CDK2 inhibitor compounds

Abstract

The present disclosure provides CDK2 inhibitor compounds that can have a fused 6-6 bicyclic core, such as a naphthyridine, quinazoline, pyridopyrimidine or related isosteric core structure that is further substituted. Also provided herein are pharmaceutical compositions including the subject CDK2 inhibitor compounds, and methods for using compositions of the disclosure as anticancer therapeutics.

Description

Atty. Docket No.: 39953-62353 (008WO)CDK2 INHIBITOR COMPOUNDS1. INTRODUCTION

[0001] Cancer remains a leading cause of death, characterized by uncontrolled cell growth, evasion of cell death, and the ability to invade surrounding tissues. Despite advances of targeted therapies and immunotherapies, treatment options for many cancers remain limited. A promising strategy for cancer therapy is the inhibition of cyclin-dependent kinases (CDKs), key regulators of cell cycle progression.

[0002] CDKs are a family of serine / threonine kinases that control the transition between the different phases of the cell cycle. They function by forming complexes with regulatory proteins known as cyclins, which activate the kinases and enable progression through the cell cycle checkpoints. Dysregulation of CDKs, whether through overexpression of cyclins, loss of CDK inhibitors, or mutations in CDKs themselves, can result in the unchecked cell division that is a characteristic of many cancers.

[0003] CDK2 regulates the Gl-to-S phase transition in the cell cycle. CDK2 is involved in several other cellular processes, including DNA replication and repair, transcription, RNA processing, and cytoskeletal organization, and deregulation of its activity has been observed in a variety of human cancers. The CCNE1 gene produces cyclin E, one of the two key protein binders of CDK2, and its overexpression 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.

[0004] Despite the therapeutic success of certain CDK inhibitors (e.g., CDK4 / 6), challenges remain in expanding their applicability to other types of cancers. There is a need for additional CDK inhibitors, such as CDK2 inhibitors, that can target a broader range of CDK-driven cancer biology, or that can be used in combination with existing therapies to enhance their effectiveness and minimize the risk of resistance. Certain cyclin dependent kinases such as CDK1 are essential to the cell cycle, and their inhibition could lead to unintended side effects. Thus, selective CDK (e.g., CDK2) inhibitors are of interest, but challenging to develop due to the similarity between the active sites of CDK2 and other CDKs, for example CDK1.

[0005] Small molecules that specifically inhibit CDKs offer several advantages over biologic therapies, including better tissue penetration, oral bioavailability, and the potential for targeting multiple CDKs involved in cancer progression. Development of new small-Atty. Docket No.: 39953-62353 (008WO)molecule CDK inhibitors has the potential to fill this therapeutic gap, offering more comprehensive treatment options for cancer patients.

[0006] The present disclosure relates to the discovery and development of novel smallmolecule CDK inhibitors that selectively target key members of the CDK family implicated in cancer. These inhibitors are designed to overcome the limitations of existing therapies, with improved potency, selectivity, and pharmacokinetic properties. The use of these smallmolecule inhibitors can provide a more effective strategy for treating a wide variety of cancers, including those resistant to current therapies.2. SUMMARY

[0007] Provided herein are CDK inhibitor compounds. The CDK inhibitor compounds can have a fused 6-6 bicyclic 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. The CDK inhibitor compounds can be CDK2 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.

[0008] Accordingly, this disclosure includes CDK inhibitor compounds of Formula I:(I)or a pharmaceutically acceptable salt thereof, wherein:Y1is N or CR1;Y2is N or CR2;Y3is N or CR3;Y5is N or CR5;R'-R3 5ancj7areindependently selected from H, optionally substituted (Cn e)al kyl, halo(Ci-6)alkyl, -COR30, -OR30, halogen, and CN, wherein R30is H or optionally substituted (Ci-6)alkyl;Atty. Docket No.: 39953-62353 (008WO)R4is optionally substituted heteroaryl (e.g., optionally substituted fused bicyclic heteroaryl), optionally substituted aryl, or substituted alkynyl; andCY6A / Ris, wherein:a) Y6, Y7, Y9, and Y10are independently CR12or N, wherein at least three of Y6, Y7, Y9, and Y10are CR12,each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, andOKX11v S'V 'Y12Z is ', wherein:X11is selected from O, NH and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2- e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl;orb) Y6, Y9, and Y10are independently CR12or N, wherein at least two of Y6, Y9, and Y10are CR12,Y7is C, and Z and Y7are cyclically linked and together with the carbon atom to which they are attached provide a 4- to 7-membered (e.g., 4-, 5-, 6- or 7- membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, - S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-, wherein each R32is independently H or optionally substituted (Ci-6)alkyl; andeach R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.

[0009] In some embodiments of Formula (I), the compound is of Formula (IA):Atty. Docket No.: 39953-62353 (008WO)RVNX / R4XX RSTY rs T JY RGR7N^NH (IA),or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments of Formula (I), the compound is of Formula (IB):RVNX / R4I YR1X JLR6R7N^NH (IB),or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the CDK inhibitor compounds of Formula (I) are CDK2 inhibitors.3. DETAILED DESCRIPTION

[0012] 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

[0013] 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 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 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. In some embodiments, the CDK inhibitor is a CDK2 inhibitor.Atty. Docket No.: 39953-62353 (008WO)

[0014] The disclosure provides CDK inhibitor compounds of Formula I:(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;L2-ZR6is of the formula, whereinA is a cyclic group selected from 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;R'-R3, R5and R7are independently selected from H, optionally substituted (Ci-6)alkyl, halo(Ci-6)alkyl, -COR30, -OR30, halogen, and CN; andR30is H or optionally substituted (Ci-6)alkyl.

[0015] In some embodiments of the compound of Formula I, one or more of Y'-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.

[0016] 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. InAtty. Docket No.: 39953-62353 (008WO)some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments the heteroaryl is pyridyl, pyridazine, pyrimidine or triazine.

[0017] In some embodiments of the compound of Formula I, R6comprises the structure 6A:wherein:Y6-Y10are 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; andZ is a group as described herein, wherein optionally Z is cyclically linked to an adjacent Y6-Y10to provide a fused 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) carbocyclic or heterocyclic ring.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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 (Ci-3)alkyl, (Ci-3)alkoxy, halogen, and nitrile. In some embodiments, R12is methyl. In some embodiments R12is Cl or F. In some embodiments, R12is nitrile.

[0022] The disclosure provides CDK inhibitor compounds of Formula I:(I)Atty. Docket No.: 39953-62353 (008WO)or a pharmaceutically acceptable salt thereof, wherein:Y1is N or CR1;Y2is N or CR2;Y3is N or CR3;Y5is N or CR5;R'-R R5and R7are independently selected from H, optionally substituted (Cn e)alkyl, halo(Ci-6)alkyl, -COR30, -OR30, halogen, and CN, wherein R30is H or optionally substituted (Ci-6)alkyl;R4is optionally substituted heteroaryl (e.g., optionally substituted fused bicyclic heteroaryl), optionally substituted aryl, or substituted alkynyl; andCY6A / Ris, wherein:a) Y6, Y7, Y9, and Y10are independently CR12or N, wherein at least three of Y6, Y7, Y9, and Y10are CR12,each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, andOKX11v s"V 'Y12Z is ', wherein:X11is selected from O, NH and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2- e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl;orb) Y6, Y9, and Y10are independently CR12or N, wherein at least two of Y6, Y9, and Y10are CR12,Y7is C, and Z and Y7are cyclically linked and together with the carbon atom to which they are attached provide a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-Atty. Docket No.: 39953-62353 (008WO)membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, - S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-, wherein each R32is independently H or optionally substituted (Ci-6)alkyl; andeach R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.

[0023] In some embodiments of the compound of Formula I, R6is of the structure 6A1:(Rl2)m (6A1)wherein m is 0, 1, 2, 3 or 4, and Z and R12are as described herein.

[0024] 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.

[0025] 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 (Ci-3)alkyl, optionally substituted (Ci-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 (Ci-3)alkyl, optionally substituted (Ci-3)alkoxy, hydroxy, halogen, or CN. In some embodiments, m is 2 and each R12is independently selected from optionally substituted (Ci-3)alkyl, optionally substituted (Ci-3)alkoxy, hydroxy, halogen, and CN. In some embodiments, m is 2 and each R12is independently selected from optionally substituted (Ci-3)alkyl, optionally substituted (Ci-3)alkoxy, hydroxy, fluorine, and CN. In some embodiments, m is 1 and R12is selected from optionally substituted (Ci-3)alkyl, optionally substituted (Ci-3)alkoxy, hydroxy, fluorine, and CN. In some embodiments,

[0026] In some embodiments of 6A1, R6is of the structure 6A2:R12(6A2)wherein R12is selected from hydrogen, halogen (e.g., F), optionally substituted (Ci-6)alkyl, and optionally substituted (Ci-6)alkoxy.Atty. Docket No.: 39953-62353 (008WO)

[0027] 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 fluorine. In some embodiments of 6A2, R12is optionally substituted (Ci-3)alkyl. In some embodiments, R12is methyl. In some embodiments, R12is trifluoromethyl. In some embodiments, R12is (Ci-3)alkoxy. In some embodiments, R12is methoxy.

[0028] In some embodiments of 6A1, R6is of the structure 6A2:R12a(6A3)wherein:R12ais selected from halogen (e.g., F), hydroxy, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy and cyano; andR12bis selected from hydrogen, halogen (e.g., F), hydroxy, optionally substituted (Cn e)alkyl, optionally substituted (Ci-6)alkoxy and cyano.

[0029] In some embodiments of 6A3, R12bis hydrogen. In some embodiments of 6A3, R12ais halogen. In some embodiments, R12ais F. In some embodiments, R12ais Cl. In some embodiments of 6A3, R12ais optionally substituted (Ci-3)alkyl. In some embodiments, R12ais methyl. In some embodiments, R12ais trifluoromethyl. In some embodiments, R12ais optionally substituted (Ci-3)alkoxy. In some embodiments, R12ais methoxy.

[0030] In some embodiments of 6A3, R12bis hydrogen. In some embodiments of 6A3, R12bis halogen. In some embodiments, R12bis F. In some embodiments of 6A3, R12bis optionally substituted (Ci-3)alkyl. In some embodiments, R12bis methyl. In some embodiments, R12bis trifluorom ethyl. In some embodiments, R12bis optionally substituted (Ci-3)alkoxy. In some embodiments, R12bis methoxy.

[0031] In some embodiments, R12ais F and R12bis H. In some embodiments, R12ais H and R12bis F. In some embodiments, R12aand R12bare both F. In some embodiments, R12aand R12bare both H.

[0032] 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,Atty. Docket No.: 39953-62353 (008WO)the heterocyclyl includes one or more oxygen atoms. In some embodiments, the heterocyclyl 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-di oxane, thiane, dithiane, morpholine, and thiomorpholine. In some embodiments, the 6-membered heterocyclyl is piperidine. In some embodiments, the heterocyclyl is tetrahydropyran.

[0033] In some embodiments of the compound of Formula I, R6isz(6AA),wherein:Y7and Z are not cyclically linked;Y6, Y7, Y9, and Y10are independently CR12or N, wherein at least three of Y6, Y7, Y9, and Y10are CR12,each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, andO X114 S'V&'YZis12, wherein:X11is selected from O, NH and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl.

[0034] In some embodiments of the compound of Formula I, R6iswherein:X11is selected from O, NH and N(Ci-6)alkyl,Atty. Docket No.: 39953-62353 (008WO)Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl,R10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-8)cycloalkyl, and optionally substituted heterocyclyl, andR12a, R12b, R12C, and R12dare independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.

[0035] In some embodiments, R12ais F and R12bis H. In some embodiments, R12ais H and R12bis F. In some embodiments, R12aand R12bare both F. In some embodiments, R12aand R12bare both H.

[0036] In some embodiments of the compound of Formula I, R6isR12a(6A5) or R12a(6A6).

[0037] In some embodiments of formula (6A4-6A6), X11is O. In some embodiments of formula (6A4-6A6), X11is NH.

[0038] In some embodiments of formula (6A4-6A6), Y12is -NR9R10. In some embodiments of formula (6A4-6A6), Y12is -NH2. In some embodiments of formula (6A4-6A6), Y12is -NR9R10, where R9is H or optionally substituted (Ci-6)alkyl; and R10is optionally substituted (Ci-6)alkyl. In some embodiments, R9is H, and R10is optionally substituted (Ci-3)alkyl (e.g., methyl or ethyl). In some embodiments of formula (6A4-6A6), Y12is -NR9R10, where R9is H, and R10is optionally substituted (C3-8)cycloalkyl. In some embodiments of formula (6A4-6A6), Y12is -NR9R10, where R9is H, and R10is optionally substituted heterocyclyl.

[0039] In some embodiments of formula (6A4-6A6), Y12is (Ci-6)alkyl. In some embodiments of formula (6A4-6A6), Y12is optionally substituted (C3-7)cycloalkyl. In some embodiments of formula (6A4-6A6), Y12is optionally substituted (C2-6)heterocyclyl.

[0040] In some embodiments of formula (6A4-6A6), R12a, R12b, R12c, and R12d, if present, are independently selected from hydrogen, halogen, hydroxy, optionally substituted (Cn e)alkyl, and optionally substituted (Ci-6)alkoxy. In some embodiments of formula (6A4-6A6), R12aand R12bare fluoro. In some embodiments of formula (6A4-6A6), R12ais fluoro and R12bis hydrogen.

[0041] In some embodiments of the compound of Formula I, R6isAtty. Docket No.: 39953-62353 (008WO)(6AA),wherein:Y6, Y9, and Y10are independently CR12or N, wherein at least two of Y6, Y9, and Y10are CR12,Y7is C, and Z and Y7are cyclically linked and together with the carbon atom to which they are attached provide a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, -S(O)2NR32C(O)-, -C(O)NR32-, -OC(O)NR32-, and -C(O)NR32C(O)-, wherein each R32is independently H or optionally substituted (Ci-6)alkyl; andeach R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.

[0042] In some embodiments of the compound of Formula I, R6is(6AA1),wherein:ring B is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, -S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-,R12a, R12b, R12C, and R12dare independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN,m is 0, 1, 2, 3 or 4,each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked to provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused), andR32is H or optionally substituted (Ci-6)alkyl.

[0043] In some embodiments of Formula I, R6is:Atty. Docket No.: 39953-62353 (008WO)R12a(6AA1)wherein ring B is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) heterocyclic ring comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, -S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-.

[0044] In some embodiments of formula (6AA1), ring B is selected from:wherein each of X1, X2, X3, X4and X5is independently selected from S(O)2, S(O)(=NR32), C(O), NH, C(R31)2, CH2 and O, provided that two neighboring X1, X2, X3, X4or X3are not each selected from S(O)2, S(O)(=NR32), and C(O); and two neighboring X1, X2, X3, X4or X5are not each selected from NH and O. In some embodiments, X1is -S(O)2- or -S(O)(=NR32)-. In some embodiments, X1is -S(O)2NR32- or -S(O)(=NR32)NR32-.

[0045] In some embodiments of formula (6AA1), R6iswherein:n is 0, 1, 2, or 3;X11is selected from O, NH and N(Ci-6)alkyl;Y13is NR32, or C(R31)2;each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked to provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused); andR32is H or optionally substituted (Ci-6)alkyl.

[0046] In some embodiments of formula (6AA2), Y13is NR32. In some embodiments of formula (6AA2), Y13is C(R31)2. In some embodiments of formula (6AA2), n is 0. In some embodiments of formula (6AA2), n is 1. In some embodiments of formula (6AA2), n is 2. InAtty. Docket No.: 39953-62353 (008WO)some embodiments of formula (6AA2), X11is O. In some embodiments of formula (6AA2), X11is NH. In some embodiments of formula (6AA2), X11is N(Ci-6)alkyl.

[0047] In some embodiments of formula (6AA2), R6isR12a(6AA3)wherein each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked and together with the carbon atom to which they are attached provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused). In some embodiments of formula (6AA3), each R31is H. In some embodiments of formula (6AA3), X11is O. In some embodiments of formula (6AA3), X11is NH. In some embodiments of formula (6AA3), X11is N(Ci-6)alkyl.

[0048] In some embodiments of formula (6AA3), R6isR12a(6AA5) or R12a(6AA4).

[0049] In some embodiments of formula (6AA3-5), X11is O. In some embodiments of formula (6AA3-5), X11is NH. In some embodiments of formula (6AA3-5), X11is N(Cn 6)alkyl.

[0050] In some embodiments of formula (6AA3-5), R12a, R12b, R12c, and R12d, if present, are independently selected from hydrogen, halogen, hydroxy, optionally substituted (Cn e)alkyl, and optionally substituted (Ci-6)alkoxy. In some embodiments of formula (6AA3-4), R12aand R12bare fluoro. In some embodiments of formula (6AA3-4), R12ais fluoro and R12bis hydrogen.

[0051] In some embodiments of formula (6AA3-4), X11is O, R12ais fluoro and R12bis hydrogen. In some embodiments of formula (6AA3-4), X11is O, R12ais fluoro and R12bis fluoro.

[0052] In some embodiments of formula (6AA3-4), X11is NH, R12ais fluoro and R12bis hydrogen. In some embodiments of formula (6AA3-4), X11is NH, R12ais fluoro and R12bis fluoro.Atty. Docket No.: 39953-62353 (008WO)

[0053] In some embodiments of formula (6AA3-4), X11is N(Ci-6)alkyl, R12ais fluoro and R12bis hydrogen. In some embodiments of formula (6AA3-4), X11is N(Ci-6)alkyl, R12ais fluoro and R12bis fluoro.

[0054] 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.

[0055] In some embodiments of Formula I, R4is optionally substituted alkynyl.

[0056] In some embodiments of Formula I, R4is optionally substituted cycloalkyl.

[0057] In some embodiments of Formula I, R4is optionally substituted cycloalkene.

[0058] In some embodiments of Formula I, R4is optionally substituted heterocyclyl.

[0059] In some embodiments of Formula I, R4is optionally substituted aryl.

[0060] In some embodiments of Formula I, R4is an optionally substituted heteroaryl.

[0061] In some embodiments of Formula I, R4is a monocyclic group.

[0062] 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.

[0063] In some embodiments of Formula I, R4is selected from substituted amine, (C2-Ce)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.

[0064] In some embodiments of Formula I, R4is selected from an optionally substituted amine. In some embodiments, the amine is substituted with two Ci-Ce alkyl groups.

[0065] 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.

[0066] 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.

[0067] 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.Atty. Docket No.: 39953-62353 (008WO)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, R4is optionally substituted oxadiazole. In some embodiments, R4is optionally substituted cyclohexanone.

[0068] In some embodiments of Formula I, R4is of Formula 4A:'qwherein: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 (Ci-e)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; andr is 0 or 1.

[0069] 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 (Ci-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.

[0070] In some embodiments of Formula 4A, r is 0. In some embodiments of Formula 4A, r is 1.Atty. Docket No.: 39953-62353 (008WO)

[0071] In some embodiments of 4A, R4is of formula 4A1:^(R15)q(4A1),wherein R15, q and r are as described herein.

[0072] In some embodiments of 4A1, r is 0. In some embodiments of 4A1, r is 1.

[0073] 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 (Ci-Cs)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.

[0074] In some embodiments of 4A, R4is of formula 4A2:(R\)qA"\ R25 / \ N'R(4A2),wherein:R25is H, or optionally substituted (Ci-e)alkyl; andR15and q are as described herein.

[0075] In some embodiments of 4A2, R25is H. In some embodiments of 4A2, R25is optionally substituted (Ci-3)alkyl.

[0076] 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 (Ci-Cs)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R15is nitrile. In some embodiments, q is 1 and R15is hydroxy.

[0077] In some embodiments of Formula I, R4is of Formula 4B:(R16)sJ(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;Atty. Docket No.: 39953-62353 (008WO)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; ands is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0078] 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.

[0079] 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 (Ci-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R16is nitrile. In some embodiments, q is 1 and R16is hydroxy.

[0080] In some embodiments of Formula I, R4is of Formula 4C:(R17)twherein: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; andu is 0, 1, or 2.

[0081] 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 (Ci-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, t is 1 and R17is nitrile. In some embodiments, t is 1 and R17is hydroxy.

[0082] 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.

[0083] In some embodiments of Formula I, R4is of Formula 4D:(R?)kufVx14k-N / 1(4D),wherein:Atty. Docket No.: 39953-62353 (008WO)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, (Ci-e)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl; andk is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0084] 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;each R18is 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 selected from H, optionally substituted Ci-6 alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl and optionally substituted aryl;each R26is independently selected from H, deuterium, 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; andv is 0, 1, 2, or 3.

[0085] 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 (Ci-3)alkyl. In some embodiments of Formula 4E, X2is S. In some embodiments of Formula 4E, X2is C=O.Atty. Docket No.: 39953-62353 (008WO)

[0086] 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.

[0087] 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 deuterium. In some embodiments, R26is optionally substituted alkyl.

[0088] 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.

[0089] 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 (Ci-3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, v is 1 and R18is (Ci-3)alkyl. In some embodiments, the (Ci-3)alkyl is methyl. In some embodiments, v is 1 and R18is halogen. In some embodiments the halogen is Cl or F.

[0090] In some embodiments of Formula 4E, v is 2, and each R18substituent is independently selected from optionally substituted (Ci-3)alkyl, nitrile, and halogen. In some embodiments, R18is methyl. In some embodiments, R18is trideuteromethyl. In some embodiments, R18is dideuteromethyl. In some embodiments, R18is monodeuteromethyl. In some embodiments, R18is fluoro.

