)alkylene-NR9-; X11is O, or NH; R51is selected from halogen, R8, -NR9R10; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone, or a thiolactone; and R52is H, optionally substituted (C1-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; m is 0, 1 or 2; and p, q, s and t are independently 0, 1, 2, 3, 4, 5 or 6.

65. The compound of claim 64, wherein -L2-Z or Z is of formula Z1 and is of one of the following structures: ,(Z1B), or (Z1C),Atty. Docket No.: 39953-58778 (002WO) wherein: R51is halogen; R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; and R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, or optionally substituted heterocyclyl.

66. The compound of claim 65, wherein -L2-Z or Z is8and R is (C1-C6)alkyl.

67. The compound of claim 66, wherein R8is methyl.

68. The compound of claim 65, wherein -L2-Z or Z isand R8is C2-C6alkenyl.

69. The compound of claim 68, wherein R8is -CH=CH2 or -C(CH3)=CH2.

70. The compound of claim 65, wherein -L2-Z or Z is and R8is C2-C6 alkynyl.

71. The compound of claim 70, wherein R8is -CCH or -CC-CH3.

72. The compound of claim 65, wherein -L2-Z or Z is and R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

73. The compound of claim 72, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.

74. The compound of claim 65, wherein -L2-Z or Z is , R9is H, and R10is H, or optionally substituted (C1-6)alkyl.Atty. Docket No.: 39953-58778 (002WO) 75. The compound of any one of claims 65-74, wherein X11is O.

76. The compound of any one of claims 65-74, wherein X11is NH.

77. The compound of claim 65, wherein -L2-Z or Z is of the formula: ,wherein R51is halogen.

78. The compound of claim 64, wherein -L2-Z or Z is of Formula Z4 wherein s is 0:wherein; R9is H; and R10is -SO2R38; and R38is optionally substituted alkyl, or amino.

79. The compound of claim 64, wherein -L2-Z or Z is of Formula Z4 wherein s is 0:, wherein; R9is H; and R10is -SO2R38wherein R38is optionally substituted alkenyl, or R10is optionally substituted thiolactone.

80. The compound of claim 79, - Formula Z4C:(Z4C) wherein m is 0, 1 or 2.Atty. Docket No.: 39953-58778 (002WO) 81. The compound of claim 64, wherein -L2-Z or Z is of Formula Z2: wherein m is 0, 1 or 2.

82. The compound of claim 64, wherein -L2-Z or Z is of Formula Z3:wherein: R52is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and t is 0, 1, or 2.

83. The compound of claim 82, wherein R52is:.

84. The compound of claim 64, wherein -L2-Z or Z is of Formula Z3A wherein t is 0, (Z3A) wherein R52is H.

85. The compound of claim 64, -L2-Z Z is of Formula Z5.(Z5) wherein q is 0, 1, or 2.Atty. Docket No.: 39953-58778 (002WO) 86. The compound of claim 64, wherein-L2-Z or Z is of Formula Z6, wherein p is 0, 1, or 2.

87. The compound of any one of claims 1 to 86, wherein R5is selected from H, CH3, CF3, and halogen.

88. The compound of claim 87, wherein R5is H.

89. The compound of any one of claims 1 to 88, wherein R7is selected from H, CH3, CF3, and halogen.

90. The compound of claim 89, wherein R7is H.

91. The compound of any one of claims 1 to 90, wherein R1is selected from H, CH3, CF3, and halogen.

92. The compound of claim 91, wherein R1is H.

93. The compound of any one of claims 1 to 92, wherein R2is selected from H, CH3, CF3, - CHF2, -CH2Cl, halogen, -C(=O)H, and -(CH2)zOH, where z is 1, 2 or 3.

94. The compound of claim 93, wherein R2is H.

95. The compound of any one of claims 1 to 94, wherein the compound is of any one of Formulae IA-IM:(IA), (IB), (IC), (ID),Atty. Docket No.: 39953-58778 (002WO)or a pharmaceutically acceptable salt thereof.