[0091] In some embodiments of Formula 4E, R4is selected from one of the following structures:

[0092] In some embodiments, R26is deuterium. In some embodiments, R18is methyl. In some embodiments, v is 1 or 2 and each R18is independent selected from methyl, trideuteromethyl, and fluorine. In some embodiments, R26is deuterium and v is 1 or 2 and each R18is independent selected from methyl, trideuteromethyl, and fluorine.

[0093] In some embodiments of Formula 4E, R4is selected from:Atty. Docket No.: 39953-62353 (008WO)wherein R25, R18and v are as defined herein.

[0094] In some embodiments of Formula 4E, R4is selected from:wherein R25, R18and v are as defined herein.

[0095] In some embodiments, v is 1 or 2, and each R18is independently selected from methyl, trideuteromethyl, and fluorine.

[0096] In some embodiments of Formula 4E, R4is selected from:wherein R25, R18and v are as defined herein.

[0097] In some embodiments, each R18is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, and halogen.

[0098] In some embodiments of Formula 4E, R4is selected from:p18a p18a R18aL D L ENL Tx>R25, R25, and R25.

[0099] In some embodiments, R18ais selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, and halogen. In some embodiments, R18ais H. In some embodiments, R18ais (Ci-3)alkyl. In some embodiments, R18ais (Ci-3)alkoxy. In some embodiments, R18ais halogen. In some embodiments, R18ais hydroxy.

[0100] In some embodiments, R18ais methyl. In some embodiments, R18ais trideuteromethyl.

[0101] In some embodiments of Formula 4E, R25is H, or optionally substituted alkyl. In some embodiments of Formula 4E, R25is optionally substituted alkyl, such as optionally substituted (Ci-6)alkyl).Atty. Docket No.: 39953-62353 (008WO)

[0102] In some embodiments of Formula 4E, 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 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.

[0103] 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; andg 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.

[0104] In some embodiments of Formula 4E, R25isR35R33R35 / X X R3® V \J™.or,and R33> R37, if present, are independently selected from H, CF3, CHF2, CH2F, CH3, OH, 0CH3, and halogen.

[0105] In some embodiments of Formula 4E, R25is of structure:Atty. Docket No.: 39953-62353 (008WO)

[0106] In some embodiments of Formula 4E, R25is of structure:

[0107] In some embodiments of Formula 4E, R4is:(R18)Vwherein R18and v are as defined herein.

[0108] In some embodiments of Formula 4E, R4is:(R18)V wherein R18and v are as defined herein.

[0109] In some embodiments of Formula 4E, R4is:(R18)V wherein R18and v are as defined herein.

[0110] In some embodiments of Formula 4E, the R4is:(R18)V wherein R18and v are as defined herein.

[0111] In some embodiments of Formula 4E, R4iswhere:Atty. Docket No.: 39953-62353 (008WO)R18ais selected from H, optionally substituted (Ci-3)alkyl, optionally substituted (Cn 3)alkoxy, hydroxy, and halogen;R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; andR12aand R12bare independently selected from hydrogen, halogen (e.g., fluoro), hydroxy, optionally substituted (Ci-3)alkyl, and optionally substituted (Ci-3)alkoxy.

[0112] In some embodiments of formula (4E-1), R12ais fluoro, and R12bis hydrogen or fluoro. In some embodiments of formula (4E-1): R12ais fluoro, and R12bis fluoro. In some embodiments of formula (4E-1): R12ais fluoro, and R12bis hydrogen.

[0113] In some embodiments of Formula (4E-1): R33, R34, and R35are each fluorine, R36is hydroxyl, R37is trifluoromethyl, and R18ais either methyl or trideuteromethyl.

[0114] In some embodiments of formula (4E-1), 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 of formula (4E-1), 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 of formula (4E-1), 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 of formula (4E-1), one or two of R33-R35are CF3. In some embodiments of formula (4E-1), one of R33-R35is CF3. In some embodiments of formula (4E-1), two of R33-R35are CF3. In some embodiments of formula (4E-1), one or two of R33-R35are OH. In some embodiments of formula (4E-1), one of R33-R35is OH. In some embodiments of formula (4E-1), two of R33-R35are OH. In some embodiments of formula (4E-1), one or both of R36-R37are H. In some embodiments of formula (4E-1), R36is H, and R37is selected from CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen. In some embodiments of formula (4E-1), both R36and R37are H.

[0115] In some embodiments of Formula I, R4is of Formula 4F:x9-x™ R30Alr29J<^(R24)yX(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;Atty. Docket No.: 39953-62353 (008WO)R24is 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;R29and R30are each independently H, or optionally substituted Ci-6 alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; andy is 0, 1, 2, or 3.

[0116] 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 (Ci-C3)alkyl. In some embodiments of Formula 4F, X2is S. In some embodiments of Formula 4F, X2is C=O.

[0117] 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 (Ci-C3)alkyl. In some embodiments of Formula 4F, X10is S. In some embodiments of Formula 4F, X10is C=O.

[0118] 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.

[0119] 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 (Ci-C3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, y is 1 and R24is (Ci-C3)alkyl. In some embodiments, y is 1 and R24is halogen. In some embodiments the halogen is Cl or F.

[0120] In some embodiments of Formula 4F, the compound is selected from:wherein R24, R25, R29, R30, and y are as defined herein.Atty. Docket No.: 39953-62353 (008WO)

[0121] In some embodiments of Formula 4F, R29and R30are each independently H, or optionally substituted (Ci-3)alkyl. In some embodiments, one of R29and R30is H, and the other is optionally substituted (Ci-3)alkyl. In some embodiments, both R29and R30are H. In some embodiments, both R29and R30are optionally substituted (Ci-3)alkyl.

[0122] 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.

[0123] In some embodiments of Formula 4F, the compound is selected from:wherein R24, R25, and y are as defined herein.

[0124] In some embodiments of Formula I, R4is of Formula 4G:R21. I«x R(4G),wherein:X8is N or CR26;R21and R22are each independently optionally substituted (Ci-Ce)alkyl; andR26is 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.

[0125] 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.

[0126] In some embodiments of Formula 4G, R21and R22are each a (Ci-Ce)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.

[0127] In some embodiments of Formula 4G, X8is N and R21and R22are each a different Ci-C6alkyl. In some embodiments R21is methyl and R22is isopropyl. In someAtty. Docket No.: 39953-62353 (008WO)embodiments, R21is methyl and R22is ethyl. In some embodiments, R21is methyl and R22is propyl. In some embodiments, R21is methyl and R21is butyl. In some embodiments, R21is methyl and R22is t-butyl.

[0128] 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.

[0129] In some embodiments of any one of Formula I, R4is of Formula 4H:R28N-R270(4H),wherein:R27and R28are each independently H, or optionally substituted (Ci-Ce)alkyl; or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group.

[0130] In some embodiments of Formula 4H, R27is H. In some embodiments R27is optionally substituted (Ci-C6)alkyl. In some embodiments of Formula 4H, R28is H. In some embodiments, R28is optionally substituted (Ci-C6)alkyl. In some embodiments R27and R28are different. In some embodiments, R27and R28are the same.

[0131] 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 41:| - p23S—R(41),wherein:R23is H, optionally substituted (Ci-Ce)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.

[0101] In some embodiments of Formula 41, R23is H. In some embodiments of Formula 41, R23is optionally substituted (Ci-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. InAtty. Docket No.: 39953-62353 (008WO)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.

[0102] In some embodiments, R23is an optionally substituted fused bicyclic heteroaryl group.

[0103] In some embodiments of Formula 41, 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 (Ci-e)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 (Ci-e)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; andx is 0, 1, or 2.

[0104] In some embodiments of Formula 41, R23is of Formula 4FAtty. Docket No.: 39953-62353 (008WO)X9-X™30n V^R29A^(R24)yX(4F).

[0105] In some embodiments of Formula 41, R23is selected from one of the following structures:wherein R24, R25, R29, R30, and y are as defined herein.

[0106] In some embodiments of Formula I, R4iswherein: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 (Ci-e)alkyl;R29and R30are each independently H, or optionally substituted (Ci-e)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkane or heterocycle; andy is 0, 1, 2, or 3.

[0107] In some embodiments, R29and R30are each independently optionally substituted (Ci-6)alkyl. In some embodiments, R29and R30are each independently (Ci-3)alkyl. In some embodiments, R29and R30are each methyl. In some embodiments, R29and R30are each ethyl. In some embodiments, R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., (C3-7)spirocycloalkyl, such as spirocyclopropyl).

[0108] In some embodiments of Formula I, R4is of any one of Formulae 4J-4L:Atty. Docket No.: 39953-62353 (008WO)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; andw is 0 to 4.

[0109] 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.

[0110] 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 (Ci-C3)alkyl, optionally substituted (Ci-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-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.

[0111] 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 optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R26is nitrile. In some embodiments, R26is amino. In some embodiments, R26is hydroxy.

[0112] 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 (Ci-C3)alkyl, optionally substituted (Ci-C3)alkoxy, amino, hydroxy, halogen, and nitrile. In some embodiments, w is 1 and R19is C1-C3 alkyl.Atty. Docket No.: 39953-62353 (008WO)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-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.

[0113] 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.

[0114] 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 (Ci-C3)alkyl, optionally substituted (Ci-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-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.

[0115] In some embodiments of Formula I, R4is of Formula 4M:(R20)x / - / x7* x6(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 Ci-Ce alkyl;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; andx is 0, 1, or 2.Atty. Docket No.: 39953-62353 (008WO)

[0116] 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-C3 alkyl. In some embodiments of Formula 4M, X2is S.

[0117] 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.

[0118] In some embodiments of Formula 4M, X6is NR25and X7is CR26. In some embodiments of Formula 4M, X2is S and X7is N.

[0119] 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-C3 alkyl.

[0120] In some embodiments of Formula 4M, the compound is:N

[0121] In some embodiments of Formula 4M, the compound is:wherein R25is as defined herein.wherein R24, R25and y are as defined herein.

[0122] 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.

[0123] In some embodiments of Formula I, Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, 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, ZAtty. Docket No.: 39953-62353 (008WO)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.

[0124] In some embodiments of Formula I, Z is alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynyl sulfonyl or heterocyclylsulfonyl. In some embodiments, Z is alkyl sulfonyl. In some embodiments, Z is cycloalkylsulfonyl. In some embodiments, Z is alkenyl sulfonyl. In some embodiments, Z is alkynyl sulfonyl. In some embodiments, Z is heterocyclylsulfonyl.

[0125] In some embodiments of Formula I, Z is alkyl sulfoximine, 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.

[0126] In some embodiments of Formula I, R6comprises one or more linkers (L1and / or L2) that connect the A ring to the core, or to the Z group (e.g., - -A-l Z, -i -A-Z, or -A-L2-Z). In some embodiments, the one or more linkers are optionally substituted (Ci-6)alkylene. In some embodiments, the one or more linkers are independently -CH2-, -(CH₂)₂-, or -(CH₂)₂-. In some embodiments of Formula I, L1and L2are absent. In some embodiments, L1is absent and L2is an optionally substituted (Ci-6)alkylene. In some embodiments, L2is absent and L1is an optionally substituted (Ci-6)alkylene. In some embodiments both L1and L2are optionally substituted (Ci-6)alkylene.

[0127] In some embodiments of Formula I, R6is of the formula

[0128] 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 some 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 y-thiolactone. In some embodiments, Z is a carboxy group. In some embodiments, Z is a hydroxy or a hydroxyalkyl group. In someAtty. Docket No.: 39953-62353 (008WO)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 (Ci-6)alkyl). In some embodiments, Z comprises an optionally substituted thiolactone. In some embodiments the thiolatone is a y-thiolactone.

[0129] In some embodiments of Formula I, -L2-Z or Z is of one of Z1-Z6:^.'Y9R (Zl), O (Z2),V't (Z3), MS R9-"" (Z4),O(Z5), and ^^0H(Z6), wherein:Y9is absent, -O-, -NR9-, -(Ci-6)alkylene-O-, -(Ci-6)alkylene-NR9-;X11is O, orNH;R51is selected from halogen, R8, -NR9R10, (Ci-6)alkyl, (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and substituted versions thereof;R8is (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof;R9is H or optionally substituted (Ci-6)alkyl;R10is H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, optionally substituted heterocyclyl, a sulfone (e.g., of formula Zl), or a thiolactone (e.g., of formula Z2); andR52is H, optionally substituted (Ci-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl;m is 0, 1, or 2; andp, q, s and t are independently 0, 1, 2, 3, 4, 5 or 6.

[0130] In some embodiments of Zl, -L2-Z or Z is of the Formula Zl A:C>,0• / sz'R5\ZIA),wherein:R51is halogen, -NR9R10, optionally substituted (Ci-e)alkyl, or optionally substituted (C2- e)alkenyl.Atty. Docket No.: 39953-62353 (008WO)

[0131] In some embodiments of Z1A, R51is halogen. In some embodiments of Z1A, R51is F. In some embodiments of Z1A, R51is (Ci-6)alkyl. In some embodiments of Z1A, R51is -NR9R10. In some embodiments of Zl A, R51is (C2-e)alkenyl.

[0132] In some embodiments of Zl, -L2-Z or Z is of Formula Z1D:O X11S'r >12V(Z1D),wherein:X11is selected from O, NH, and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-8)cycloalkyl, and optionally substituted heterocyclyl.

[0133] In some embodiments of Formula Z1D, when X11is NH or N(Ci-6)alkyl, the sulfoximino or sulfonamidamido containing group may be present in a chiral form:O. NR’ R’N OV ^.,19 >.,19', or ',where R’ is NH or N(Ci-6)alkyl, and that both chiral forms are meant to be included in the formula and compounds of this disclosure unless explicitly indicated otherwise.

[0134] In some embodiments of Zl, -L2-Z or Z is of the Formula Z1B:x°(Z1B),wherein:X11is O, or NH; andR8is (Ci-6)alkyl (e.g., (Ck,,)cycloalkyl). (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof.

[0135] In some embodiments of Z1B, X11is O. In some embodiments of Z1B, X11is NH. In some embodiments of Z1B, R8is (Ci-6)alkyl. In some embodiments of Z1B, R8is methyl. In some embodiments of Z1B, R8is (C2-e)alkenyl. In some embodiments of Z1B, R8is -CH=CH2 or -C(CH3)=CH2. In some embodiments of Z1B, R8is (C2-e)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 optionallyAtty. Docket No.: 39953-62353 (008WO)substituted (C3-7)heterocyclyl. In some embodiments of Z1B, R8is R8is (C3-4)cycloalkyl. In some embodiments of Z1B, R8is (C2-4)heterocyclyl.

[0136] In some embodiments of Z1B, X11is NH, R8is (Ci-6)alkyl. In some embodiments of Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Z1B, X11is NH, and R8is heterocyclyl.

[0137] In some embodiments of Z1B, X11is O, R8is (Ci-6)alkyl. In some embodiments of Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Z1B, X11is O, and R8is heterocyclyl.

[0138] In some embodiments of Zl, -L2-Z or Z is of the Formula Z1C:x;izo_ ozD10YS'N'RR9(Z1C),wherein:X11is O, orNH;R9is H or optionally substituted (Ci-6)alkyl; andR10is H, optionally substituted (Ci-6)alkyl, optionally substituted (Cs-slcycloalkyl, optionally substituted heterocyclyl.

[0139] 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 (Ci-6)alkyl. In some embodiments of Z1C, R10is H. In some embodiments of Z1C, R10is (Ci-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 (Ci-6)alkyl. In some embodiments of Z1C, R9is H, and R10H.

[0140] In some embodiments of Z1C, X11is NH, R9is H and R10is (Ci-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.

[0141] In some embodiments of Z1C, X11is O, R9is H and R10is (Ci-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.

[0142] In some embodiments of Z4, -L2-Z or Z is of the Formula Z4A:OkS-R,°R9(Z4A),wherein:Atty. Docket No.: 39953-62353 (008WO)R9is H; andR10is -SO2R38; andR38is optionally substituted alkyl, or amino.

[0143] In some embodiments of Z4A, R38is (Ci-6)alkyl. In some embodiments of Z4A, R18is methyl. In some embodiments of Z4A, R38is ethyl.

[0144] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z4B:O\AN-R’“R9(Z4B),wherein:R9is H; andR10is -SO2R38wherein R38is optionally substituted alkenyl, orR10is optionally substituted thiolactone.

[0145] 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 y-thiolactone.

[0146] In some embodiments Z4B is of the Formula Z4C:wherein m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0147] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z2:(r^\0(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.

[0148] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z3:O(Z3)wherein:Atty. Docket No.: 39953-62353 (008WO)R52is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; andt is 0, 1, or 2.

[0149] In some embodiments of Z3, R52is (Ci-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 embodiments, R52is:O

[0150] In some embodiments of Z3, t is 1. In some embodiments of Z3, t is 2. In some embodiments of Z3, t is 0.

[0151] In some embodiments, Z3 is of the Formula Z3 A:O, R520(Z3A),wherein R52is H.

[0152] In some embodiments of Formula I, -L2-Z or Z is of the Formula Z5:wherein q is 0, 1, or 2.

[0153] In some embodiments of Z5, q is 0. In some embodiments of Z5, q is 1. In some embodiments of Z5, q is 2.

[0154] 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.

[0155] In some embodiments of Formula I, -L2-Z or Z is a non-electrophilic hydrophilic group.

[0156] In some embodiments, of Formula I, Z is a non-electrophilic hydrophilic group of the formula Zl, wherein R51is optionally substituted alkyl or amino. In some embodiments, Z is Zl, and R51is amino. In some embodiments, Z is Zl and R51is optionally substitutedAtty. Docket No.: 39953-62353 (008WO)alkyl. As such, in some embodiments of Formula I, Z is an alkylsulfone. In some embodiments, Z is an alkylsulfone of Formula Z1D:53VSORX(Z1D)wherein R53is H or optionally substituted Ci-Ce alkyl. In some embodiments of Z1D, R53is H. In some embodiments of Z1D, R13is C1-C3 alkyl.

[0157] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z4, wherein;R9is H; andR10is of the formula -SO2R38; andR38is optionally substituted alkyl, or amino.

[0158] 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.

[0159] 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.

[0160] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of formula Z3, where R52is H (i.e., Z is -CO2H).

[0161] In some embodiments of Formula I, Z is an electrophilic reactive hydrophilic group.

[0162] In some embodiments, of Formula I, Z is an electrophilic reactive hydrophilic group of the formula Zl, wherein R51is optionally substituted (C2-e)alkenyl. As such, in some embodiments of Formula I, Z is an alkenyl sulfone (e.g., a vinylsulfone). In some embodiments, Z is an alkenyl sulfone of Formula Z1E:wherein R14is H or optionally substituted (Ci-6)alkyl. In some embodiments of Z1E, R14is H. In some embodiments of Z1E, R14is optionally substituted C1-C3 alkyl.

[0163] 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 someAtty. Docket No.: 39953-62353 (008WO)cases, R38is -CH=CH2. In some embodiments, Z is a carboxamide of Formula Z4, R10is thiolactone. In some embodiments, Z is of Formula Z4C.

[0164] 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.

[0165] In some embodiments of Formula I, Z is of Formula Z1 A, where R51is halogen. In some embodiments, R51is F.

[0166] In some embodiments of Formula I, Z is of Formula Z3, wherein R52is optionally substituted (Ci-6)alkyl or a heterocyclyl. In some embodiments, Z is of Formula Z3, where R52is a heterocycle. In some embodiments, R52is:O

[0167] In some embodiments of the compound of Formula I, two or more of Y'-Y3are CR1, CR2and CR3respectively. In some embodiments of the compound of Formula I, Y^Y3are CR1, CR2and CR3respectively. In some embodiments, each of R'-R3are H. In some embodiments, at least one of R'-R3isnot 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 Ci-6 alkyl.

[0168] In some embodiments of the compound of Formula I, Y3is N. In some embodiments of the compound of Formula I, Y3is CR3.

[0169] 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.

[0170] 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.

[0171] In some embodiments of Formula I, Y5is N.Atty. Docket No.: 39953-62353 (008WO)

[0172] 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.

[0173] 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.

[0174] In some embodiments of Formula I, Y1is N.

[0175] In some embodiments of Formula I, Y2is CR2. In some embodiments, R2is selected from H, CH3, CF3, - CHF2, -CH2CI, 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 -CH2CI. 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, where z is 2. In some embodiments, R2is -(CH2)ZOH, where z is 3. In some embodiments, R2is H.

[0176] In some embodiments of Formula I, Y2is N.

[0177] In some embodiments of Formula I, the compound is of Formula IA:RVNX / R4XX R5\ YR7V 'AH (IA)or a pharmaceutically acceptable salt thereof, where R1, R2, R4, R5, R6and R7are as defined herein.

[0178] In some embodiments of Formula I, the compound is of Formula IB:RVNX / R4R1I TX> JL R6R7N^NH (IB)or a pharmaceutically acceptable salt thereof, where R1, R2, R4, R6and R7are as defined herein.

[0179] In some embodiments of Formula I, the compound is of Formula IC:Atty. Docket No.: 39953-62353 (008WO)R3XX R67irx Y JI R®R7N^NH (IQor a pharmaceutically acceptable salt thereof, where R1- R7are as defined herein.

[0180] In some embodiments of Formula I, the compound is of Formula ID:R3I IR1is. JL 06R7N^NH (ID)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 IE:or a pharmaceutically acceptable salt thereof, where R2- R7are as defined herein.

[0182] 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.

[0183] In some embodiments of Formula I, the compound is of Formula IG:Atty. Docket No.: 39953-62353 (008WO)R2^N^R4R7X NI^N R6H (IG)or a pharmaceutically acceptable salt thereof, where R2, R4, R5, R6and R7are as defined herein.

[0184] In some embodiments of Formula I, the compound is of Formula IH:RI / N^ R4l\LNJiR6R7N^NH (IH)or a pharmaceutically acceptable salt thereof, where R2, R4, R6and R7are as defined herein.

[0185] In some embodiments of Formula I, the compound is of Formula IJ:R1H(U)or a pharmaceutically acceptable salt thereof, where R1, R4, R5, R6and R7are as defined herein.

[0186] In some embodiments of Formula I, the compound is of Formula IK:(IK)or a pharmaceutically acceptable salt thereof, where R1, R4, R6and R7are as defined herein.

[0187] In some embodiments of Formula I, the compound is of Formula IL:Atty. Docket No.: 39953-62353 (008WO)R3N-V*4R1' T J¥LR5R6R7N^NH (IL)or a pharmaceutically acceptable salt thereof, where R1, R3, R4, R5, R6and R7are as defined herein.

[0188] 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.

[0189] In some embodiments of Formula I, the compound is of Formula IA.

[0190] In some embodiments of Formula I, the compound is of Formula IB.

[0191] In some embodiments of Formula I, or any one of Formulae IA-IM, ring A is as defined herein.

[0192] 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.

[0193] In some embodiments of Formula I, IA, or IC, R1, R2, R5and R7are each H.

[0194] In some embodiments of any one of Formula I or Formulae IA-IM, R6is selected from:wherein:Atty. Docket No.: 39953-62353 (008WO)R8is optionally substituted (Ci-6)alkyl, optionally substituted (C2-e)alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;R9is H or optionally substituted (Ci-6)alkyl;R10is a sulfone or a thiolactone;R52is H, optionally substituted (Ci-6)alkyl, or optionally substituted heterocyclyl; R55is H, optionally substituted (Ci-6)alkyl; andm is an integer from 0 to 2.

[0195] In some embodiments of any one of Formula I or Formulae IA-IM, R6iswherein:X11is selected from O, NH and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl.

[0196] 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 (Ci-6)alkyl. In some embodiments, R8is -CH3 or -CH2-R13, and R13is optionally substituted (Ci-6)alkyl. In some embodiments of 6C, R8is optionally substituted (C2-e)alkenyl. In some embodiments of 6C, R8is -CH=CH2 or -CH=CH-R14, and R14is optionally substituted (Ci-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 6C, R8is optionally substituted (C2-6)heterocyclyl. In some embodiments of 6C, R8is (C2-4)heterocyclyl.

[0197] 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 (Ci-6)alkyl. In some embodiments, R8is -CH3 or -CH2-R13, and R13is optionally substituted (Ci-6)alkyl. In some embodiments of 6D, R8is optionally substituted (C2-e)alkenyl. In some embodiments of 6D, R8is -CH=CH2 or -CH=CH-R14, and R14is optionally substituted (Ci-6)alkyl. In some embodiments of 6D, R8is optionally substituted (C3-7)cycloalkyl. In some embodiments ofAtty. Docket No.: 39953-62353 (008WO)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.

[0198] 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 (Cn e)alkyl.

[0199] 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 (Cn e)alkyl.

[0200] 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.

[0201] 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.

[0202] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 61. In some embodiments of 61, R52is H. In some embodiments of 61, R52is optionally substituted (Ci-6)alkyl. In some embodiments, R52is -CH3 or -CH2-R13, and R13is optionally substituted (Ci-6)alkyl. In some embodiments of 61, R52is optionally substituted (C2-6)heterocyclyl. In some embodiments of 61, R52is (C2-4)heterocyclyl.

[0203] In some embodiments of any one of Formula I or Formulae IA-IM, R6is of Formula 6J. In some embodiments of 6J, Y12is optionally substituted (Ci-6)alkyl. In some embodiments, Y12is -NR9R10. In some embodiments of 6J, Y12is optionally substituted (C3- 7)cycloalkyl. In some embodiments of 6J, R8is (C3-4)cycloalkyl. In some embodiments of 6J, Y12is optionally substituted (C2-6)heterocyclyl. In some embodiments of 6J, Y12is (C2-4)heterocyclyl.

[0204] In some embodiments of any one of 6C-6J, the A ring is selected from optionally substituted phenyl, optionally substituted pyridyl. In some embodiments of any one of 6C-6J, the A ring is optionally substituted phenyl. In some embodiments of 6C-6J, the A ring is optionally substituted pyridyl.

[0205] In some embodiments of any one of Formula I or Formulae IA-IM, R4is selected from any one of Formulae 4A-4M:Atty. Docket No.: 39953-62353 (008WO)R28R21N-R27v8 _ o22 r?23X R(4G), O (4H), § —R(41),wherein,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 Ci-6 alkyl;R23is H, optionally substituted Ci-6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl;R25is H, or optionally substituted Ci-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 (Ci-e)alkyl, or R27and R28together with the nitrogen atom to which they are attached form an optionally substituted cyclic group;Atty. Docket No.: 39953-62353 (008WO)R29and R30are each independently H, or optionally substituted Ci-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; andx is 0, 1, or 2; andR6is selected from:wherein:Y6-Y10groups are independently selected from C-Z, CR12or N, wherein one of Y6-Y10is C-Z; andeach R12is independently selected from H, optionally substituted alkyl, halogen, and CN.

[0206] In some embodiments of any one of Formula I or Formulae IA-IM, R4is selected from any one of Formulae 4A-4M:R28R21N-R27y i 8 _ o22 -M > p23X R(4G), O (4H),? —R(41),Atty. Docket No.: 39953-62353 (008WO)wherein,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 Ci-6 alkyl;R23is H, optionally substituted Ci-6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl;R25is H, or optionally substituted Ci-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 (Ci-e)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 Ci-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;Atty. Docket No.: 39953-62353 (008WO)v and y are each independently an integer from 0 to 3;w is 0, 1, 2, 3, or 4; andx is 0, 1, or 2; and7TYR6is J ' * / (6AA), wherein:a) Y6, Y7, Y9, and Y10are independently CR12or N, wherein at least three of Y6, Y7, Y9, and Y10are CR12,each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, andO X114 S'V&'YZis12, wherein:X11is selected from O, NH and N(Ci-6)alkyl,Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2- e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,R9is H or optionally substituted (Ci-6)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl;orb) Y6, Y9, and Y10are independently CR12or N, wherein at least two of Y6, Y9, and Y10are CR12,Y7is C, and Z and Y7are cyclically linked and together with the carbon atom to which they are attached provide a 4- to 7-membered (e.g., 4-, 5-, 6- or 7- membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, - S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-, wherein each R32is independently H or optionally substituted (Ci-6)alkyl; andeach R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.Atty. Docket No.: 39953-62353 (008WO)

[0207] In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4A, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4B, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4C, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4D, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4E, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4F, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4G, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4H, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4I, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4J, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4K, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4L, and R6is of Formula 6A or 6AA. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4M, and R6is of Formula 6A or 6AA.

[0208] 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 ofAtty. Docket No.: 39953-62353 (008WO)Formula 6B. In some embodiments of any one of Formula I or Formulae IA-IM, R4is of Formula 4M, and R6is of Formula 6B.

[0209] In some embodiments of any one of Formula I or Formulae IA-IM, R4is selected from Table 1.Table 1: Example R4groupsComprising Example structureAlkyl / Alkenyl NOHAmine1 I CJ IY N vV I Y^H0'ZP Alkynyl==—H I-— 1 VOH, _ 05 - YCN5 YV 'NH25' — ' OCH350 \ / 1 / OHHN / < Et 1 JL ( T >0 II '\5 5 5 0 0 0HN^\ HN" A „ HN~A■j V7 "l V°H7 x\JOX25 5 10HN^T HN^j°Me0If J £ J X JL >° 1H5 5 5Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)

[0210] In some embodiments of any one of Formula I or Formulae IA-IM, R6is selected from Table 2Table 2: Exemplary R6groupsComprising: Exemplary structureAryl9 / OA^NH2OVJ 9Jf y o rj o jQpo yyjjOKOxX_ 0 Y\o V'A II • >o\\ JL1 1 HN '' / P ■'—J9 HN P '9[ |j NH | H NH JL J0Ji J5 5F5F5Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)F F F FF F FAtty. Docket No.: 39953-62353 (008WO)CH3S \\=NHoheteroaryl

[0211] 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.

[0212] 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.

[0213] 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 C1-3 alkyl, halogen, and nitrile. In some embodiments, R12is methyl. In some embodiments R12is Cl or F. In some embodiments, R12is nitrile.Atty. Docket No.: 39953-62353 (008WO)

[0214] 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.

[0215] In some embodiments, of Formula IIB, one or more of Y'-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.

[0216] In some embodiments of the compound of Formula IIB, two or more of Y'-Y3are CR1, CR2and CR3respectively. In some embodiments of the compound of Formula IIB, Y1-Y3are CR1, CR2and CR3respectively. In some embodiments, each of R'-R3are H. In some embodiments, at least one of R'-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 Ci-6 alkyl.

[0217] 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.

[0218] In some embodiments of Formula IIB, Y5is CR5. In some embodiments, R5is H.

[0219] In some embodiments of Formula IIB, Y5is N.

[0220] In some embodiments of Formula IIB, the compound is of the Formula IIIB:H(IIIB),wherein R1, R2, Y5, R4and Z are as defined herein.

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

[0222] In some embodiments of Formula IIB-IIIB, R4is of any one of Formulae 4A-4M. In some embodiments, R4is selected from Table 1.

[0223] In some embodiments of Formula IIB-IIIB, Z is of any one of Formulae Z1-Z6.

[0224] In some embodiments of Formula I, the compound is of Formula IA, or a pharmaceutically acceptable salt thereof.Atty. Docket No.: 39953-62353 (008WO)

[0225] In some embodiments of Formula IA, the compound is of Formula IVA or IVB: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 (Ci-6)alkyl, hydroxyl, halogen, and CN; andR1, R2, R4, R5, R7, and Z are as defined herein.

[0226] In some embodiments of Formula IVA-B, Y6, Y7, Y9and Y10are each CR12. In some embodiments of Formula IVA-B, each R12is H. In some embodiments of Formula IVA-B, at least one R12is not H. In some embodiments of Formula IVA-B, at least one R12is selected from C1-3 alkyl, halogen, and nitrile. In some embodiments of Formula IVA-B, at least one R12is methyl. In some embodiments of Formula IVA-B, at least one R12is Cl or F. In some embodiments of Formula IVA-B, at least one R12is nitrile.

[0227] In some embodiments of Formula IVA-B, at least one of Y6, Y7, Y9or Y10is N. In some cases of Formula IVA-B, Y6or Y10is N. In some cases of Formula IVA-B, both Y6and Y10are N. In some cases of Formula IVA-B, Y7or Y9is N. In some cases of Formula IVA-B, both Y7and Y9are N.

[0228] In some embodiments of Formula IVA-B, Y6, Y7, Y9, and Y10are each independently CH or CR12and the compound is of the formula VA or VB:or a pharmaceutically acceptable salt thereof,wherein m is 0, 1, 2, 3, or 4.

[0229] In some embodiments of Formula IVA-VB, R4is of any one of Formulae 4A-4M. In some embodiments of Formula IVA-VB, R4is selected from a group of Table 1.

[0230] In some embodiments, the compound of Formula VA or VB is of the Formula VIA or VIB:Atty. Docket No.: 39953-62353 (008WO)or a pharmaceutically acceptable salt thereof,wherein R1, R2, R5, R7, R12, R18, X2, X3, X4, Z, m, and v are as defined herein.

[0231] In some embodiments of Formula VIA-B, X2is C(R26)2. In some embodiments of Formula VIA-B, each R26is H. In some embodiments of Formula VIA-B, at least one R26group is optionally substituted alkyl. In some embodiments of Formula VIA-B, X2is O. In some embodiments of Formula VIA-B, X2is NR25. In some embodiments of Formula VIA-B, R25is H. In some embodiments of Formula VIA-B, R25is (Ci-C3)alkyl. In some embodiments of Formula VIA-B, X2is S. In some embodiments of Formula VIA-B, X2is C=O.

[0232] In some embodiments of Formula VIA-B, X3is N. In some embodiments of Formula VIA-B, X3is CR26. In some embodiments of Formula VIA-B, R26is H. In some embodiments of Formula VIA-B, R26is optionally substituted alkyl.

[0233] In some embodiments of Formula VIA-B, X4is N. In some embodiments of Formula VIA-B, X4is CR26. In some embodiments of Formula VIA-B, R26is H. In some embodiments of Formula VIA-B, R26is optionally substituted alkyl.

[0234] In some embodiments of Formula VIA-B, X2is NR25, X3is CR26and X4is CR26. In some embodiments of Formula VIA-B, X2is NR25, X3is N and X4is CR26. In some embodiments of Formula VIA-B, X2is O, X3is CR26and X4is N.

[0235] In some embodiments of Formula VIA-B, R4is selected from one of the following structures:R25R25

[0236] In some embodiments of Formula VIA-B, R4is selected from:Atty. Docket No.: 39953-62353 (008WO)wherein R25, R18and v are as defined herein.

[0237] In some embodiments of Formula VIA-B, R4is selected from:wherein R25, R18and v are as defined herein.

[0238] In some embodiments of Formula VIA-B, R4is selected from:wherein R25, R18and v are as defined herein.

[0239] In some embodiments of any one of Formulae IVA-VIB, Z is of any one of Formulae Z1-Z6.

[0240] In some embodiments of any one of Formulae IVA-VIB, Z is of Formulae ZIB or Z1Cx11oxV / ° v^*10K(ZIB) or R9(Z1C), wherein X11, R8, R9, and R10are as defined herein.R8is (Ci-6)alkyl, (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof;R9is H or optionally substituted (Ci-6)alkyl;R10is H, optionally substituted (Ci-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; andX11is O, orNH.

[0241] In some embodiments of Formula VIA-B, Z is Z1C, and X11is O. In some embodiments of Formula VIA-B, Z is Z1C, and X11is NH. In some embodiments of Formula VIA-B, Z is Z1C, and R9is H. In some embodiments of Formula VIA-B, Z is Z1C, and R9is (Ci-6)alkyl. In some embodiments of Formula VIA-B, Z is Z1C, and R10is H. InAtty. Docket No.: 39953-62353 (008WO)some embodiments of Formula VIA-B, Z is Z1C, and R10is (Ci-6)alkyl. In some embodiments of Formula VIA-B, Z is Z1C, and R10is optionally substituted cycloalkyl. In some embodiments of Formula VIA-B, Z is Z1C, and R10is optionally substituted heterocyclyl. In some embodiments of Formula VIA-B, Z is Z1C, R9is H, and R10is (Cn e)alkyl. In some embodiments of Formula VIA-B, Z is Z1C, R9is H, and R10H.

[0242] In some embodiments of Formula VIA-B, Z is Z1C, X11is NH, R9is H and R10is (Ci-6)alkyl. In some embodiments of Formula VIA-B, Z is Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Formula VIA-B, Z is Z1C, X11is NH, R9is H and R10is ethyl.

[0243] In some embodiments of Formula VIA-B, Z is Z1C, X11is O, R9is H and R10is (Ci-6)alkyl. In some embodiments of Formula VIA-B, Z is Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Formula VIA-B, Z is Z1C, X11is O, R9is H and R10is ethyl.

[0244] In some embodiments of Formula VIA-B, Z is of Formula Z1B, and X11is O. In some embodiments of Formula VIA-B, Z is Z1B, and X11is NH. In some embodiments of Formula VIA-B, Z is Z1B, and R8is (Ci-6)alkyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is methyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is (C2-e)alkenyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is -CH=CH2 or -C(CH3)=CH2. In some embodiments of Formula VIA-B, Z is Z1B, and R8is (C2-e)alkynyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is -CCH or -CC-CH3. In some embodiments of Formula VIA-B, Z is VIA-B, and R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is optionally substituted (C3-7)heterocyclyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is (C3-4)cycloalkyl. In some embodiments of Formula VIA-B, Z is Z1B, and R8is (C2-4)heterocyclyl.

[0245] In some embodiments of Formula VIA-B, Z is Z1B, X11is NH, and R8is (Cn e)alkyl. In some embodiments of Formula VIA-B, Z is Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Formula VIA-B, Z is Z1B, X11is NH, and R8is heterocyclyl.

[0246] In some embodiments of Formula VIA-B, Z is Z1B, X11is O, and R8is (Cn e)alkyl. In some embodiments of Formula VIA-B, Z is Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Formula VIA-B, Z is Z1B, X11is O, and R8is heterocyclyl.

[0247] In some embodiments of Formula I, the compound is of the formula:Atty. Docket No.: 39953-62353 (008WO)or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments of Formula VIC, R4is selected from:

[0249] In some embodiments of Formula VIC, R4is selected from:wherein:R18ais selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, and halogen.

[0250] In some embodiments of Formula VIC, R25is H, or optionally substituted alkyl (e.g., optionally substituted (Ci-6)alkyl). In some embodiments, R25is:D35 p33wherein:R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; andg and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

[0251] In some embodiments, the compound of Formula VIA is of the Formula VIIA or VIIB:Atty. Docket No.: 39953-62353 (008WO)or a pharmaceutically acceptable salt thereof, wherein:R25is optionally substituted (Ci-e)alkyl or optionally substituted -C(=O)Ci-6 alkyl; Xnis O orNH;R41is R8orN(R9)R10;R8is (Ci-6)alkyl, (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof;R9is H or optionally substituted (Ci-6)alkyl; andR10is H, optionally substituted (Ci-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; andwherein R1, R2, R5, R7, R12, R18, m, and v are as defined herein.

[0252] In some embodiments of any one of Formulae VA-VIIB, each R12is H (or m is 0). In some embodiments of any one of Formulae VA-VIIB,, m is 1, 2, 3, or 4, and at least one R12is not H. In some embodiments of any one of Formulae VA-VIIB, at least one R12is selected from C1-3 alkyl, halogen, and nitrile. In some embodiments of any one of Formulae VA-VIIB, at least one R12is methyl. In some embodiments of any one of Formulae VA-VIIB, at least one R12is halogen. In some embodiments of any one of Formulae VA-VIIB, at least one R12is Cl or F. In some embodiments, at least one R12is nitrile.

[0253] In some embodiments of Formula VIA-B, or VIIA-B, v is 0, such that there are no R18substituents. In some embodiments, v is 1-3, and each R18substituent is independently selected from (Ci-3)alkyl, hydroxy, halogen, and nitrile. In some embodiments, v is 1 and R18is (Ci-3)alkyl. In some embodiments, v is 1 and R18is halogen. In some embodiments the halogen is Cl or F.

[0254] In some embodiments, the compound of Formula VIIA or VIIB is of the Formula VIIIA or VIIIB:Atty. Docket No.: 39953-62353 (008WO)(VIIIB) or a pharmaceutically acceptable salt thereof, wherein:R25is optionally substituted (Ci-e)alkyl;R18is H, halogen (e.g., fluorine), optionally substituted (Ci-e)alkyl (e.g., methyl, trideuteromethyl, etc.), or optionally substituted (Ci-6)alkoxyl; andR12is H, halogen (e.g., fluorine), optionally substituted (Ci-e)alkyl or optionally substituted (Ci-6)alkoxyl;wherein X11, and R41are as defined herein.

[0255] In some embodiments of any one of Formulae VA-B, VIA-B, VIIA-B, or VIIIA-B, R25is of structure:p35 p33wherein 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, OH, OCH3, and halogen. In some embodiments, both R36and R37are H.Atty. Docket No.: 39953-62353 (008WO)

[0256] In some embodiments of any one of Formulae VA-B, VIA-B, VIIA-B, or VIIIA- B, R25is of structure:HO CF3CF3

[0257] In some embodiments of any one of Formulae VA-B, VIA-B, VIIA-B, or VIIIA- B, R25is of structure:HOH3[ CH3

[0258] In some embodiments of any one of Formulae VA-B, VIA-B, VIIA-B, or VIIIA-B, R12is H. In some embodiments, R12is (Ci-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 (Ci-6)alkoxyl. In some embodiments, R12is methoxy.

[0259] In some embodiments of any one of Formulae VA-B, VIA-B, VIIA-B, or VIIIA-B, R18is H. In some embodiments, R18is (Ci-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 (Ci-6)alkoxyl. In some embodiments, R18is methoxy.

[0260] In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, R41is R8(as defined herein). In some embodiments, R41is (Ci-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(Ci-6)alkyl. In some embodiments of Formula VIIA or VIIIA, X11is NH. In some embodiments, X11is O.

[0261] In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is NH, and R41is (Ci-6)alkyl. In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is NH, and R41is cycloalkyl. In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is NH, and R41is heterocyclyl.Atty. Docket No.: 39953-62353 (008WO)

[0262] In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is O, R41is (Ci-6)alkyl. In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is O, and R41is cycloalkyl. In some embodiments of Formula VA-B, VIA-B, VIIA-B, or VIIIA-B, X11is O, and R41is heterocyclyl.

[0263] In some embodiments, the compound is of formula (XIA):or a pharmaceutically acceptable salt thereof, wherein:R18ais selected from H, optionally substituted (Ci-3)alkyl, optionally substituted (Ci-3)alkoxy, hydroxy, and halogen;R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; andR12aand R12bare independently selected from hydrogen, halogen (e.g., fluoro), hydroxy, optionally substituted (Ci-3)alkyl, and optionally substituted (Ci-3)alkoxy.

[0264] In some embodiments of formula (XIA), R12ais fluoro, and R12bis hydrogen or fluoro. In some embodiments of formula (XIA), R12ais fluoro, and R12bis fluoro. In some embodiments of formula (XIA), R12ais fluoro, and R12bis hydrogen.

[0265] In some embodiments of formula (XIA), R12ais fluoro, R12bis hydrogen, R18ais methyl or tri deuteromethyl.

[0266] In some embodiments of formula (XIA), X11is O. In some embodiments of formula (XIA), X11is NH.

[0267] In some embodiments of formula (XIA), Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof.