96. The compound of claim 95, wherein R3is CN.

97. The compound of claim 95, wherein R3is H.

98. The compound of any one of claims 95 to 97, wherein R1, R2, R5and R7are each H.

99. The compound of any one of claims 95 to 98, wherein R6is selected from:, , , wherein: A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted versions thereof; R8is optionally substituted (C1-6)alkyl, optionally substituted (C2-6)alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;Atty. Docket No.: 39953-58778 (002WO) R9is H, or optionally substituted (C1-6)alkyl; R10is a sulfone, or a thiolactone; R52is H, optionally substituted (C1-6)alkyl, or optionally substituted heterocyclyl; R55is H, or optionally substituted (C1-6)alkyl; and m is an integer from 0 to 2.

100. The compound of claim 99, wherein R6is of Formula:

101. The compound of claim 99, wherein R6is of Formula:

102. The compound of any one of claims 100 to 101, wherein: R8is -CH3 or -CH2-R13, and R13is optionally substituted (C1-6)alkyl.

103. The compound of any one of claims 100 to 101, wherein: R8is -CH=CH2 or -CH=CH-R14, and R14is optionally substituted (C1-6)alkyl.

104. The compound of any one of claims 100 to 101, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

105. The compound of any one of claims 100 to 101, wherein R8is (C3-4)cycloalkyl or (C2- 4)heterocyclyl.Atty. Docket No.: 39953-58778 (002WO) 106. The compound of claim 99, wherein R6is of Formula:

107. The compound of claim 99, wherein R6is of Formula:

108. The compound of any one of claims 106 to 107, wherein R9is H, and R10is H, or optionally substituted (C1-6)alkyl.

109. The compound of any one of claims 99 to 108, wherein the A ring is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4- piperidinyl, and optionally substituted cyclohexyl.

110. The compound of any one of claims 95 to 109, wherein: R4is selected from any one of Formulae 4A-4M:(4J), (4K), (4L), and (4M), wherein,Atty. Docket No.: 39953-58778 (002WO) X1is O, CH2, or C(R26)2; X12is CH2, C(R15)2, O, NCOR25, or NR25; X14is O, NCOR43, or NR43; X2, X6, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, X4, X5, X7and X8are each independently selected from N and CR26; each R15-R20and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R21and R22are each independently optionally substituted C1-6alkyl; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R25is H, or optionally substituted (C1-6)alkyl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R27and R28are each independently H, or optionally substituted (C1-6)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently an integer from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; andAtty. Docket No.: 39953-58778 (002WO) R6is selected from:Y11is selected from O, S, CH2, CHR11, C(R11)2, and NR9; R9is H, optionally substituted (C1-6)alkyl, -L2-Z, or Z; each R11is independently selected from -L2-Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylcarbonyloxy, hydroxyl, halogen, and CN; k is 0 or 1; n is an integer from 0 to 9. Y6-Y10groups are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; and each R12is independently selected from H, optionally substituted alkyl, halogen, and CN.

111. The compound of claim 110, wherein R4is selected from Table 1.

112. The compound of claim 110, wherein R6is selected from Table 2.

113. The compound of any one of claims 95 to 112, wherein the compound is of Formula (IA):, or a pharmaceutically acceptable salt thereof.Atty. Docket No.: 39953-58778 (002WO) 114. The compound of claim 113, wherein the compound is of Formula IV: or a pharmaceutically acceptableY6, Y7, Y9, and Y10are independently selected from CR12and N, wherein at least two of Y6, Y7, Y9, and Y10are CR12; and each R12is independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxy, hydroxyl, halogen, and CN.

115. The compound of claim 114, wherein Y6, Y7, Y9, and Y10are each independently CH or CR12and the compound is of Formula V:or a pharmaceutically acceptable salt thereof, wherein m is an integer from 0 to 4.