[0268] In some embodiments of formula (XIA), Y12is -NR9R10, whereinR9is H or optionally substituted (Ci-3)alkyl, andR10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl. In some embodiments, R9is H.

[0269] In some embodiments of formula (XIA), Y12is -NR9R10, whereinAtty. Docket No.: 39953-62353 (008WO)R9is H or optionally substituted (Ci-3)alkyl, andR10is H, or optionally substituted (Ci-6)alkyl. In some embodiments, R9is H.

[0270] In some embodiments of formula (XIA), Y12is -NR9R10, whereinR9is H or optionally substituted (Ci-3)alkyl, andR10is optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl. In some embodiments, R9is H.

[0271] In some embodiments of formula (XIA), Y12is -NR9R10, whereinR9is H, andR10is optionally substituted (Ci-3)alkyl. In some embodiments, R9is H, and R10is CH3, or CD3. In some embodiments, R9is H, and R10is -CH2CH3, or -CD2CD3.

[0272] In some embodiments of formula (XIA), Y12is (Ci-6)alkyl. In some embodiments, Y12is (Ci-3)alkyl. In some embodiments, Y12is (C3-6)cycloalkyl. In some embodiments, Y12is CH3, or CD3. In some embodiments, Y12is -CH2CH3, or -CD2CD3.

[0273] In some embodiments of formula (XIA), 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 of formula (XIA), 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 of formula (XIA), at least one of R33-R37is a halogen. In some embodiments, the halogen is F. In some embodiments of formula (XIA), the halogen is Cl. In some embodiments of formula (XIA), one or two of R33-R35are CF3. In some embodiments of formula (XIA), one of R33-R35is CF3. In some embodiments of formula (XIA), two of R33-R35are CF3. In some embodiments of formula (XIA), one or two of R33-R35are OH. In some embodiments of formula (XIA), one of R33-R35is OH. In some embodiments of formula (XIA), two of R33-R35are OH. In some embodiments of formula (XIA), one or both of R36-R37are H. In some embodiments of formula (XIA), R36is H, and R37is selected from CF3, CHF2, CH2F, OH, OCH3, and halogen. In some embodiments of formula (XIA), both R36and R37are H.

[0274] In some embodiments of formula (XIA), R33is OH, and R34and R35are each independently methyl or CF3. In some embodiments of formula (XIA), R36and R37are each H

[0275] In some embodiments of formula (XIA), R25is of structure:HO CF3r ^cF3Atty. Docket No.: 39953-62353 (008WO)

[0276] In some embodiments of formula (XIA), R25is of structure:HOH3[ CH3

[0277] In some embodiments of formula (XIA), Y5is N. In some embodiments of formula (XIA), Y5is CR5, where R5is as defined herein.

[0278] In some embodiments, the compound of Formula V is of the Formula VIC or VID:or a pharmaceutically acceptable salt thereof, wherein:R1, R2, R5, R7, R12, R23, Z, and m are as defined herein.

[0279] In some embodiments of Formula VIC-D, R23is H. In some embodiments of Formula VIC-D, R23is optionally substituted (Ci-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.

[0280] In some embodiments of Formula VIC-D, 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;Atty. Docket No.: 39953-62353 (008WO)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 (Ci-e)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 (Ci-e)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; andx is 0, 1, or 2.

[0281] In some embodiments of Formula VIC-D, R23is of Formula 4F

[0282] In some embodiments of Formula VIC-D, R23is selected from one of the following structures:wherein R24, R25, R29, R30, and y are as defined herein.

[0283] In some embodiments of Formula VIC-D, Z is of Formulae ZIB or Z1CX1J z°X1? / OR10V N'RXR(ZIB) or R9(Z1C),wherein X11, R8, R9, and R10are as defined herein.R8is (Ci-6)alkyl, (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof;Atty. Docket No.: 39953-62353 (008WO)R9is H or optionally substituted (Ci-6)alkyl;R10is H, optionally substituted (Ci-6)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; andX11is O, orNH.

[0284] In some embodiments of Formula VIC-D, Z is Z1C, and X11is O. In some embodiments of Formula VIC-D, Z is Z1C, and X11is NH. In some embodiments of Formula VIC-D, Z is Z1C, and R9is H. In some embodiments of Formula VIC-D, Z is Z1C, and R9is (Ci-6)alkyl. In some embodiments of Formula VIC-D, Z is Z1C, and R10is H. In some embodiments of Formula VIC-D, Z is Z1C, and R10is (Ci-6)alkyl. In some embodiments of Formula VIC-D, Z is Z1C, and R10is optionally substituted cycloalkyl. In some embodiments of Formula VIC-D, Z is Z1C, and R10is optionally substituted heterocyclyl. In some embodiments of Formula VIC-D, Z is Z1C, R9is H, and R10is (Cn e)alkyl. In some embodiments of Formula VIC-D, Z is Z1C, R9is H, and R10H.

[0285] In some embodiments of Formula VIC-D, Z is Z1C, X11is NH, R9is H and R10is (Ci-6)alkyl. In some embodiments of Formula VIC-D, Z is Z1C, X11is NH, R9is H and R10is methyl. In some embodiments of Formula VIC-D, Z is Z1C, X11is NH, R9is H and R10is ethyl.

[0286] In some embodiments of Formula VIC-D, Z is Z1C, X11is O, R9is H and R10is (Ci-6)alkyl. In some embodiments of Formula VIC-D, Z is Z1C, X11is O, R9is H and R10is methyl. In some embodiments of Formula VIC-D, Z is Z1C, X11is O, R9is H and R10is ethyl.

[0287] In some embodiments of Formula VIC-D, Z is of Formula Z IB, and X11is O. In some embodiments of Formula VIC-D, Z is Z1B, and X11is NH. In some embodiments of Formula VIC-D, Z is Z1B, and R8is (Ci-6)alkyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is methyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is (C2- 6)alkenyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is -CH=CH2 or -C(CH3)=CH2. In some embodiments of Formula VIB, Z is Z1B, and R8is (C2-e)alkynyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is -CCH or -CC-CH3. In some embodiments of Formula VIC-D, Z is Z1B, and R8is optionally substituted (C3-7)cycloalkyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is optionally substituted (C3- 7)heterocyclyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is (C3-4)cycloalkyl. In some embodiments of Formula VIC-D, Z is Z1B, and R8is (C2-4)heterocyclyl.Atty. Docket No.: 39953-62353 (008WO)

[0288] In some embodiments of Formula VIC-D, Z is Z1B, X11is NH, and R8is (Cn e)alkyl. In some embodiments of Formula VIC-D, Z is Z1B, X11is NH, and R8is cycloalkyl. In some embodiments of Formula VIC-D, Z is Z1B, X11is NH, and R8is heterocyclyl.

[0289] In some embodiments of Formula VIC-D, Z is Z1B, X11is O, and R8is (Cn e)alkyl. In some embodiments of Formula VIC-D, Z is Z1B, X11is O, and R8is cycloalkyl. In some embodiments of Formula VIC-D, Z is Z1B, X11is O, and R8is heterocyclyl.

[0290] In some embodiments, the compound of Formula VIC-D, is of the Formula VIIC-D:(VIID)R1, R2, R5, R7, R12, R24, R25, R29, R30, X11, R41, y and m are as defined herein.

[0291] In some embodiments, the compound of Formula VIIC-D is of the Formula VIIIC-D:(VIIID) 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.

[0292] In some embodiments, the compound of Formula VIIIC-D of the formula:Atty. Docket No.: 39953-62353 (008WO)(VIIIE)or a pharmaceutically acceptable salt thereof,wherein R12a, R12b, R12c, and R12dare independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.

[0293] In some embodiments of formula VIIIE, R12a, and R12bare independently fluoro or hydrogen. In some embodiments of formula VIIIE, R12cand R12dare each hydrogen, n some embodiments of formula VIIIE, R12a, and R12bare each fluoro.

[0294] In some embodiments, the compound of Formula VIIIE is of the Formula IXA or IXB:or a pharmaceutically acceptable salt thereof, wherein:R12, R29, R30, X11, and R41are as defined herein.

[0295] In some embodiments of Formula I, the compound is of the formula IXC:or a pharmaceutically acceptable salt thereof.Atty. Docket No.: 39953-62353 (008WO)

[0296] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA- B, R12is H. In some embodiments, R12is (Ci-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 (Ci-6)alkoxyl. In some embodiments, R12is methoxy.

[0297] In some embodiments of formula IXC, R12a, and R12bare independently fluoro or hydrogen. In some embodiments of formula IXC, R12cand R12dare each hydrogen, n some embodiments of formula IXC, R12a, and R12bare each fluoro.

[0298] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA- C, R29and R30are each independently optionally substituted (Ci-6)alkyl. In some embodiments, R29and R30are each independently (Ci-3)alkyl. In some embodiments, R29and R30are each methyl. In some embodiments, R29and R30are each ethyl.

[0299] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, 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.

[0300] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, R41or Y12is R8(as defined herein). In some embodiments, R41or Y12is (Ci-6)alkyl. In some embodiments, R41or Y12is selected from methyl, ethyl or propyl. In some embodiments, R41or Y12is methyl. In some embodiments, R41or Y12is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl. In some embodiments, R41or Y12is (C3-4)cycloalkyl or (C2-4)heterocyclyl. In some embodiments, R41or Y12is N(R9)R10. In some embodiments, R41or Y12is NH2. In some embodiments, R41or Y12is -NH(Ci-6)alkyl. In some embodiments of Formula VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is NH. In some embodiments, X11is O.

[0301] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is NH, and R41or Y12is (Ci-6)alkyl. In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is NH, and R41or Y12is cycloalkyl. In some embodiments of Formula VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is NH, and R41or Y12is heterocyclyl.

[0302] In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is O, R41or Y12is (Ci-6)alkyl. In some embodiments of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is O, and R41or Y12is cycloalkyl. In some embodimentsAtty. Docket No.: 39953-62353 (008WO)of any one of Formulae VIC-D, VIIC-D, VIIIC-D, or IXA-C, X11is O, and R41or Y12is heterocyclyl.

[0303] In some embodiments of Formula I, or any one of Formulae IA-XI, the compound is selected from one of Tables 3 or 4, or a pharmaceutically acceptable salt thereof.

[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-XI, R7is selected from H, CH3, CF3, and halogen. In some embodiments of Formula I, or any one of Formulae IA-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, -CH2CI, 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 -CH2CI. 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 XIIA or XIIB:N R4, / N R4% II A R6 ft II A. R6H (XIIA), or H (XIIB)or an isotopically labelled derivative thereof, or a pharmaceutically acceptable salt thereof, wherein:R4is selected from:Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)Atty. Docket No.: 39953-62353 (008WO)

[0309] In some embodiments of Formula XIIA or XIIB, R6isembodiments of Formula XIIA or XIIB, R6is. In some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6isAtty. Docket No.: 39953-62353 (008WO)In some embodiments of Formula XIIA or XIIB, R6isHNembodiments of Formula XIIA or XIIB, R6is. Insome embodiments of Formula XIIA or XIIB, R6isof Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA orIn some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6is embodiments of Formula XIIA or XIIB, R6is. In some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA orAtty. Docket No.: 39953-62353 (008WO)XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6is. In some embodiments of Formula XIIA or XIIB, R6is embodiments of Formula XIIA or XIIB, R6is. In some embodiments of Formula XII A or XIIB, R6is In some embodiments of Formula XIIA or C>, T NHXIIB, R6is. In some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6is embodiments of Formula XIIA or XIIB, R6is. In some embodiments ofAtty. Docket No.: 39953-62353 (008WO)Formula XII A or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6is In some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6isIn some embodiments of Formula XIIA or XIIB, R6isIn some embodiments, R6isembodiments, R6isIn some embodiments, R6issome embodiments, R6isAtty. Docket No.: 39953-62353 (008WO)some embodiments, R6is H0In some embodiments, R6isembodiments, R6is In some embodiments, R6is In some embodiments, R6isembodiments, R6isIn some embodiments, R6isAtty. Docket No.: 39953-62353 (008WO). In some embodiments, R6isZCD3HN3S=NH 'o. In some embodiments, R6is. In some embodiments, R6HN'CH= S=NH 'o F. In some embodiments,. In some embodiments,ZCD,HN3HN'CH3S=NHT1'oR6is. In some embodiments, R6is. In some HN"CH3T,-S=NH o embodiments, R6is. In some embodiments, R6is. In CH3S \\=NH o some embodiments, R6is. In some embodiments, R6is CH3IS=NH'oIn some embodiments, R6is. In some embodiments, R6isAtty. Docket No.: 39953-62353 (008WO)In some embodiments, R6is. In some embodiments, R6is In some embodiments, R6is. In some embodiments,In some embodiments, R6isF. In some CH3embodiments, R6isFsome embodiments, R6isFIn some embodiments, R6is some embodiments, R6is In some embodiments, R6issome embodiments, R6issome embodiments, R6is In some embodiments, R6isAtty. Docket No.: 39953-62353 (008WO)some embodiments,R6is In some embodiments,R6issome embodiments, R6isFIn some embodiments, R6is In some embodiments of Formula XIIA orXIIB, R6is F

[0310] Tables 1-3 and the experimental section illustrate exemplary compounds of Formula I and of this disclosure. Compounds provided by the present disclosure can be prepared in a manner similar to those exemplified in the Examples section. Compounds are racemic or achiral unless specified otherwise (e.g., as a single enantiomer of known relative stereochemical configuration but unknown absolute stereochemical configuration).Table 3: Exemplary compounds of Formula ICpd. No. Structure NameOH4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 120 H |2,6-naphthyridin-l-yl)cyclohex- oxH \ i H \ 3-en-l-olAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Namet14-(7-((4- (methylsulfonyl)phenyl)amino)- 1212,6-naphthyridin-l-yl)cyclohex- 3 -ene-1 -carbonitrileNxl-(7-((4- (vinylsulfonyl)phenyl)amino)- 1222,6-naphthyridin-l- -3? z yl)pyrrolidine-3 -carbonitrile A, J N. Jj ^\ 1= Z A—_ / z / AV~ \0 / _ T A / \ / A}z—IZ l-(7-((4- (vinylsulfonyl)phenyl)amino)- 123hy2,6-naphthyridin-l-yl)piperidine- A 3 -carbonitrileA xW LU\ x OW"\ O' 0H 5-ethynyl-N-(4- 124 (methylsulfonyl)phenyl)-2,6- 0 \ J\ x-N. J J T A naphthyri din-3 -amine0\N-NL N 5-(l-methyl-lH-l,2,3-triazol-4- H T yl)-N-(4- 1253 A r ii Y (methylsulfonyl)phenyl)-2,6- O c. A 1 A x K lAI x-A 1 A x naphthyri din-3 -amine5-(lH-benzo[d]imidazol-5-yl)-N- 126 (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5-(cyclohex- 1 -en- 1 -yl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -aminel-(7-((4-formylphenyl)amino)- 2,6-naphthyridin-l-yl)piperidine- 4-carbonitrile4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzonitrile4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2, 6-naphthyridin- 1 -yl)but-3 -yn- l-ol4-(7-((4- (vinylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)benzonitrileAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameHN^\fl YN-(4-(methylsulfonyl)phenyl)-5- 135 H T ( 1 H-pyrrolo [2, 3 -c]pyri din-5 -yl)- 2,6-naphthyridin-3-amine 0. 1 J KI 1 J«ox> Nn- 3-(7-((4- (vinylsulfonyl)phenyl)amino)- 136 H |ZT / / < O Z^ 2,6-naphthyridin-l- 0 1 J KI \ / / A 1 J yl)benzonitrile 0> / A — Ax / Z^ZXZDM >z7 V Vz_ — / A. / 5-(3-(methoxymethyl)phenyl)-N- 137 2 z — (4-(vinylsulfonyl)phenyl)-2,6- Z T naphthyri din-3 -aminexW, 0\ O- (•N-(4-(methylsulfonyl)phenyl)-5- 138 (pyridin-4-ylethynyl)-2,6- Hnaphthyri din-3 -amine° \x' x 1A A J N Nx I A.05-(4,5-dihydrothiazol-2-yl)-N-(4- 139 (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN11 -(7-((3 -formylphenyl)amino)- 140 2,6-naphthyridin-l-yl)piperidine- H 4-carbonitrile° iDrMYAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5-(2-(trifluoromethoxy)phenyl)- 141 N-(4-(vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 142 zm -nH | 2,6-naphthyridin-l- yl)cyclohexaneC) T 1 Y 1 V 1 A - 1 -carbonitrile ° \ / JS 14 / — A / / N I Il-(7-((3-(2- hydroxyethyl)phenyl)amino)- 1432,6-naphthyridin-l-yl)piperidine- H Y4-carbonitrileN=N5-(l-methyl-lH-l,2,3-triazol-5- H 1 yl)-N-(4- 144(methylsulfonyl)phenyl)-2,6- v YUYV NUVUA naphthyri din-3 -amine oN / T°5-(benzo[d]oxazol-5-yl)-N-(4- M145 H T (vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine vU NJU0HNN-(4-(methylsulfonyl)phenyl)-5- 146 H (l,2,3,6-tetrahydropyridin-4-yl)- 2,6-naphthyridin-3-amine (D i 1i V 1 r 1 ^A 1 1Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name0 H3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 147H 2,6-naphthyridin-l- ^N yl)ethynyl)cyclobutan- 1 -ol 0 J J N 10HN-NJoc 5-(4-methyl-lH-indazol-5-yl)-N- 148 H | (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineO \K' 1 A1 Y J V M X -AJs. A JH 5-(prop-l-yn-l-yl)-N-(4- 149 zY / N\Y\z (vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine8' JU XX0H(lr,4r)-4-((7-((4- (methylsulfonyl)phenyl)amino)- 1502,6-naphthyridin-l- Hyl)ethynyl)cyclohexan-l-ol ^N%JU XXX1N5-(l-methylpiperidin-4-yl)-N-(4- 151 H | (methylsulfonyl)phenyl)-2,6- ^N naphthyri din-3 -amine °* xj XXAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameNT5-(l-ethylpiperidin-4-yl)-N-(4- 152 H | (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine oxr II V I r I u J S i5-(l- (cyclohexylmethyl)piperidin-4- 153 yl)-N-(4- H 1 (methylsulfonyl)phenyl)-2,6- \ / = \ Z -— naphthyri din-3 -amine UJ NJU ) ( ^z A— / )\ o=z'A / / 2 z —Z T °<y / Nl-(4-(7-((4- (methylsulfonyl)phenyl)amino)- 154, 0. H 1 2,6-naphthyridin-l-yl)piperidin- \ O- l-yl)ethan-l-one%JU «JJ0l-(4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 1552,6-naphthyridin-l-yl)piperidin- 1 -yl)prop-2-en- 1 -oneN I I0 4-((7-((4- (vinylsulfonyl)phenyl)amino)- 1562,6-naphthyridin-l- H yl)ethynyl)benzonitrile JU NUU0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameOH4-(7-((4- 157 H 0 | (vinylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)phenol vU NUU0\-N5-(l,4-dimethyl-lH-indazol-5- yl)-N-(4- 158 H (methylsulfonyl)phenyl)-2,6- OK naphthyri din-3 -amineJJ J KI JU J-s'bFAFTQ 5-(3-(trifluoromethyl)phenyl)-N- 160 H 1 (4-(vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine°» AJ N^JU0F\z°\z%FV Q 5-(3-(trifluoromethoxy)phenyl)- H161 T N-(4-(vinylsulfonyl)phenyl)-2,6- o '.' / N 1 AYY J V Ji Y 1 S J naphthyri din-3 -amine0HN5-(lH-indol-6-yl)-N-(4- 162 H T (vinylsulfonyl)phenyl)-2,6- O. 1 rr JNY J,^ 1 S J naphthyri din-3 -amine00HN-X5'-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 163 UJ72,6-naphthyridin-l- H |yl)spiro[cyclopropane- 1,3'- NUU indolin]-2'-one-s'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name5-(4-methyl-l-(tetrahydro-2H- pyran-4-yl)-lH-indazol-5-yl)-N- 164(4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine0N-N5-(4-methyl-2-(tetrahydro-2H- pyran-4-yl)-2H-indazol-5-yl)-N- 165 _ / / Z~# A A- (4-(methylsulfonyl)phenyl)-2,6- H naphthyri din-3 -amineA 0C 1 rvY K 2 y zZ — z—) J I II AZ 1 J. 0. o N-N\ O' \ O'5-(2,4-dimethyl-2H-indazol-5- yl)-N-(4- 166 QH | (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineO' 1 rV J Y Ji v 1 S J5-(5-methyl-l,2,4-oxadiazol-3- yl)-N-(4- 167(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineO^NH2(lr,4r)-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 168 2,6-naphthyridin-l- H yl)ethynyl)cyclohexane- 1 - carboxamide%JU NUU's'bAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name00-^methyl 2-(7-((4- N. S(m ethyl sulfonyl)phenyl)amino)- 169 H | 2,6-naphthyridin-l-yl)-4,5- \O x'W x dihydrothiazole-4-carboxylate c> H \ i H \-s'bZI / z— / A / 5 -( 1 -i sopropylpiperidin-4-yl)-N- 170 H | (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -aminexrvY' \A ' ' z —o II I I J i\ / \ = Z A -—^z_ v \zOA / / 2 z —Z T5-(l-allylpiperidin-4-yl)-N-(4- 171 (methylsulfonyl)phenyl)-2,6-, 0. naphthyri din-3 -amine\ o- JON5-(l-benzylpiperidin-4-yl)-N-(4- 172 (methylsulfonyl)phenyl)-2,6- H 1 naphthyri din-3 -amine rrNT^AAJ N< JU-s'b5-(l-(4- methoxybenzyl)piperidin-4-yl)- 173N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-amineAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name / QNN-(4-(methylsulfonyl)phenyl)-5- 174 (l-(pyridin-3-ylmethyl)piperidin- H | 4-yl)-2,6-naphthyri din-3 -amine \O xW x(D 1 J J, 1 J”'0ZI / z— / / AO ) ( - -, X N-(4-(methylsulfonyl)phenyl)-5- 175 / X n / \) ( zw — / - — (l-(methylsulfonyl)piperidin-4- V 1 \' ii / __' 'Zo - yl)-2,6-naphthyridin-3-amineo=s=o1N 5-(l- (i sopropyl sulfonyl)piperidin-4- 176 yl)-N-(4- H | (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine o. J rv J V J| v 1 S JO^NHNN-methyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 177H | 2,6-naphthyridin-l-yl)piperidine- 1 -carboxamide rrN^ SOx JU J Ji JU J1O^NH(lr,4r)-N-methyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 178H • 2,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamide °x JU J Ji JU JAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name(lr,4r)-N-ethyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 1792,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamide(lr,4r)-4-(7-((4- \ i (m ethyl sulfonyl)phenyl)amino)- 180 z,. z > — ' —— 2,6-naphthyridin-l-yl)-N- H s propylcyclohexane- 1 - / \ o ' — 'zcarboxamideV A OK 1 J 2 N z — 1 JIZO^NH. 0\ o' (lr,4r)-N-isopropyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 181H • 2,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamide 1 J N< JUzO^0HN-'N^ N-N} A 5-(4-methyl-l-(piperidin-4-yl)- lH-indazol-5-yl)-N-(4- 182(methylsulfonyl)phenyl)-2,6- H naphthyri din-3 -amine fW vS°K JU J KI JI J-s'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH XN-N( jl 5-(4-chloro-lH-indazol-5-yl)-N- 183 H TCl(4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine\o. X ro kJ N< JU-s'bHN-NZI JL°'hXT ri 5-(4-fluoro-lH-indazol-5-yl)-N- 184 H / Z— TF(4-(methylsulfonyl)phenyl)-2,6- / / Anaphthyri din-3 -amine kJ &oN< JU\\oHN-^5-(lH-indol-5-yl)-N-(4- 185 H (vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineJ T. JYV NJYJAo7-((4- (m ethyl sulfonyl)phenyl)amino)- 186l-(piperidin-l-yl)-2,6- naphthyridine-3-carbaldehydeJ4-((5-(4-cyanopiperidin- 1 -yl)- 187 2,6-naphthyridin-3- yl)amino)benzenesulfonamide i?t J1 1l-(7-((4- (vinylsulfonyl)phenyl)amino)- 188hJH<2,6-naphthyridin-l-yl)azetidine- ^N 3 -carbonitrile%JU XX0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name8-(cyclohex- 1 -en- 1 -yl)-N-(4- (m ethyl sulfonyl)phenyl)quinazol in-2-amine189N l-(3-((4- (methylsulfonyl)phenyl)amino)is oquinolin-5-yl)piperidine-4- carbonitrile190 6H |°, JJ MUk C / N l-(2-((4- 0’- (m ethyl sulfonyl)phenyl)amino)q IZ uinazolin-8-yl)piperidine-4- ^=z carbonitrile191 6 / ) Z1 \\ / / HCXI XX?5-(cyclohex- 1 -en- 1 -yl)-N-(4- (methylsulfonyl)phenyl)isoquino H lin-3 -amine192<* XX MUHN^U - - \___ / N-NJL5-(4-methyl-l-(pyrrolidin-3- ylmethyl)-lH-indazol-5-yl)-N- 193H (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine‘t JU NUUoAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name3-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 1942,6-naphthyridin-l-yl)-lH- \O z indazol- 1 -yl)propanenitrileN-N^^nJ / A5-(4-methyl-2-(pyrrolidin-3- ylmethyl)-2H-indazol-5-yl)-N- 195 QCH S / 1 R (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine c> 1 J J. I J-s'b / — \NHN-Nj? A5-(2-(azetidin-3-ylmethyl)-4- methyl-2H-indazol-5-yl)-N-(4- 196 QCH 1 (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineR R JUR^R J K NI<^R JURxR J-s'bN-N3-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 1972,6-naphthyridin-l-yl)-2H- indazol -2-y l)prop anenitri 1 e R 'xR 1 RR xR JYNY N NR R 1RS xR J-s'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameL ijO^NH4-(7-((4- N (m ethyl sulfonyl)phenyl)amino)- 198 2,6-naphthyridin-l-yl)-N- (pyri din-3 -yl)piperidine- 1 - H | carboxamideJU NUU-s'b0 / Z'XY\ / X / °X(lr,4r)-N-(2-methoxyethyl)-4-(7- ((4- 199 Cx (m ethyl sulfonyl)phenyl)amino)- T J J J ° 2,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamide HO^>1H(lr,4r)-N-cyclobutyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2002,6-naphthyridin-l- H • yl)cyclohexane- 1 -carboxamide 8' J rUvV «U'YUY00^k / N^O((lr,4r)-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 201 2,6-naphthyridin-l- H • yl)cyclohexyl)(morpholino)meth anoneo. 1 YY J V J, Y JUX JAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name9O^NH(lr,4r)-4-(7-((4- (methylsulfonyl)phenyl)amino)- 202 2,6-naphthyridin-l-yl)-N- phenylcyclohexane-1 - H • carboxamide<3 J TUYV iJYUU(lS,3R)-3-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 203 o 2,6-naphthyridin-l- 7 \ A Z - —_ / \ / / A yl)cyclohexan- 1 -olbo- (cis, racemic) / A / J z A — / / IZ IZ / Z3-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2042,6-naphthyridin-l- „0C. 9 yl)cyclohexan- 1 -one\ O \ O''HN-NJ Aex 5-(lH-indazol-5-yl)-N-(4- 205 H I (vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine°J rUrNY NU9Ui S^ 'b / _ JDH / N / -N A 2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 206 OC 2,6-naphthyridin-l-yl)-2H- H 1indazol-2-yl)ethan- 1 -ol°" JU NUU0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name5-(l-(azetidin-3-ylmethyl)-4- methyl-lH-indazol-5-yl)-N-(4- 207H (methylsulfonyl)phenyl)-2,6- U rU naphthyri din-3 -amineOK 1 J KI 1 J^--NHN-N5-(2-(2-(azetidin-3-yl)ethyl)-4- methyl-2H-indazol-5-yl)-N-(4- 208QC (methylsulfonyl)phenyl)-2,6- H | naphthyri din-3 -amineJ TUYV NUVUN-s'bHN-NjfY 5-(6-methyl-lH-indazol-5-yl)-N- 209 H | (4-(vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine rrNuA°JU NUU^ 'bN1 -(7-((4-hy droxy-3 - (hydroxymethyl)phenyl)amino)- 2102,6-naphthyridin-l-yl)piperidine- H Y4-carbonitrileH0H Y llNHCT ^HVl-(7-((4- (vinylsulfonyl)phenyl)amino)- 211H5 2,6-naphthyridin-l-yl)pyrrolidin- OK 1 ^! JTN^ KI JAU JN 3-ol0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Namemethyl (lr,4r)-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 213 2,6-naphthyridin-l- yl)ethynyl)cyclohexane- 1 - H carboxylateXX's'b5-(cyclopropylethynyl)-N-(4- 214 (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineOH4-(7-((4- „oc X(m ethyl sulfonyl)phenyl)amino)- 215 \ O' H |2,6-naphthyridin-l- oxr H r \ V i X J \ » yl)cyclohexan- 1 -ol'VHN— 1^AI-NX 5-(l-(2-(azetidin-3-yl)ethyl)-4- methyl-lH-indazol-5-yl)-N-(4- 216(methylsulfonyl)phenyl)-2,6- H. N. A, naphthyri din-3 -amine O N V IIO 'K' / 1 \ J K NI <s 1 J's'b(3-(7-((4- H | (vinylsulfonyl)phenyl)amino)- 2172,6-naphthyridin-l- %JU NXU yl)phenyl)methanol0Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name4-(cyclohex- 1 -en- 1 -yl)-N-(4- (methylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-6-amine 218\O.N l-(2-((4- (m ethyl sulfonyl)phenyl)amino)p yrido[3,4-d]pyrimidin-8- yl)piperidine-4-carbonitrile ZX219 6H / z— | / A / / \ / <z> Z — # X _ / / A A Z~- CN / \J / \ _ _ \ Z z - x A / \ 7—=_\ / H / '=A / zXN-No — ' / HA IZ / / V z—xz fx 5-(4-methoxy-lH-indazol-5-yl)- 220 H T °' N-(4-(methylsulfonyl)phenyl)- rYm 2,6-naphthyridin-3-amine. 0\ O'oX HOl-(7-((4-((2-. j hydroxyethyl)sulfonyl)phenyl)a 221mino)-2,6-naphthyridin- 1 - yl)pyrrolidin-3-ol HO^%2-((4-((5-(6-methyl-lH-indazol- 5-yl)-2,6-naphthyridin-3- 222yl)amino)phenyl)sulfonyl)ethan- l-ol(lr,4r)-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2232,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamideAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameIIO^JMH(lr,4r)-N-allyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2242,6-naphthyridin-l- H • yl)cyclohexane- 1 -carboxamide U rU8' JU NUUoU<(lr,4r)-N, N-dimethyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 225H • 2,6-naphthyridin-l- yl)cyclohexane- 1 -carboxamide rUr^uO. 1 J M 1 JQO^NH (lr,4r)-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 226 2,6-naphthyridin-l-yl)-N- (tetrahydro-2H-pyran-4- H • yl)cyclohexane- 1 -carboxamide vO tC-s'b'XN^'s|(4-methylpiperazin-l-yl)((lr,4r)- 4-(7-((4- 227 (m ethyl sulfonyl)phenyl)amino)- H • 2,6-naphthyridin-l- yl)cyclohexyl)methanone c> '' C 1 Y 1 V N I<sV > H< A iAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name((lr,4r)-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 228 2,6-naphthyridin-l- H • yl)cyclohexyl)(thiomorpholino) methanonec \>' Z JU\A \ N ix A JU / A \ / — N5-(l-methylpyrrolidin-3-yl)-N- 229 H | (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine NJU0i— i / / A / 2 z — 5-(l-benzylpyrrolidin-3-yl)-N- 230 H IZ | (4-(methylsulfonyl)phenyl)-2,6- rVr'rS naphthyri din-3 -amine<t A J N< JU- xs\ OOT.'0b 0"I-S A}-0' 5-(l-(4- methoxybenzyl)pyrrolidin-3-yl)- 231 H | N-(4-(methylsulfonyl)phenyl)- Ox JU J N JU J 2,6-naphthyridin-3-amine -s'bN-(4-(methylsulfonyl)phenyl)-5- (l-(pyridin-3- 232ylmethyl)pyrrolidin-3 -yl)-2, 6- naphthyri din-3 -aminertTA}~c' 5-(l-(4-chlorobenzyl)pyrrolidin- 3-yl)-N-(4- 233 H |(methylsulfonyl)phenyl)-2,6- ° 'x'- / N J rU A JrN^ N YN< X JU4J^ naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name / — N l-(3-(7-((4- (methylsulfonyl)phenyl)amino)- 234 H | 2,6-naphthyridin-l-yl)pyrrolidin- 0. 1 J KI 1 J l-yl)propan-l-one-s'bOx s / <. / —N0N-(4-(methylsulfonyl)phenyl)-5- 235 H I ( 1 -(methyl sulfonyl)pyrrolidin-3 - yl)-2,6-naphthyridin-3-amine o 1 iY A n J, 1i A »O "xS )s-!— N05-(l- (isopropylsulfonyl)pyrrolidin-3- 236 H | yl)-N-(4- (methylsulfonyl)phenyl)-2,6- OyJ rU V J r KI v JU S J naphthyri din-3 -amine-s'bOx / - ° 5-(l-(allylsulfonyl)pyrrolidin-3- yl)-N-(4- 237 H | (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine;<a wO. S Px.i— N0N-(4-(methylsulfonyl)phenyl)-5- (l-(pyridin-3- 238H | ylsulfonyl)pyrrolidin-3-yl)-2,6- naphthyri din-3 -amine iiVr^S'' JU J K NI <s ^A JUx. JAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name0^05-(l- (cyclopropylsulfonyl)pyrrolidin- 239 H | 3-yl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine\x ^x\x03-(7-((4- H (m ethyl sulfonyl)phenyl)amino)- 2402,6-naphthyridin-l-yl)cyclohex- (D J TI JYV 1 A JS J 2-en-l-olN=nHhi l5-(lH-indazol-6-yl)-N-(4- 241 MH T (vinylsulfonyl)phenyl)-2,6- (rVr'YA naphthyri din-3 -amineC) 1' \' z\; Z xJ Mx / N XA JXSx xJ\\0N-N 5-(4-methyl-l-(l- methylpiperidin-4-yl)-lH- 242 oc indazol-5-yl)-N-(4- (methylsulfonyl)phenyl)-2,6- H 1 naphthyri din-3 -amine O 'K' x^ 1Xx? X^ M Nx 1 X-^NO^^N-N5-(4-methyl-l-((l- methylazetidin-3-yl)methyl)-lH- 243 indazol-5-yl)-N-(4- H(methylsulfonyl)phenyl)-2,6- °v 1 r xrJNY M^JS XJ naphthyri din-3 -amine-s'bAtty. Docket No.: 39953-62353 (008WO)Structure Name5-(tert-butyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-(4-methyl-lH-indazol-5-yl)-N- (4-(vinylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-((lr,4r)-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)cyclohexyl)acetamide5-(((lr,4r)-4- aminocyclohexyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN4-(6-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-2,6- diazaspiro[3.3]heptan-2- yl)benzonitrileAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameN II(E)-l-(7-((4-((3- (dimethylamino)prop- 1 -en- 1 - 249 6 yl)sulfonyl)phenyl)amino)-2,6- naphthyridin-l-yl)piperidine-4- carbonitrile0NH2N-N o2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 250 Q2,6-naphthyridin-l-yl)-2H- H |indazol-2-yl)acetamideC> JU J N J JJ1 14-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 252 2,6-naphthyridin-l- yl)ethynyl)cyclohexane- 1 - Hcarbonitrile°x 1 J N l / Sx0t1l-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 259 JJ 2,6-naphthyridin-l-yl)piperidine- 4-carbonitrileva -a" oHO^^N-N2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 267H 2,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)ethan- 1 -olOx 1 J N 1 J-s'bAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-methyl-4-(oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6-((7-((4- (cyclobutanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknown6-((7-((4- (cyclobutanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-fluoro-4- (oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-fluoro-4-(oxetane-3 - sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6-((7-((4-((3,3- difluorocyclobutyl)sulfonyl)-2- methoxyphenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one6'-((7-((4- (cyclopropanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (2,2,2- trifluoroethylsulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name6'-((7-((4-((2,2,2- trifluoroethyl)sulfonyl)phenyl)a 282 mino)-2,6-naphthyridin- 1 - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one3,3-diethyl-6-((7-((2-fluoro-4- ((2,2,2- 283 trifluoroethyl)sulfonyl)phenyl)a mino)-2,6-naphthyridin- 1 - yl)ethynyl)indolin-2-one3,3-diethyl-6-((7-((2-methyl-4- (2,2,2- trifluoroethylsulfonimidoyl)phen 284yl)amino)-2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methyl-4- (2,2,2- trifluoroethylsulfonimidoyl)phen 285yl)amino)-2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((2-methyl-4- ((2,2,2- trifluoroethyl)sulfonyl)phenyl)a mino)-2,6-naphthyridin- 1 - yl)ethynyl)indolin-2-one3-(2-hydroxyethyl)-3-methyl-6- ((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3-(2-hydroxyethyl)-3-methyl-6- ((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown6'-((7-((4-(ethylsulfonimidoyl)- 2-methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4-(ethylsulfonimidoyl)- 2-methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methyl-4-(oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown3 -hydroxy-3 -methyl-6-((7-((4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3 -hydroxy-3 -methyl-6-((7-((4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name6-((7-((2-(difluoromethyl)-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - 294yl)ethynyl)-3,3-diethylindolin-2- oneSingle isomer, unknown6-((7-((2-(difluoromethyl)-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - 295yl)ethynyl)-3,3-diethylindolin-2- oneSingle isomer, unknown6'-((7-((4- (cyclopropanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- 297 naphthyridin-1- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4- (cyclopropanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- 298 naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6-((7-((4- (cyclopropanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknown6-((7-((4- (cyclopropanesulfonimidoyl)-2- methoxyphenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknown6-((7-((4-(3,3- difluorocyclobutane-1- sulfonimidoyl)-2- fluorophenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknown6-((7-((4-(3,3- difluorocyclobutane-1- sulfonimidoyl)-2- fluorophenyl)amino)-2,6- naphthyridin- 1 -yl)ethyny l)-3,3 - diethylindolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6-((7-((4-(3,3- difluorocyclobutane-1- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -diethylindolin-2-one Single