116. The compound of claim 115, wherein the compound is of Formula VIA:or a pharmaceutically acceptable salt thereof.

117. The compound of(Z1B) or (Z1C), wherein:Atty. Docket No.: 39953-58778 (002WO) R8is (C1-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.

118. The compound of claim 116 or 117, wherein the compound is of Formula VIIA:or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl or optionally substituted -C(=O)C1-6 alkyl; X11is O or NH; R41is R8or N(R9)R10; R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; and R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

119. The compound of claim 118, wherein the compound is of Formula VIIIA:(VIIIA) or a pharmaceutically acceptable salt thereof, wherein: R25is optionally substituted (C1-6)alkyl;Atty. Docket No.: 39953-58778 (002WO) R18is H, halogen, optionally substituted (C1-6)alkyl, or optionally substituted (C1- 6)alkoxy; and R12is H, halogen, optionally substituted (C1-6)alkyl or optionally substituted (C1- 6)alkoxy.

120. The compound of any one of claims 118 to 119, wherein R25is selected from methyl, ethyl, propyl, isopropyl, isobutyl, isopentyl, and substituted versions thereof.

121. The compound of any one of claims 118 to 120, wherein R25is of structure:wherein R33– R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

122. The compound of claim 121, wherein R35is OH.

123. The compound of claim 122, wherein R25is:

124. The compound of any one of claims 118 to 123, wherein R41is R8.

125. The compound of claim 124, wherein R8is (C1-6)alkyl.

126. The compound of claim 124, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

127. The compound of claim 126, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.

128. The compound of any one of claims 118 to 123, wherein R41is N(R9)R10.

129. The compound of claim 128, wherein R41is NH2 or -NH(C1-6)alkylAtty. Docket No.: 39953-58778 (002WO) 130. The compound of any one of claims 117 to 129, wherein X11is O.

131. The compound of any one of claims 117 to 129, wherein X11is NH.

132. The compound of claim 115, wherein the compound is of Formula VIB:or a pharmaceutically m an from 0 to 4.

133. The compound of claim 132, wherein the compound is of Formula VIIB:. or a pharmaceutically acceptable salt thereof, wherein: each R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R25is H, or optionally substituted (C1-6)alkyl; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; and y is 0, 1, 2, or 3.Atty. Docket No.: 39953-58778 (002WO) 134. The compound of claim 133, wherein the compound is of Formula VIIIB:or a pharmaceutically 135. The compound of claim 133 or 134, wherein the compound is of Formula IX:or a pharmaceutically acceptable salt thereof.

136. The compound of any one of claims 133 to 135 wherein R12is H, halogen, optionally substituted (C1-6)alkyl or optionally substituted (C1-6)alkoxy.

137. The compound of claim 136, wherein R12is H.

138. The compound of claim 136, wherein R12is (C1-6)alkyl.

139. The compound of claim 138, wherein R12is methyl.

140. The compound of claim 136, wherein R12is halogen.

141. The compound of claim 136, wherein R12is (C1-6)alkoxy.

142. The compound of claim 141, wherein R12is methoxy.Atty. Docket No.: 39953-58778 (002WO) 143. The compound of any one of claims 133 to 142, wherein R29and R30are each independently optionally substituted (C1-6)alkyl.

144. The compound of claim 143, wherein R29and R30are each independently (C1-3)alkyl.

145. The compound of claim 144, wherein R29and R30are each methyl.

146. The compound of claim 144, wherein R29and R30are each ethyl.

147. The compound of any one of claims 133 to 142, wherein R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group.

148. The compound of claim 147, wherein the optionally substituted spirocyclic group is spirocyclopropyl or spirocyclobutyl.