isomer, unknown6-((7-((4-(3,3- difluorocyclobutane-1- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -diethylindolin-2-one Single isomer, unknown6'-((7-((2-methoxy-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name6'-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- 307yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown3,3-diethyl-6-((7-((4- (ethylsulfonimidoyl)-2- methoxyphenyl)amino)-2,6- 308naphthyridin-1- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((4- (ethylsulfonimidoyl)-2- methoxyphenyl)amino)-2,6- 309naphthyridin-1- yl)ethynyl)indolin-2-one Single isomer, unknown6'-((7-((4-(ethylsulfonimidoyl)- 2-methoxyphenyl)amino)-2,6- naphthyridin-1- 310yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4-(ethylsulfonimidoyl)- 2-methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6-((7-((2-(difluoromethyl)-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6'-((7-((2-methoxy-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methoxy-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((2-methyl-4- (oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((2-methoxy-4- (S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown3,3-bis(methoxymethyl)-6-((7- ((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown6'-((7-((2-methoxy-4-(oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methoxy-4-(oxetane-3- sulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-methoxy-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methyl-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methyl-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown3 -(hy droxymethyl)-3 -methyl-6- ((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name3 -(hy droxymethyl)-3 -methyl-6- ((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 3302,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3 -(hy droxymethyl)-3 -methyl-6- ((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 3312,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown6'-((7-((2-methyl-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - 332yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methyl-4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - 333yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-methoxy-4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methoxy-4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown3,3-diethyl-6-((7-((2-methyl-4- (S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methyl-4- (S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name3,3-diethyl-6-((7-((4- (i sopropyl sulfonyl)-2- methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)indolin-2-one6-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3-diethylindolin-2- oneSingle isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((2-methoxy-4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name0 / HN y.5 -fluoro-3, 3 -dimethyl-6-((7 -((2- methyl-4- V T(m ethyl sulfonyl)phenyl)amino)- 3422,6-naphthyridin-l- H ' yl)ethynyl)indolin-2-one rrVvSN< JU-s'b0 / HN 13,3,5-trimethyl-6-((7-((4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 3432,6-naphthyridin-l- H yl)ethynyl)indolin-2-one Single isomer, unknown HN Ji J J, JY %V!HNy 6'-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- 344yl)ethynyl)spiro[cyclobutane- H l,3'-indolin]-2'-one^N Single isomer, unknown HN J J J, JHNJ 6'-((7-((2-methoxy-4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- 345yl)ethynyl)spiro[cyclobutane- H l,3'-indolin]-2'-one YVNVAV Single isomer, unknown HN [ T J. Jl\ / S 0j b iAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-methoxy-4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown5-amino-3,3-dimethyl-6-((7-((4- (propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown6'-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((2-methyl-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name0 IHN. V3,3-dimethyl-6-((7-((4- (m ethyl sulfonyl)-2- 352 (trifluoromethyl)phenyl)amino)- F^F | |2,6-naphthyridin-l- Hyl)ethynyl)indolin-2-one XrVxSC> k U KI J J0HN6'-((7-((4- J(cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- 353yl)ethynyl)spiro[cyclopropane- H l,3'-indolin]-2'-one^N Single isomer, unknown HN fl J J N.x A J£TS'b6'-((7-((4-(propan-2- ) ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- 354yl)ethynyl)spiro[cyclopropane- H l,3'-indolin]-2'-one^N Single isomer, unknown HN jf J J T100 rHN \6'-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- 355yl)ethynyl)spiro[cyclopropane- H l,3'-indolin]-2'-one^N Single isomer, unknownHN" XJ L IT0Atty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4-(ethylsulfonyl)-2- methylphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one6'-((7-((4-(ethylsulfonyl)-2- methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one6'-((7-((4-(S-methylsulfonimidoyl)phenyl)amino)-2,6-naphthyridin-l -yl)ethynyl)spiro[cyclopropane-l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4-(S-methylsulfonimidoyl)phenyl)amino)-2,6-naphthyridin-l -yl)ethynyl)spiro[cyclopropane-l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((2-methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-one6’-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6’-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4-(S-methylsulfonimidoyl)phenyl)amino)-2,6-naphthyridin-l -yl)ethynyl)spiro[cyclobutane-l,3'-indolin]-2'-oneSingle isomer, unknown3,3-diethyl-6-((7-((4- (i sopropyl sulfonyl)-2- methylphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)indolin-2-oneAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((4- (ethylsulfonyl)-2- methylphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)indolin-2-one3,3-diethyl-6-((7-((4- (ethylsulfonyl)-2- methoxyphenyl)amino)-2,6- naphthyridin-1- yl)ethynyl)indolin-2-one6'-((7-((2-methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one6'-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one6-((7-((3-hydroxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6-((7-((2-hydroxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6'-((7-((2-methyl-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name6'-((7-((4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - 382yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- 383yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- 384yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneSingle isomer, unknown6'-((7-((4- (cyclopropylsulfonyl)phenyl)ami 385 no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4- (i sopropyl sulfonyl)pheny l)amino )-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-one6’-((7-((4- (cyclobutylsulfonyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-one6'-((7-((4- (cyclopropylsulfonyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one6'-((7-((4- (i sopropyl sulfonyl)pheny l)amino )-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4- (cyclobutylsulfonyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one3,3-diethyl-6-((7-((2-methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one6'-((7-((4- (ethylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one5-((2-aminopyridin-3- yl)ethynyl)-N-(4- (cyclopropylsulfonyl)phenyl)- 2,6-naphthyridin-3-amineAtty. Docket No.: 39953-62353 (008WO)Name5-((2-aminopyridin-3- yl)ethynyl)-N-(4- (i sopropyl sulfonyl)pheny 1 )-2, 6 - naphthyri din-3 -amine5-((2-aminopyridin-3- yl)ethynyl)-N-(4- (ethylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(imino)(i soprop yl)-16-sulfanoneSingle isomer, unknown6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)pyridazin-3 (2H)-one Single isomer, unknown6'-((7-((4- (ethylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- l,3'-indolin]-2'-oneAtty. Docket No.: 39953-62353 (008WO)Name6-((7-((3 -chloro-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6-((7-((4- (cyclopropylsulfonyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)-3,3-diethylindolin-2- one6-((7-((4- (cyclobutylsulfonyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)-3,3-diethylindolin-2- one6-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3-diethylindolin-2- oneSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown6-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3-diethylindolin-2- oneSingle isomer, unknown3,3-diethyl-6-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(cyclobutyl)(im ino)-16-sulfanone(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(cyclopropyl)(i mino)-16-sulfanoneSingle isomer, unknown5-((2-aminopyridin-3- yl)ethynyl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-aminopyridin-3- yl)ethynyl)-N-(5- (methylsulfonyl)pyridin-2-yl)- 2,6-naphthyridin-3-amine5-((2-aminopyridin-3- yl)ethynyl)-N-(2-methyl-4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name6-((7-((3 -fluoro-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6-((7-((2-chloro-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one3,3-dimethyl-6-((7-((2-methyl-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one3,3-dimethyl-6-((7-((6- (methylsulfonyl)pyridin-3- yl)amino)-2,6-naphthyridin-l- yl)ethynyl)indolin-2-oneAtty. Docket No.: 39953-62353 (008WO)Name3,3-diethyl-6-((7-((4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown3,3-diethyl-6-((7-((4- (i sopropyl sulfonyl)pheny l)amino )-2,6-naphthyridin-l - yl)ethynyl)indolin-2-oneAtty. Docket No.: 39953-62353 (008WO)Structure Name3,3-diethyl-6-((7-((4- (ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one6-((7-((4-(propan-2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyridazin-3 (2H)-one4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N-(l-methylpiperidin- 4-yl)benzenesulfonamide4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N-(piperidin-4- yl)benzenesulfonamide4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N-(tetrahydro-2H- pyran-4-yl)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Name4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N- cyclopropylbenzenesulfonamide6-((7-((4- (cyclopropanesulfonimidoyl)phe nyl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3 -dimethylindolin- 2-oneSingle isomer, unknown6-((7-((2-fluoro-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one3,3-dimethyl-6-((7-((5- (methylsulfonyl)pyridin-2- yl)amino)-2,6-naphthyridin-l- yl)ethynyl)indolin-2-oneAtty. Docket No.: 39953-62353 (008WO)Name6-((7-((2-methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one4-((5-((3,3-dimethyl-2- oxoindolin-6-yl)ethynyl)-2,6- naphthyri din-3 -yl)amino)-N- (piperidin-4- yl)benzenesulfonamide4-((5-((3,3-dimethyl-2- oxoindolin-6-yl)ethynyl)-2,6- naphthyri din-3 -yl)amino)-N- (tetrahydro-2H-pyran-4- yl)benzenesulfonamide6-((7-((4- (cyclopropylsulfonyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)-3,3 -dimethylindolin- 2-oneAtty. Docket No.: 39953-62353 (008WO)Name6'-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclopropane- l,3'-indolin]-2'-one4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N- ethylbenzenesulfonamide4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-3- methylbenzenesulfonamide4-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)-N-( 1 -methyl- 1 H- pyrazol-4- yl)benzenesulfonamide3,3-dimethyl-6-((7-((4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-dimethyl-6-((7-((4-(S- methylsulfonimidoyl)phenyl)ami no)-2,6-naphthyridin-l - yl)ethynyl)indolin-2-one Single isomer, unknown6-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3 -dimethylindolin- 2-oneSingle isomer, unknown6-((7-((4- (cyclobutanesulfonimidoyl)phen yl)amino)-2,6-naphthyridin-l- yl)ethynyl)-3,3 -dimethylindolin- 2-oneSingle isomer, unknown3,3-dimethyl-6-((7-((4-(propan- 2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name3,3-dimethyl-6-((7-((4-(propan- 2- ylsulfonimidoyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one Single isomer, unknownN-cyclobutyl-4-((5-((3,3- dimethyl-2-oxoindolin-6- yl)ethynyl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide6-((7-((4- (i sopropyl sulfonyl)pheny l)amino )-2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-one6-((7-((4- (ethylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3, 3 -dimethylindolin-2-oneAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name0 pHN 1) 6'-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 460 2,6-naphthyridin-l- yl)ethynyl)spiro[cyclobutane- Hl,3'-indolin]-2'-one'N°. XX XX^bX ry — HHX X-.l / \ X / \= Z A= Z A——3,3-diethyl-6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 4612,6-naphthyridin-l-... HN... f yl)ethynyl)indolin-2-oneN». O JI JL,'-- - 0HN6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - 462yl)ethynyl)-3,3 -dimethylindolin- H 2-one / VNS^V Single isomer, unknownHNXX XX^ 'b0HN6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - 463yl)ethynyl)-3,3 -dimethylindolin- H 2-oneSingle isomer, unknownH\XX XX^ 'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name""' NH24-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- 466 H yl)amino)-3- fluorobenzenesulfonamide H2N %XXFXX^^NH24-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- 467 H yl)amino)-3-fluoro-N- methylbenzenesulfonamide. %XXXXN 'nH °r^NL ifY^NH24-((5-((2-aminopyridin-3- I I yl)ethynyl)-2,6-naphthyridin-3- 468 H 1 yl)amino)-N-(4-(piperazin-l- yl)pyrimidin-2- yl)benzenesulfonamider1N N N N1 H °HNXXNX^NH24-((5-((2-aminopyridin-3- yl)ethynyl)-2,6-naphthyridin-3- 469 H 1 yl)amino)-N- methylbenzenesulfonamide °XJ XXN %H °\,FFHO / FN-N methyl(4-((5-(4-methyl-l-(3,3,3- X trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 470indazol-5-yl)-2,6-naphthyridin-3- H o Tc yl)amino)phenyl)(methylimino)- r¥ 16-sulfanoneo NA LN- / NY J. A 1i% AN / Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Nameethyl(imino)(4-((5-(4-methyl-l- (3,3,3 -trifluoro-2-hy droxy-2- 473 (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)phenyl)-16-sulfanone(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- 474 yl)amino)phenyl)(ethyl)(imino)- 16-sulfanoneSingle isomer, unknown4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2, 6-naphthyridin- 1 -yl)but-3 -yne- 1,2-diolN-(4-(methylsulfonyl)phenyl)-5- (py razol o [ 1, 5 -a] py ri din-3 - ylethynyl)-2,6-naphthyridin-3- amine5-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)benzo[d]oxazol- 2(3H)-oneAtty. Docket No.: 39953-62353 (008WO)Name(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(imino)(methyl) -16-sulfanoneSingle isomer, unknown(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(imino)(methyl) -16-sulfanoneSingle isomer, unknown6-((7-((4- (ethylsulfonimidoyl)phenyl)amin o)-2,6-naphthyridin-l - yl)ethynyl)pyridazin-3 (2H)-one3,3-dimethyl-6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)indolin-2-one(4-((5 -((2-aminopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- yl)amino)phenyl)(ethyl)(imino)- 16-sulfanoneAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name05-((7-((4-(S- "”'C methylsulfonimidoyl)phenyl)ami 491 no)-2,6-naphthyridin-l - yl)ethynyl)benzo[d]oxazol- H2(3H)-oneHN Jf J J I5-((4-aminopyrimidin-5- yl)ethynyl)-N-(4- 492(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine « - - D1) 6-((7-((4-(S- F.x0\ O' methylsulfonimidoyl)phenyl)ami 497no)-2,6-naphthyridin-l - yl)ethynyl)pyridazin-3 (2H)-one0■NHVA methyl 3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 4982,6-naphthyridin-l-yl)ethynyl)- H lH-indazole-6-carboxylateVU XXAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name5-((3-fluoro-4- methoxyphenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-chloro-3-methylpyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)oxazolo[4,5- b]pyridin-2(3H)-one5-([ 1, 2, 4]tri azolof 1,5-a]pyridin- 8-ylethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5 -((7 -fluoro- 1 H-indazol-3 - yl)ethynyl)-N-(4- 503(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine2,2-dimethyl-4-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 5042, 6-naphthyridin- 1 -yl)but-3 -yn- l-olN-(5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 505 2,6-naphthyridin-l- yl)ethynyl)thiazol-2- yl)acetamide3, 3 -di chi oro- 1 -(4-((7 -((4 - (methylsulfonyl)phenyl)amino)- 506 2,6-naphthyridin-l- yl)ethynyl)phenyl)piperidin-2- oneAtty. Docket No.: 39953-62353 (008WO)Name5-((5-methylpyrazin-2- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-fluoropyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-fluoro-5-methylpyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-methoxypyridazin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -aminel-methyl-5-((7-((4- (methylsulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyrazin-2(lH)-oneAtty. Docket No.: 39953-62353 (008WO)Name5-((lH-pyrrolo[3,2-c]pyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-cyclopropylpyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzo[d]oxazol- 2(3H)-one5-((2-chloro-7H-pyrrolo[2,3- d]pyrimidin-5-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Namemethyl 5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)picolinate5-((lH-pyrrolo[2,3-b]pyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyrimidine-2- carbonitrile5-((3-amino-4-methoxypyridin- 2-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name1J 4-((7-((4-(S- methylsulfonimidoyl)phenyl)ami 526no)-2,6-naphthyridin-l - H yl)ethynyl)benzonitrileHN [ J J. Tluc X5-((4-methoxy-2- methylphenyl)ethynyl)-N-(4- 527(methylsulfonyl)phenyl)-2,6- H naphthyri din-3 -amine<t JU ) z— A / ZX IZ XX F CxW u\ O' UJ ) l-(difluoromethyl)-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 5282,6-naphthyridin-l- Hyl)ethynyl)pyridin-2(lH)-one u °. XX XX5-((2-(difluoromethyl)pyridin-4- yl)ethynyl)-N-(4- 529(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5 -((2-amino-4-chl oro-3 - fluorophenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- ((1, 4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)ethynyl)-2,6-naphthyridin- 3 -amine6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- lH-indole-3-carbonitrile(6-amino-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyridin-3-yl)methanol5-((6-amino-5- (difluorom ethoxy )pyri din-3 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5-([ 1, 2, 4]tri azolof 1,5-a]pyridin- 5-ylethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine3-amino-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)picolinonitrile5 -((5 -aminopyridazin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-(dimethylamino)pyrimidin- 5-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5-((6-(difluoromethoxy)pyridin- 3-yl)ethynyl)-N-(4- 539(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((4,5-dimethylthiazol-2- yl)ethynyl)-N-(4- 540(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-amino-4,6- dimethylpyrimidin-5-yl)ethynyl)- 541N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-amine2-(6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 542 2,6-naphthyridin-l-yl)ethynyl)- lH-benzo[d]imidazol-2- yl)propan-2-olAtty. Docket No.: 39953-62353 (008WO)Name2-methyl-l-(6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- lH-benzo[d]imidazol- 1 - yl)propan-2-ol5-((4-(methylamino)pyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((lH-pyrazolo[3,4-b]pyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((4-amino-3,5- difluorophenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- ((l-(2,2,2-trifluoroethyl)-lH- pyrazol-4-yl)ethynyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5 -((4-fluoro- 1 H-indazol-3 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((5-amino-3-chloropyrazin-2- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine6-methyl-3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)picolinonitrile3 -fluoro-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzonitrileAtty. Docket No.: 39953-62353 (008WO)Name5-((3,5-dimethylpyrazin-2- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((2-amino-5 -fluoropyri din-3 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((2-amino-5 -fluoropyri din-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-amino-2-chloropyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((3 -amino- 1 H-pyrazol-5 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name2-fluoro-5 -((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)phenol5-((lH-pyrazolo[3,4-b]pyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine2-methyl-l-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- lH-pyrazolo[3,4-c]pyridin- 1 - yl)propan-2-ol5-((2-amino-4- (trifluoromethyl)phenyl)ethynyl) -N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-amineAtty. Docket No.: 39953-62353 (008WO)Name2-methyl-3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzonitrile5-((2-methylpyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- ((6-morpholinopyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- amine3 -amino-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzonitrileAtty. Docket No.: 39953-62353 (008WO)Name5-((6-methoxypyrimidin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((5-amino-2-chloropyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-amino-4- methylphenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine3-fluoro-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzonitrile5-((3-aminopyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5-((lH-indazol-3-yl)ethynyl)-N- (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((lH-pyrrolo[3,2-b]pyridin-6- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((4-amino-5-chloropyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-amino-6- chlorophenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-chloroimidazo[ 1,2- b]pyridazin-3-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5-((2-methoxypyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-amino-3-chloropyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-amino-6-methylpyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((5-methyl-lH-pyrazol-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyridin-2(lH)-oneAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5-((6-aminopyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-methoxypyrazin-2- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((5-fluoro-2-methoxypyridin- 4-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -aminemethyl 3-amino-6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyrazine-2- carb oxy late2-methyl-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 5892,6-naphthyridin-l- yl)ethynyl)benzonitrileAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name2-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 5962,6-naphthyridin-l- yl)ethynyl)phenyl)propan-2-olHN-NJU 5-(6-methyl-lH-indazol-5-yl)-N- 597 H I (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine VU NU / 4 / U-s'b 2 z —Z IU^NL ifY'' NH2o. Q 5-((2-aminopyridin-3-.iV yl)ethynyl)-N-(4- 598 \ O"H (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine°" XJ « JU0oHN-U5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 600 M2,6-naphthyridin-l-yl)indoline- 2, 3-dioneOK 1 J M 1 J-s'bHN-N(U 5-(lH-indazol-5-yl)-N-(4- 601 H I (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine rV Y^rSVU NUU-s'bAtty. Docket No.: 39953-62353 (008WO)Name3 -fluoro-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)phenol5-(benzo[d]oxazol-6-ylethynyl)- N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-aminemethyl 6-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-lH- indazole-3-carboxylate1-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)piperidin-l-yl)propan- 2-olSingle isomer, unknownAtty. Docket No.: 39953-62353 (008WO)Name1-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)piperidin-l-yl)propan- 2-olSingle isomer, unknown2-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)piperidin-l-yl)acetic acid2-methyl-2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)propanamide5-((lH-pyrazolo[3,4-c]pyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name6-chloro-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyridazin-3 (2H)-one5-((3-amino-l,2,4-triazin-6- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((5-(l-(2-hydroxyethyl)-4- methyl-lH-indazol-5-yl)-2,6- naphthyri din-3 -yl)amino)-2- (m ethyl sulfonyl)phenol2-(5 -(7 -((3 -methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-4-methyl- 1 H-indazol- 1 -yl)ethan- 1 -ol6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)pyridazin-3 (2H)-oneAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameN 3-(6-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 619 2,6-naphthyridin-l-yl)-3,4- dihy droi soquinolin-2( 1 H)- H yl)butan-l-ol<3 J CU JTV M Y JUS J^. N / V - z z ' ' N> - — 2-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6202,6-naphthyridin-l- H yl)ethynyl)phenyl)acetonitrile ^N°-'XJ OL-s'bH5-((lH-indazol-7-yl)ethynyl)-N- 621 H (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine %XJ XAYN'"[15-((5-aminopyrazin-2- yl)ethynyl)-N-(4- 622(methylsulfonyl)phenyl)-2,6- Hnaphthyri din-3 -amine°\ X J N 1x8.0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameJjN-(4-(methylsulfonyl)phenyl)-5- 623 H (pyridin-3-ylethynyl)-2,6- naphthyri din-3 -amine XX•XXNil2-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 624 H 2,6-naphthyridin-l-yl)isoindolin- 1-one°XJ XX<c )HX 6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6272,6-naphthyridin-l- Hyl)ethynyl)pyri din-3 -ol0 J J N 1 / SxV0f'^OHNl-(6-(7-((4- AT (m ethyl sulfonyl)phenyl)amino)- 628 2,6-naphthyridin-l-yl)-3,4- dihy droi soquinolin-2( 1 H)- H Tyl)propan-2-ol1 J KI 1 JAtty. Docket No.: 39953-62353 (008WO)NameN-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)phenyl)acetamideN-(2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-2H- indazol-2-yl)ethyl)acetamide5-((2-aminopyrimidin-5- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-methyl-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzamideAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name5-((l-cyclopropyl-lH-pyrazol-4- yl)ethynyl)-N-(4- 635(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((4- (difluoromethoxy)phenyl)ethynyl 636)-N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-amine5 -(( 1 -methyl - 1 H-py razol -5 - yl)ethynyl)-N-(4- 637(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((lH-indazol-6-yl)ethynyl)-N- 638 (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameOH / N / 'N A 2-(5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 639 (Y 2,6-naphthyridin-l-yl)-2H- H T indazol-2-yl)ethan- 1 -ol JU NU>N-methyl-2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 640 \ Z= Z A— 2,6-naphthyridin-l-yl)-lH- _ / / A A Z-U _ _ / \ A indazol- 1 -yl)acetamide / \ \ °iz O°^IZ I U \ yz / / zZ N II\ c u ur\ O' oc 2,3-dimethyl-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6432,6-naphthyridin-l- H yl)ethynyl)benzonitrileJ TUYV NUAUI 7-s'b2-methyl-7-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 6442,6-naphthyridin- 1 -yl)- 1,4- dihydroisoquinolin-3(2H)-oneAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5-((lH-indazol-5-yl)ethynyl)-N- (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((6-methoxypyridin-3- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)ethynyl)- 3-(trifluoromethyl)benzonitrile5 -(( 1 H-b enzo[d]imidazol -6- yl)ethynyl)-N-(4- 648(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name7-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 6492,6-naphthyridin- 1 -yl)- 1,4- dihydroisoquinolin-3(2H)-one2-fluoro-4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6502,6-naphthyridin-l- yl)ethynyl)benzonitrile2,3 -difluoro-4-((7 -((4- (m ethyl sulfonyl)phenyl)amino)- 6512,6-naphthyridin-l- yl)ethynyl)benzonitrile2-(4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6522,6-naphthyridin-l- yl)ethynyl)phenyl)ethan- 1 -olAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Namemethyl 4-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 653 \ 2,6-naphthyridin-l- \O x yl)ethynyl)piperidine-l- carb oxy lateu ZI -ZT.. / / z- z Z— N°0 / 0^ / —z~ # A / A— 5-(3-(l -methyl- IH-pyrazol -4- ^ f ' oz —— yl)pyrrolidin-l-yl)-N-(4- 654H V (methylsulfonyl)phenyl)-2,6- Os 1 fY J r K NI-xAA 1 A J naphthyri din-3 -amineN-N5-(4-chloro-2-methyl-2H- indazol-5-yl)-N-(4- 655 H yCl(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine<t JU NUU-8'b2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 6562,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)acetonitrileHO^JO 2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 657H O I C 2,6-naphthyridin-l-yl)-lH-indol- rrNY^A l-yl)ethan-l-ol%JU NUU-s'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name5-(7-methyl-lH-indazol-6-yl)-N- 658 (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((2-methoxypyridin-4- yl)ethynyl)-N-(4- 660(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine o_ _ / \ / / A\ Z A= Z—yy \ / / / =H 00O / V Az'z2Z I z — N-Njf AIZ 2-(5-(7-((4- (cyclopropylsulfonyl)phenyl)ami 662 no)-2,6-naphthyridin-l -yl)-4- HAo c m ethyl- IH-indazol- 1 -yl)ethan- 1 - \ O' rYNY0\ O' ol% JL J UJ0bHN-N0^5-((lH-pyrazol-4-yl)ethynyl)-N- 664 H (4-(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineOKC H Y \ V i Y H A \-s'bN I I0 4-((7-((4-((2- hydroxyethyl)sulfonyl)phenyl)a 665mino)-2,6-naphthyridin- 1 - H yl)ethynyl)benzonitrile ox1 rY JNT J"A N|-S A 01 JHO^-Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameC )HN^:> 5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 6672,6-naphthyridin-l- H\O x yl)ethynyl)pyridin-2(lH)-oneXW xX ZI h Ji 1hr) 5-((7-((4- — / / A A (m ethyl sulfonyl)phenyl)amino)- 669VXUz2,6-naphthyridin-l- H yl)ethynyl)picolinonitrile%XX XAXl-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 6722,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)propan-2-olH°\N-NX4-((5-(l-(2-hydroxyethyl)-4- methyl-lH-indazol-5-yl)-2,6- 673H naphthyri din-3 - yl)amino)benzenesulfonamide rf / X%AJ N, JjH2N sN-r / CHX X l-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 675 QCH | 2,6-naphthyridin-l-yl)-2H- indazol-2-yl)propan-2-ol °^X rJV rvANUU-s'bAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name2-(4-methyl-5-(7-((4- (m ethyl sulfonyl)phenyl)amino)- 6762,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)acetamideF A L-FH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- Ji (trifluoromethyl)propyl)- 1H- 679 indazol-5-yl)-2,6-naphthyridin-3- o _ / _ A / X Z#~ c yl)amino)benzenesulfonimidami H T deZ V°^^ Single isomer, unknown W I " JUH2N "NHIZFN F. 0 FAJ-FSA'H°\ o' N-cyclobutyl-4-((5-(4-methyl-l- N-N (3,3,3 -trifluoro-2-hy droxy-2- X (trifluoromethyl)propyl)- 1H- 680 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonimidami H derrVYN Single isomer, unknown n vU UJH NHFN FF'N^Z-FH0 / F N-cyclopropyl-4-((5-(4-methyl- N-N 1 -(3, 3,3 -trifluoro-2-hy droxy-2- X (trifluoromethyl)propyl)- 1H- 681 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)benzenesulfonimidami H | deSingle isomer, unknownA °SXJ^N' ''H NHAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameF \ J-FH0 / F N-methyl-4-((5-(4-methyl- 1 - N-N (3,3,3 -trifluoro-2-hy droxy-2- JL (trifluoromethyl)propyl)- 1H- 683 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonimidami H deSingle isomer, unknown vU NJU^N'S"H NH\,FFh° •'7' > 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- } A(trifluoromethyl)propyl)- 1H- 684 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)-N-(2,2,2- H 1trifluoroethyl)benzenesulfonamid XYYS eVUy FH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- 1 A (trifluoromethyl)propyl)- 1H- 685 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)-N- H T phenylbenzenesulfonimidamide ^¥Y A Single isomer, unknown ri vUN C H NH° / HNx jkN-cyclobutyl-4-((5-((3,3- dimethyl-2-oxoindolin-6- yl)ethynyl)-2,6-naphthyridin-3- 688yl)amino)benzenesulfonimidami H deSingle isomer, unknown oK1 H I H iH NHAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameF \ J-FH0 / F N-methyl-4-((5-(4-methyl- 1 - N-N (3,3,3 -trifluoro-2-hy droxy-2- JL (trifluoromethyl)propyl)- 1H- 689 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonimidami H deAV A Single isomer, unknown vU NJU^N'S"H NH NFF FAJ-FH0 / F N-cyclobutyl-4-((5-(4-methyl-l- N-N (3,3,3 -trifluoro-2-hy droxy-2- JL (trifluoromethyl)propyl)- 1H- 690 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonimidami H derArvA Single isomer, unknown n vU1UJH NH NFFH0 / F N-cyclopropyl-4-((5-(4-methyl- N-N 1 -(3, 3,3 -trifluoro-2-hy droxy-2- Ji (trifluoromethyl)propyl)- 1H- 691 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)benzenesulfonimidami H 1X der n r 11 A Single isomer, unknown A W W^Nx''H NHFN FF '^J-FH0 / F N-ethyl-4-((5-(4-m ethyl- 1 - N-N (3,3,3 -trifluoro-2-hy droxy-2- X (trifluoromethyl)propyl)- 1H- 692 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)benzenesulfonimidami H T deSingle isomer, unknown %AJ NJLJ-''X'"'NX''H NHAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Namey Ff \H0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- } A (trifluoromethyl)propyl)- 1H- 693 O ' O indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)-N- H | phenylbenzenesulfonimidamide Single isomer, unknown Q u )N ''H NH"'1ZTF\ / FF-nHTm0 / F 4-((5 -(4-methyl- 1 -(3,3,3- \ / t oz _ _ N-N trifluoro-2-hydroxy-2- j AOOOOv (trifluoromethyl)propyl)- 1H- 694 O”"Z / V> -n indazol-5-yl)-2,6-naphthyridin-3- OCH 1 yl)amino)-N-(5-methyl-6- morpholinopyridin-2- rrNr>iI l lAJ N JU yl)benzenesulfonamide l^N N N 1< UHV FF \ J-FH0 / FN-N N-ethyl-4-((5-(4-m ethyl- 1 - } A (3,3,3 -trifluoro-2-hy droxy-2- 695 (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- H yl)amino)benzenesulfonamide IYVYIW1MU'S''H0N-(5-methoxy-6- morpholinopyridin-2-yl)-4-((5- (4-m ethyl- 1 -(3, 3,3-trifluoro-2- 697 hydroxy-2- (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameFA UFH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 701 indazol-5-yl)-2,6-naphthyridin-3- H o I c yl)amino)-N-(5-methyl-4- morpholinopyridin-2- rt vOrNw yl)benzenesulfonamideFFvMH0 / F N-(5-methoxy-4- N 1-N A morpholinopyrimidin-2-yl)-4- ((5-(4-methyl-l-(3,3,3-trifluoro- 702 2-hydroxy-2- H o I c (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- vGNw yl)amino)benzenesulfonamide MHFyH0' \M F / FFN-(4-methoxy-6- N-N morpholinopyridin-2-yl)-4-((5- X (4-m ethyl- 1 -(3, 3,3-trifluoro-2- 703 hydroxy-2- ""0 H o I c (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- n w vu yl)amino)benzenesulfonamide MHyFF\M--FHO / F N-(6-methoxy-4- N )-N A morpholinopyridin-2-yl)-4-((5- (4-m ethyl- 1 -(3, 3,3-trifluoro-2- 704 hydroxy-2- M H O \ C (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide N N ''MHAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameF' NX-FHO7 S 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 706 indazol-5-yl)-2,6-naphthyridin-3- ocH T yl)amino)-N-(5-methyl-4- morpholinopyrimidin-2- yl)benzenesulfonamide XX VCXNW OHST FF^ XH0 / F N-(4-methoxy-6- N-N morpholinopyrimidin-2-yl)-4- X } ((5 -(4-methyl- 1 -(3, 3,3-trifluoro- 707 2-hydroxy-2- OC X H I (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- X A9SXJ XXN yl)amino)benzenesulfonamide X^N N N 'kOHFFNFFH07 X N-(3-(2-hydroxypropan-2-yl)-4- N-N methoxyphenyl)-4-((5-(4- X methyl- 1 -(3,3, 3 -trifluoro-2- 709 hydroxy-2- OC (trifluoromethyl)propyl)- 1H-HT indazol-5-yl)-2,6-naphthyridin-3- rYNyYS yl)amino)benzenesulfonamide Xl %xj iju'6FN >=FY-4-FH0' / XFN-(4-(2-hydroxypropan-2- N-Nyl)pyridin-2-yl)-4-((5-(4-methyl- 1 -(3, 3,3 -trifluoro-2-hy droxy-2- 710oc (trifluoromethyl)propyl)- 1H-H1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide n %xrNwHCT | H0Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameUFFF \ UH0' / XFN-N N-(6-(2-hydroxypropan-2- X yl)pyridin-2-yl)-4-((5-(4-methyl- 1 -(3, 3,3 -trifluoro-2-hy droxy-2- 711oc (trifluoromethyl)propyl)- 1H- H | indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A w NJUH(Z]NH 0FFNA JfFH0 / FN-(3-(2-hydroxypropan-2- N-Nyl)phenyl)-4-((5-(4-methyl- 1 - (3,3,3 -trifluoro-2-hy droxy-2- 712oc (trifluoromethyl)propyl)- 1H- H 1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A W w'0FFN"\ L F-FH0 / FN-N 4-((5 -(4-methyl- 1 -(3,3,3- trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 713 O indazol-5-yl)-2,6-naphthyridin-3- H 1yl)amino)-N-(2- morpholinophenyl)benzenesulfo n vu N JU namideY ' H 'bNuAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameNFFF-\ _ Z-FHO / FN-N N-(2-methoxyphenyl)-4-((5-(4- methyl- 1 -(3,3, 3 -trifluoro-2- hydroxy-2- 714(trifluoromethyl)propyl)- 1H- H indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide Cl vU wH oFJ FF. J-FH0' / XF4-((5 -(4-methyl- 1 -(3,3,3- N-Ntrifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 715indazol-5-yl)-2,6-naphthyridin-3- ocH 1 yl)amino)-N-(o- tolyl)benzenesulfonamide fn U MUH °y FF \ i-FH0 / FN-(3-methoxyphenyl)-4-((5-(4- N-Nmethyl- 1 -(3,3, 3 -trifluoro-2- hydroxy-2- 717(trifluoromethyl)propyl)- 1H- ocH 1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide n uu N< JUy FF' \_t-FH0 / FN-(4-methoxyphenyl)-4-((5-(4- N-Nmethyl- 1 -(3,3, 3 -trifluoro-2- hydroxy-2- 718(trifluoromethyl)propyl)- 1H- ocHindazol-5-yl)-2,6-naphthyridin-3- 1yl)amino)benzenesulfonamide UL NUU^^N%H0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameFN FF ' Z-FH0 / FN-(5-methoxypyridin-2-yl)-4- N-N) A ((5-(4-methyl-l-(3,3,3-trifluoro- 2-hydroxy-2- 719(trifluoromethyl)propyl)- 1H- ocH1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamideH 'o0\,FFF-\ j-FH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- JL (trifluoromethyl)propyl)- 1H- 720 OC indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(6- H T (trifluoromethyl)pyridin-2- yl)benzenesulfonamideF^X Nl N A.F [L H °H07 \|-NJL (S)-N-(sec-butyl)-4-((5-(l-(2- hydroxy-2-methylpropyl)-4- methyl-lH-indazol-5-yl)-2,6- 722H naphthyri din-3 - yl)amino)benzenesulfonamide rrNT^rS? W N< JU absolute''' / ''' HN'S'b07 FF V-t-FH0 / FN-N 4-((5 -(4-methyl- 1 -(3,3,3- X trifluoro-2-hydroxy-2- 726 (trifluoromethyl)propyl)- 1H- oc indazol-5-yl)-2,6-naphthyridin-3- H | yl)amino)benzenesulfonamide %A rJ¥NT N<" JYUSH2NAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameFJ FF \ U-FHO' / XF4-((5 -(4-methyl- 1 -(3,3,3- N-Ntrifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 727indazol-5-yl)-2,6-naphthyridin-3- ocH I yl)amino)-N-(pyrimidin-2- yl)benzenesulfonamideH °FN FF \ _ / U A / A z J- -FH0 / I34-((5 -(4-methyl- 1 -(3,3,3- N-Ns U trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 728 TZindazol-5-yl)-2,6-naphthyridin-3- ocH 1 yl)amino)-N- phenylbenzenesulfonamide uQ. w N JUH °J F^3FV-4-FH0 / FN-N N-benzyl-4-((5 -(4-methyl- 1- (3,3,3 -trifluoro-2-hy droxy-2- 729 (trifluoromethyl)propyl)- 1H- ocH T indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide uNru%JU NJU( j "0N-benzyl-4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 730indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameFH0' / XFN-NN-ethyl-4-((5-(4-m ethyl- 1 - (3,3,3 -trifluoro-2-hy droxy-2- (trifluoromethyl)propyl)- 1H- 731 ocH I indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(pyrimidin-2- rrY rSNYU yl)benzenesulfonamideNVHO / SN-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 734 ocyl)amino)-N-methyl-N- (pyrimidin-2- yl)benzenesulfonamide10FA A-FH0 / FN-(6-methoxypyridin-2-yl)-4- N-Ni A ((5-(4-methyl-l-(3,3,3-trifluoro- 2-hydroxy-2- 735(trifluoromethyl)propyl)- 1H- OCH | indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide JQ W wH0FJ FFY-X-FH0 / FN-(4,6-dimethylpyrimidin-2-yl)- N-N4-((5 -(4-methyl- 1 -(3,3,3- trifluoro-2-hydroxy-2- 736(trifluoromethyl)propyl)- 1H- OCindazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A tv' N N ''H0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameFN FF ' Z-FH0 / FN-(4-methoxypyrimidin-2-yl)-4- N-N) A ((5-(4-methyl-l-(3,3,3-trifluoro- 2-hydroxy-2- 737(trifluoromethyl)propyl)- 1H- ocH I indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide n vO " wX'O^N N ''H0H0 / XF 4-((5 -(4-methyl- 1 -(3,3,3- N-Nj A trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 738 indazol-5-yl)-2,6-naphthyridin-3- OCH | yl)amino)-N-(3- morpholinophenyl)benzenesulfo n %xj NJU namide00 H' '6\f FF'\_4-FH0 / FN-(3, 5 -dimethoxyphenyl)-4-((5 - N-Ni A (4-methyl- 1 -(3, 3,3-trifluoro-2- hydroxy-2- 739(trifluoromethyl)propyl)- 1H- OC^0 H I indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide n °sxj LJU\ rFF -\ i-FH0' / XF 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 740 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)-N-(4-HT (trifluoromethyl)pyridin-2- yl)benzenesulfonamide, n %xn x j^ N x'F [L H °Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameOFFF^K XFH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 741 indazol-5-yl)-2,6-naphthyridin-3- Cxhyl)amino)-N-(4- imorpholinopyridin-2- n vCTOT yl)benzenesulfonamide 0 '6yFF' \_t-FH0 / FN-(4,6-dimethoxypyridin-2-yl)- N-N4-((5 -(4-methyl- 1 -(3,3,3- trifluoro-2-hydroxy-2- 742(trifluoromethyl)propyl)- 1H- oc^0 H \ indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A. v T r ii Y1 1 vU NJUOX O N" ''H0FNFF\_t-FH0 / FN-(5-methoxypyrimidin-2-yl)-4- N-N) A ((5-(4-methyl-l-(3,3,3-trifluoro- 2-hydroxy-2- 743(trifluoromethyl)propyl)- 1H- OCH 1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide vU I / ON N ''H01FFFA L-FH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 744 indazol-5-yl)-2,6-naphthyridin-3- OC yl)amino)-N-(4-HT (trifluoromethyl)pyrimidin-2- yl)benzenesulfonamide.. O AO'IXJN N xxF [L H0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameFN FF ' / _FH0 / FN-(4,6-dimethoxypyrimidin-2- N-N) A yl)-4-((5 -(4-methyl- 1 -(3,3,3- trifluoro-2-hydroxy-2- 745(trifluoromethyl)propyl)- 1H- oc^0 H ] indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A0 N N ''H0HO j YN_N(S)-4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- / _ / _# A A Z~ indazol-5-yl)-2,6-naphthyridin-3- 746 o Tc H yl)amino)-N-(4-hydroxybutan-2- N U VU / 'A yl)benzenesulfonamide Q U 4J> IS, / \ absoluteIZ N OH0HH0 / ^N-N, k (R)-4-((5-(l-(2-hydroxy-2- \ o m" methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 747 o Tc H yl)amino)-N-(4-hydroxybutan-2- v UArMVY UA yl)benzenesulfonamide v S, / N? _x\ absolute / OH0H1 -(5 -(7 -((3 -bromo-4- (m ethyl sulfonyl)phenyl)amino)- 749 2,6-naphthyridin-l-yl)-4-methyl- 1 H-indazol- 1 -yl)-2- methylpropan-2-olH07 \-NJi 1 -(5 -(7 -((2-bromo-4- (m ethyl sulfonyl)phenyl)amino)- 750 OC 2,6-naphthyridin-l-yl)-4-methyl- H 1 1 H-indazol- 1 -yl)-2- YYN^'r^ methylpropan-2-ol''sAA'.BrN A'A'oAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameF X J-F N-(4-(4-(2-HOX^F hydroxyethyl)piperazin- 1 - N-N) A yl)pyrimidin-2-yl)-4-((5-(4- methyl- 1 -(3,3, 3 -trifluoro-2- 755 a hydroxy-2-hi (trifluoromethyl)propyl)- 1H- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamideHO-^N1X 1 H °FJ FF \ pH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- X (trifluoromethyl)propyl)- 1H- 756 