149. The compound of any one of claims 133 to 148, wherein R41is R8.

150. The compound of claim 149, wherein R8is (C1-6)alkyl.

151. The compound of claim 149, wherein R8is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

152. The compound of claim 151, wherein R8is (C3-4)cycloalkyl or (C2-4)heterocyclyl.

153. The compound of any one of claims 133 to 148, wherein R41is N(R9)R10.

154. The compound of claim 153, wherein R41is NH2 or NH-(C1-6)alkyl.

155. The compound of any one of claims 133 to 154, wherein X11is O.

156. The compound of any one of claims 133 to 154, wherein X11is NH.Atty. Docket No.: 39953-58778 (002WO) 157. The compound of claim 113, wherein the compound is of Formula X: or a pharmaceutically acceptableeach R11is independently selected from optionally substituted alkyl, optionally substituted alkoxy, halogen, OH, and CN; and n is an integer from 0 to 9.

158. The compound of claim 157, wherein R4is selected from:, wherein: X2, X9and X10are each independently selected from NR25, C(R26)2, C=O, O and S; X3, and X4are each independently selected from N and CR26; X12is CH2, CHR42, C(R42)2, NCOR43, or NR43; each R15, R18, and R24is an optional substituent independently selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R23is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and CN; R29and R30are each independently H, or optionally substituted (C1-6)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., optionally substituted spirocyclopropyl or spirocyclobutyl);Atty. Docket No.: 39953-58778 (002WO) R42is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; R43is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 r is 0 or 1; and v and y are each independently an integer from 0 to 3.

159. The compound of claim 157 or 158, wherein the compound is of Formula XI:or a pharmaceutically acceptable salt thereof.

160. The compound of claim 159, wherein: X12is CHR42; and R42is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

161. The compound of claim 160, wherein: R42is -C(=O)R42a, -C(=O)NHR42a, -NHC(=O)R42a, wherein R42ais H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, or optionally substituted aryl; R42is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; orAtty. Docket No.: 39953-58778 (002WO) R42is optionally substituted –(CH2)zcycloalkyl, optionally substituted – (CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted – (CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

162. The compound of claim 159, wherein: X12is NR43; and R43is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

163. The compound of claim 161, wherein: R43is optionally substituted -C(=O)C1-6 alkyl, optionally substituted - C(=O)cycloalkyl, optionally substituted -C(=O)heterocycle, optionally substituted - C(=O)heteroaryl or optionally substituted -C(=O)aryl; R43is optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; or R43is optionally substituted –(CH2)zcycloalkyl, optionally substituted – (CH2)zheterocycle, optionally substituted –(CH2)zheteroaryl or optionally substituted – (CH2)zaryl, wherein z is 1, 2, 3, 4 or 5.

164. The compound of any one of claims 157 to 163, wherein Z is of the formula:, wherein: R8is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X11is O, or NH.Atty. Docket No.: 39953-58778 (002WO) 165. The compound of any one of claims 1-164, wherein the compound is selected from any one of compounds 1-965 and the compounds of Tables 3 to 15, or a pharmaceutically acceptable salt thereof.

166. A pharmaceutical composition comprising a compound of any one of claims 1 to 165 and a pharmaceutically acceptable excipient.

167. A method of inhibiting cyclin-dependent kinase (CDK), the method comprising contacting a biological sample containing a CDK with an amount of a compound of any one of claims 1 to 165 effective to inhibit the CDK.

168. A method of inhibiting CDK in a subject, comprising administering to a subject a compound of any one of claims 1 to 165, or a pharmaceutical composition according to claim 166, to inhibit CDK in the subject.

169. The method of claim 167 or 168, wherein the CDK is CDK2.

170. The method of claim 167 or 168, wherein the CDK is CDK4.

171. A method of treating a disease or disorder associated with CDK2 in a subject, the method comprising administering to a subject in need thereof a dose of a compound of any one of claims 1 to 165, or a pharmaceutical composition of claim 166.

172. The method of claim 171, wherein the disease or disorder associated with CDK2 is cancer.

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