indazol-5-yl)-2,6-naphthyridin-3- 0\H 1 yl)amino)-N-(4-(4- methylpiperazin-l-yl)pyrimidin- n %xiNw 2-yl)benzenesulfonamide X'N N N 'kHo TX jXj i1, 1, 1, 3,3, 3 -hexafluoro-2-((5-(4-H. X fluoro-7-((4- (m ethyl sulfonyl)phenyl)amino)- 7572,6-naphthyridin-l-yl)-4-methyl- A / N-N lH-indazol-l-yl)methyl)propan- 2-olF\ XOHFFAH0 / \|-NN-cyclohexyl-4-((5-(l-(2- hydroxy-2-methylpropyl)-4- 758 oc methyl-lH-indazol-5-yl)-2,6- H 1naphthyri din-3 - yl)amino)benzenesulfonamide [ ] %AJH0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / F 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- 759 indazol-5-yl)-2,6-naphthyridin-3- oc yl)amino)-N-(4- H 1 methylpyrimidin-2- yl)benzenesulfonamide n. WN' ''H0 / N~N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 760 ocH 1 yl)amino)-N-(l-(2- rrNrvA hydroxyethyl)piperi din-3 - l l o, L II i II Jyl)benzenesulfonamideN ''H0H0 / \|— N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 761 oc indazol-5-yl)-2,6-naphthyridin-3- H 1yl)amino)-N-(l-methylpiperidin- 1 1 C> I L^ 1NA J| Y 1A J 3-yl)benzenesulfonamide AAMA^H 0H0 / N-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 762 cH T yl)amino)-N-(l-(2- r T v n Y hydroxyethyl)piperidin-4- 1 1 W N< JU yl)benzenesulfonamideH0H0 / XN-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 763 OC indazol-5-yl)-2,6-naphthyridin-3- H |yl)amino)-N-(l-methylpiperidin- 4-yl)benzenesulfonamide ^ iA % XTN'nH0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / \-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 764 indazol-5-yl)-2,6-naphthyridin-3- H JL ^ yl)amino)-N-(piperidin-4- yl)benzenesulfonamideHO 'OON %H0HO7 \-NJi 1 -(5 -(7 -((2-methoxy-6- (methylsulfonyl)pyridin-3- 766 oc yl)amino)-2,6-naphthyridin-l- H 1 _ / / # A A Z~- yl)-4-methyl- IH-indazol- 1 -yl)-2- methylpropan-2-ol. S N O NU / . / A ZVL">'b 1 g YIZy FH07 S 4-((5 -(4-methyl- 1 -(3,3,3- N-N trifluoro-2-hydroxy-2- ZI (trifluoromethyl)propyl)- 1H- 769 [TY indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(4- d ° H Imorpholinopyrimidin-2- yl)benzenesulfonamide n %XX WI^N N N ''NVH4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 770 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(tetrahydrofuran-3- yl)benzenesulfonamideH0 / SN-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 771H yl)amino)-N-(l- methylpyrrolidin-3- -N7^. N YY yl)benzenesulfonamide ^^N 'kH0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 772yl)amino)-N-(4- morpholinopyridin-2- yl)benzenesulfonamideHO7 ~\|--NJL 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 773 o0^ H ^ _7 / A / z A~ c| yl)amino)-N-(5- morpholinopyridin-2- O. W MJ yl)benzenesulfonamideH ° IZHO / \-N. 0.. i A 4-((5-(l-(2-hydroxy-2- zi °'' methylpropyl)-4-methyl-lH- oc indazol-5-yl)-2,6-naphthyridin-3- 774 H 1 yl)amino)-N-(4-(2- 0 hydroxypropan-2-yl)pyridin-2- n vCT w yl)benzenesulfonamideH Q0^[ H0H0 / N-NN-(4,6- bis(trifluoromethyl)pyridin-2-yl)- 4-((5-(l-(2-hydroxy-2- 775 < •,methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- Fn> U< L yl)amino)benzenesulfonamide NAV^ ^'0N A F H0H0 / \l~N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 791 oc indazol-5-yl)-2,6-naphthyridin-3- H 1yl)amino)-N-(pyrrolidin-3-H / N~I o. L T I LJ yl)benzenesulfonamideNH 'n0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 792 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(piperi din-3 - p- yl)benzenesulfonamideIZO \ x" W xH0 / N-NA ZI JL 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 793 4 A indazol-5-yl)-2,6-naphthyridin-3- Hyl)amino)-N-(tetrahydro-2H-?— / zA / A A pyran-4-yl)benzenesulfonamide °jj N< JUVVzA— ^ HN'S'b0H07 \|-NJi N-cyclopropyl-4-((5-(l-(2- hydroxy-2-methylpropyl)-4- 794 methyl-lH-indazol-5-yl)-2,6- Hnaphthyri din-3 - rrVYA yl)amino)benzenesulfonamide A W MUA ''H0H0 / N-N] AN-ethyl-4-((5-(l -(2 -hydroxy -2- methylpropyl)-4-methyl-lH- 795 ocH | indazol-5-yl)-2,6-naphthyridin-3- xZ\ xNXx<?\ Ar n v TI Y yl)amino)benzenesulfonamide W NAU-^ M '®'H0H07 \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 796 indazol-5-yl)-2,6-naphthyridin-3- Hyl)amino)-N-0K k K NIzZ JU\^ xj methylbenzenesulfonamide "\ xSNH 'h0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- X methylpropyl)-4-methyl-lH- 797 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(pyrimidin-4- 0 yl)benzenesulfonamideIZO^H0 / N-N°'0 4-((5-(l-(2-hydroxy-2- ZI JL°'0 methylpropyl)-4-methyl-lH- ZIo^ _ / / A Azc indazol-5-yl)-2,6-naphthyridin-3- 798 ^ _ / Z / Z A AH | yl)amino)-N-(6- 5 i fz A.r V r i methoxypyridazin-3- — / Zi A / A YX l VJ g w -UU yl)benzenesulfonamideg IZ M / / —z~ / A # AH0IZVMzz^. 0 „OT 4-((5-(l-(2-hydroxy-2- ZI x OW 'xmethylpropyl)-4-methyl-lH- Z=Z ZI indazol-5-yl)-2,6-naphthyridin-3- 799 z=Z / ) z / \\ / yl)amino)-N-(6- / \\ / (trifluoromethyl)pyridazin-3- yl)benzenesulfonamide4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 800 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(6-methylpyridazin- 3-yl)benzenesulfonamideN-(3-fluoro-5-(2-hydroxypropan- 2-yl)phenyl)-4-((5-(l-(2- hydroxy-2-methylpropyl)-4- 801methyl-lH-indazol-5-yl)-2,6- naphthyri din-3 - yl)amino)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- X indazol-5-yl)-2,6-naphthyridin-3- 802 o yl)amino)-N-(3-(2- hydroxypropan-2- yl)phenyl)benzenesulfonamideIZO^4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- ZI ^ z indazol-5-yl)-2,6-naphthyridin-3- 803 J _ / / A / AZ.- ■yl)amino)-N-(3- f I r5 i fzz morpholinophenyl)benzenesulfo 4 Q namideIZ — / " Z / A / / / / —z~ / # A AC^ / HUzH07 \-N 4-((5-(l-(2-hydroxy-2- ZI methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 804 ocH 1 yl)amino)-N-(3- frV A methoxyphenyl)benzenesulfona £ 1 °UUQWNJU mideN-(3, 5 -dimethoxyphenyl)-4-((5 - ( 1 -(2-hy droxy-2-methylpropyl)- 805 4-methyl-lH-indazol-5-yl)-2,6- naphthyri din-3 - yl)amino)benzenesulfonamideH07 \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- oc indazol-5-yl)-2,6-naphthyridin-3- 806 H 1 yl)amino)-N-(3- (trifluoromethyl)phenyl)benzene sulfonamidep^Oi wF [L H °Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 807 oc indazol-5-yl)-2,6-naphthyridin-3- H 1yl)amino)-N-(m- tolyl)benzenesulfonamide n w wH0H0 / N-NN-(3, 5 -dimethylphenyl)-4-((5 -( 1 - (2-hydroxy-2-methylpropyl)-4- _ / / ZU A A- 808 OC methyl-lH-indazol-5-yl)-2,6- naphthyri din-3 - yl)amino)benzenesulfonamide u\ %xx ' IZCMH0H0 / \-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 809 OC\zindazol-5-yl)-2,6-naphthyridin-3- H Tyl)amino)-N- phenylbenzenesulfonamide T o / Q w MUH °HO'U^'n-n4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 810 OCi H I yl)amino)-N-(5-(2- HO Jhydroxypropan-2-yl)pyridin-2- V i Ou yl)benzenesulfonamide4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 811yl)amino)-N-(6-(2- hydroxypropan-2-yl)pyridin-2- yl)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / Vl-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 812 indazol-5-yl)-2,6-naphthyridin-3- H |yl)amino)-N-(6-methoxypyridin- 2-yl)benzenesulfonamide A w «A"" CT N A AH0H0 / N-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 813 oc indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(4-methoxypyridin- 2-yl)benzenesulfonamide XI vA WH0H0 / \|-NN-(4,6-dimethoxypyridin-2-yl)- 4-((5-(l-(2-hydroxy-2- 814 oc methylpropyl)-4-methyl-lH- ^0 H Iindazol-5-yl)-2,6-naphthyridin-3- A Ar Aii i yl)amino)benzenesulfonamide JU A1" AUAT 'N N ''H0H0 / N~NX 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- oc indazol-5-yl)-2,6-naphthyridin-3- 815 H 1 yl)amino)-N-(6- (trifluoromethyl)pyridin-2- FACL VA " AA yl)benzenesulfonamide> A N N %F H0H0 / \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- oc indazol-5-yl)-2,6-naphthyridin-3- 816H1 yl)amino)-N-(4- (trifluoromethyl)pyridin-2- yl)benzenesulfonamide A A " WF H0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 817 oc indazol-5-yl)-2,6-naphthyridin-3- H 1yl)amino)-N-(6-methylpyridin-2- yl)benzenesulfonamide JQ W MUH0H0 / N-NJL FT N-(4,6-dimethylpyridin-2-yl)-4- ((5-(l -(2-hydroxy-2- 818 OC methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- / / / _ _U zJ z A / A A / A yl)amino)benzenesulfonamide %XJN'OuH04 Q g MIZ IZ2-methyl- 1 -(4-methyl-5 -(7-((3 - methyl-4- 836. fO xW 0,.t (m ethyl sulfonyl)phenyl)amino)- \ \ \ O O'' 2,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)propan-2-ol1 -(5 -(7 -((3 -methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 837 2,6-naphthyridin-l-yl)-4-methyl- 1 H-indazol- 1 -yl)-2- methylpropan-2-olHOV \-NJi ft 1 -(5 -(7 -((2-methoxy-4- (m ethyl sulfonyl)phenyl)amino)- 838 OC 2,6-naphthyridin-l-yl)-4-methyl- H T1 H-indazol- 1 -yl)-2- O. A I JNM J. I J? methylpropan-2-olx'o 1Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameH0 / \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 841 oc indazol-5-yl)-2,6-naphthyridin-3- H 1 yl)amino)-N-(4-methylpyridin-2- \O xXW x yl)benzenesulfonamideH0J ' ZIH0 / 2 N-N \\ 4-((5-(l-(2-hydroxy-2- j ( u methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 842 O 1^U1H O I C yl)amino)-N-(6- X r ¥ / v — / z~ / A # A A. morpholinopyrida_ / Z A / AU~Vzii *■ zin-3- i %XJ N JU yl)benzenesulfonamideH0IZ Q 4H0 / \|-NN-(4-((5-(l -(2-hydroxy-2- methylpropyl)-4-methyl-lH- 843 indazol-5-yl)-2,6-naphthyridin-3- M / H yl)amino)phenyl)-l,3-dimethyl- u. IL \\ oAK^ ■w"— N J,0 r II r H y lH-pyrazole-4-sulfonamide '' N0H2-methyl-l-(4-methyl-5-(7-((4- (methylsulfonyl)-3- 844 (trifluoromethyl)phenyl)amino)- 2,6-naphthyridin-l -yl)- 1H- indazol- 1 -yl)propan-2-ol2-methyl-l-(4-methyl-5-(7-((2- methyl-4- 845 (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)propan-2-olAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameHOJ \-NJi 1 -(5 -(7 -((2-fluoro-4- (m ethyl sulfonyl)phenyl)amino)- 846 oc 2,6-naphthyridin-l-yl)-4-methyl- H T1 H-indazol- 1 -yl)-2- (D 1 u JJ Y J, U 1 S J methylpropan-2-ol ''s^^F'oH0 / \-NJi l-(5-(7-((2-chloro-4- (m ethyl sulfonyl)phenyl)amino)- 847 oc 2,6-naphthyridin-l-yl)-4-methyl- H 11 H-indazol- 1 -yl)-2- (D 1 u JJ Y Ji U 1 S J methylpropan-2-ol Sr'Y^CIN^YY'oH0 / XN-N2-methyl-l-(4-methyl-5-(7-((5- (methylsulfonyl)pyridin-2- 848 ocH 1 yl)amino)-2,6-naphthyridin-l-. N. ^I\L A.yl)- IH-indazol- 1 -yl)propan-2-ol d J WH0 / ^N-Nj A 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 849 ocyl)amino)-N-(5-(4- \ ^ r iT v H Y methylpiperazin-l-yl)pyrimidin- 2-yl)benzenesulfonamide ^N^N" NH0HO / ^N-Nj 'A, 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 850 OCO / '" Y H \ yl)amino)-N-(5- morpholinopyrimidin-2- Vx N JU yl)benzenesulfonamideN N" UH0Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name“A / ?0\1Nxethyl6-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 851 2,6-naphthyridin-l- ft yl)ethynyl)imidazo[ 1,2-IZo, H a]pyridine-2-carboxylate ft°Xj XXX A ZIcA (R)-6-((7-((5-(3,4- a ) dimethylpiperazin- 1 -y 1 ) - 6 - s hydroxypyridin-3-yl)amino)-2,6- 853naphthyridin-1- 1I 1 H yl)ethynyl)pyridazin-3 (2H)-one absoluteXJ XX HO N XN-(l-methyl-lH-imidazol-2-yl)- \ O'4-((5-(prop- 1 -yn- 1 -yl)-2,6- 854 ft naphthyri din-3 - yl)amino)benzenesulfonamideH07 XI-NX 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- oc indazol-5-yl)-2,6-naphthyridin-3- 855H 1 yl)amino)-N-(4-methyl-4H- l,2,4-triazol-3- o, i n i h i yl)benzenesulfonamide N^N " XH0sl-N'h5-((l -methyl- lH-indazol-5- yl)ethynyl)-N-(4- 856(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name5 -(b enzo [d] [ 1, 3 ] di oxol -5 - ylethynyl)-N-(4- 857(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- 858 ((4-(methylthio)phenyl)ethynyl)- 2,6-naphthyridin-3-amine5-((2-methyl-2H-indazol-6- yl)ethynyl)-N-(4- 859(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((4-fluoro- 1 H-indazol-6- yl)ethynyl)-N-(4- 860(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameOHL L h 7-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 8612,6-naphthyridin-l- yl)ethynyl)quinazolin-4-ol T x r x0N N —H4-((5 -((4-(4-methylpiperazin- 1 - ( yl)phenyl)ethynyl)-2,6- b864 naphthyri din-3 -yl)amino)-N- (pyrimidin-2- H yl)benzenesulfonamide ^NCt %XJ NJLN N %H0C HN^ (S)-6-((7-((5-(3,4- ) dimethylpiperazin- 1 -y 1 ) - 6 - s hydroxypyridin-3-yl)amino)-2,6- 865naphthyridin-1- 11 1 H yl)ethynyl)pyridazin-3 (2H)-one ^N absoluteHO x Ny xx06-((7-((6-hydroxy-5-(4-(2- "6hydroxyethyl)piperazin- 1 - 866 yl)pyridin-3-yl)amino)-2,6-HO^N^H1 1 naphthyridin-1- yl)ethynyl)pyridazin-3 (2H)-one X YY N uXA X iHO NAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 867yl)amino)-N-( 1 -methyl- 1 H- imidazol-2- yl)benzenesulfonamideN-(4,6-difluoropyrimidin-2-yl)- 4-((5-(l-(2-hydroxy-2- 868 methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide5-((6-ethoxypyridin-3- yl)ethynyl)-N-(4- 869(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- ((6-(trifluoromethyl)pyri din-3 - yl)ethynyl)-2,6-naphthyridin-3- amineAtty. Docket No.: 39953-62353 (008WO)Name5 -((3, 5 -difluoropyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((2, 5 -difluoropyridin-4- yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((5 -fluoropyri din-3 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5 -((6-fluoropyri din-3 - yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(4-(methylsulfonyl)phenyl)-5- ((3,4,5-trifluorophenyl)ethynyl)- 2,6-naphthyridin-3-amineAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameJc: r4-((5 -((4-(4-methylpiperazin- 1 - yl)phenyl)ethynyl)-2,6- 876 c naphthyri din-3 - yl)amino)benzenesulfonamide H '°\ g JL y T X / i XH2NH N-(4-morpholinopyrimidin-2-yl)- 4-((5-(prop- 1 -yn- 1 -yl)-2,6- 878 ^x^Nxi< J< Xr / naphthyri din-3 - kl yl)amino)benzenesulfonamide Ox>HN-(4-methoxypyrimidin-2-yl)-4- H ((5-(prop- 1 -yn- 1 -yl)-2,6- 879 ^Yx^N^x^ X'N naphthyri din-3 - yl)amino)benzenesulfonamide X) £ NI NH% " X0XJ kXH0 / N-NN-(5-fluoropyrimidin-2-yl)-4- ((5-(l -(2-hydroxy-2- 880 ex methylpropyl)-4-methyl-lH- H 1indazol-5-yl)-2,6-naphthyridin-3- Y Nl N v yl)amino)benzenesulfonamide " 'kH0Or WH0 / \-NN-(4-fluoropyrimidin-2-yl)-4- ((5-(l -(2-hydroxy-2- 881 ex methylpropyl)-4-methyl-lH- H 1indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide F^ rNt N ''H0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name5-((5-methoxypyridin-3- yl)ethynyl)-N-(4- 882(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine5-((4-methyl-lH-imidazol-5- yl)ethynyl)-N-(4- 883(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineN-(5-methylpyrimidin-2-yl)-4- ((5-(prop- 1 -yn- 1 -yl)-2,6- 889naphthyri din-3 - yl)amino)benzenesulfonamideN-(4,6-dimethoxypyrimidin-2- yl)-4-((5-(prop- 1 -yn- 1 -yl)-2,6- naphthyri din-3 - yl)amino)benzenesulfonamide4-((5-(prop- 1 -yn- 1 -yl)-2,6- naphthyri din-3 -yl)amino)-N-(4- 891(trifluoromethyl)pyrimidin-2- yl)benzenesulfonamide4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 892yl)amino)-N-(4-(4- methylpiperazin-l-yl)pyrimidin- 2-yl)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 893yl)amino)-N-(4- morpholinopyrimidin-2- yl)benzenesulfonamideH07 \-NX 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 894 o^ _7 / A / A z~F H | c yl)amino)-N-(5-F^XX H °S(trifluoromethyl)pyrimidin-2-°-CJ yl)benzenesulfonamideIZ XXX. 0..H0 / N-Nzi °'' X N-(5-chloropyrimidin-2-yl)-4- oc ((5-(l -(2-hydroxy-2- 895 methylpropyl)-4-methyl-lH- H 1indazol-5-yl)-2,6-naphthyridin-3-C|\^N Y yl)amino)benzenesulfonamide Yl vU JJUN N A.H0H0 / \|-NX 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 896H o 1c yl)amino)-N-(5- v methylpyrimidin-2- yl)benzenesulfonamideNi N v 'k0a"roHH0 / N-NX 4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 897H O TC yl)amino)-N-(4- methoxypyrimidin-2- yl)benzenesulfonamide X A'\y 'N N %\kH0'C^ XX)1Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameH0 / Vl-NN-(4,6-dimethoxypyrimidin-2- yl)-4-((5-(l-(2-hydroxy-2- 898 methylpropyl)-4-methyl-lH- ^0 H Iindazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide A vQNW0 N N ''H0SN:'x 5-((3-methylisothiazol-5- yl)ethynyl)-N-(4- 899H (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine °XX XX\sx5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 900 2,6-naphthyridin-l- H yl)ethynyl)thiophene-2- carbonitrile<3 XX XX / =N.ZNH5-((5-methyl-lH-imidazol-2- yl)ethynyl)-N-(4- 901H (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineX °XX XXX i ^ xNY^OH3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 902 H 2,6-naphthyridin-l- yl)ethynyl)pyridin-2-olA (IVJ Y N^XJUS0Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameN-(4-methylpyrimidin-2-yl)-4- H ((5-(prop- 1 -yn- 1 -yl)-2,6- 905naphthyri din-3 - f x °sXI lA yl)amino)benzenesulfonamide •'-" N N" AH0H07 \|-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 906 ocH 1 yl)amino)-N-(5- methoxypyrimidin-2- ^ / / _ A / AZ. ■yl)benzenesulfonamide'X N y N. X^ / q / H0g wIZ / A / 4-((5-(l-(2-hydroxy-2- 2 z — methylpropyl)-4-methyl-lH- IZindazol-5-yl)-2,6-naphthyridin-3- 907 „oZT yl)amino)-N-(4- (trifluoromethyl)pyrimidin-2- Q.<\ Z yl)benzenesulfonamide\ / X O / "H0 / N-N4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 908 OCH T yl)amino)-N-(4- methylpyrimidin-2- n vG 'w yl)benzenesulfonamideN XH05-((2-methoxy-3-methylpyridin- 4-yl)ethynyl)-N-(4- 909(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amineAtty. Docket No.: 39953-62353 (008WO)Name5-((6-methoxy-4-methylpyridin- 3-yl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine3-fluoro-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)phenol5-((4-fluoro-3- methoxyphenyl)ethynyl)-N-(4- (methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine2-amino-4-fluoro-5-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l- yl)ethynyl)benzoic acid6-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- yl)amino)thiochromane 1,1- dioxideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name5-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- indazol-5-yl)-2,6-naphthyridin-3- 915yl)amino)-2,3- dihydrobenzo[b]thiophene 1,1- dioxidel-(5-(7-((3-(4-(2- hydroxyethyl)piperazin- 1 -yl)-4- (m ethyl sulfonyl)phenyl)amino)- 919^ _7 / / A z A- 2,6-naphthyridin-l-yl)-4-methyl- 1 H-indazol- 1 -yl)-2- ^ z_ / A / A methylpropan-2-olg MIZg uHO7 \-NIZ4-((5-(l-(2-hydroxy-2- IZ.—' methylpropyl)-4-methyl-lH- 921 ocOv"' H 1 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)benzenesulfonamide b ' C) 0 / k00 K NI<s / J0 JoH2sNT.H0 / N-N2-methyl-l-(4-methyl-5-(7-((4- oc (morpholinosulfonyl)phenyl)ami 922 H T no)-2,6-naphthyridin-l-yl)-lH- C) 1 rV J r KI v 1 A J indazol- 1 -yl)propan-2-ol'oH0 / ^N-N] \\2-methyl-l-(4-methyl-5-(7-((4- oc (piperidin-1- 923 H T yl sulfonyl)phenyl)amino)-2, 6- naphthyridin- 1 -yl)- IH-indazol- 1 - O 0 / 1\^ J K NI / / 10 ^ J yl)propan-2-ol / \ Sr N ''[ J °Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 924 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(pyridin-2- p yl)benzenesulfonamideIZO \ x" W xHO7 \-NZI Ji4-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 925H 0 _ / / Z A A^ / 7 _ A z A / indazol-5-yl)-2,6-naphthyridin-3-r¥NyA4 _ / / / Z. A A- ■ yl)amino)benzenesulfonic acidaJJ — / * A / s NJJ AH0'b 4 MIZ g wIZ IZN-(4,6-dimethylpyrimidin-2-yl)-. 0. xotxW k 4-((5-(l-(2-hydroxy-2- 926 / O zz „z.>r<Z '—x°' 'I methylpropyl)-4-methyl-lH- 0X° indazol-5-yl)-2,6-naphthyridin-3- A5 yl)amino)benzenesulfonamide (54-((5-(l-(2-hydroxy-2- methylpropyl)-4-methyl-lH- 927 indazol-5-yl)-2,6-naphthyridin-3- yl)amino)-N-(pyrimidin-2- yl)benzenesulfonamide2-methyl- 1 -(4-methyl-5 -(7-((3 - (4-methylpiperazin- 1 -yl)-4- 931 (m ethyl sulfonyl)phenyl)amino)- 2,6-naphthyridin-l-yl)-lH- indazol- 1 -yl)propan-2-olAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameN4-((7-((4-((4-methylpiperazin- 1 - yl)sulfonyl)phenyl)amino)-2,6- 933naphthyridin-1- yl)ethynyl)benzonitrile4-((7-((4- (morpholinosulfonyl)phenyl)ami 934no)-2,6-naphthyridin-l - yl)ethynyl)benzonitrile4-((5-((4-cyanophenyl)ethynyl)- 2,6-naphthyridin-3-yl)amino)-N- 935(pyridin-2- yl)benzenesulfonamide4-((5-((4-cyanophenyl)ethynyl)- 2,6-naphthyridin-3-yl)amino)-N- (4,6-dimethylpyrimidin-2- yl)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name5-((4-methoxyphenyl)ethynyl)- 941 N-(4-(methylsulfonyl)phenyl)- 2,6-naphthyridin-3-amine4-((7-((3- (m ethyl sulfonyl)phenyl)amino)- 9422,6-naphthyridin-l- yl)ethynyl)benzonitrile5-((4-chlorobicyclo[2.2.2]octan- 1 -yl)ethynyl)-N-(4- 944(methylsulfonyl)phenyl)-2,6- naphthyri din-3 -amine3-((7-((4- (m ethyl sulfonyl)phenyl)amino)- 945 2,6-naphthyridin-l- yl)ethynyl)bicyclo[ 1.1.1 ]pentane -1 -carboxamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Namerr? rr ° 4-((7-((4- H(m ethyl sulfonyl)phenyl)amino)- 946 2,6-naphthyridin-l- yl)ethynyl)bicyclo[2.2.2]octane- 1 -carbonitrileN1 8-((4-cyanophenyl)ethynyl)-2- ((4- (m ethyl sulfonyl)phenyl)amino)q 'O / uinazoline-7-carbonitrile 955N^. ( _ / / \ A \ x,z—— / zIZ8-(cyclohex- 1 -en- 1 -yl)-N-(4- (methylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-2-amine 956\ O't 1 J 8-(4-cyanopiperidin-l-yl)-2-((4- 1 (m ethyl sulfonyl)phenyl)amino)q uinazoline-7-carbonitrile 957N^JJHjOf ooN II l-(2-((4- (m ethyl sulfonyl)phenyl)amino)p yrido[3,4-d]pyrimidin-8- yl)piperidine-4-carbonitrile 958H | / N / N vVkO0Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Namesi l-(6-((4- (m ethyl sulfonyl)phenyl)amino)- l,7-naphthyridin-4-yl)piperidine- 4-carbonitrile959H; XX XX'oh l-(6-((4- 1 1 (m ethyl sulfonyl)phenyl)amino)p yrido[3,4-d]pyrimidin-4- yl)piperidine-4-carbonitrile 960 rH |XNh k C / / SsXX N r K C / 0N l-(2-((4- I I 0 °IZ (m ethyl sulfonyl)phenyl)amino)q >=Z uinazolin-8-yl)piperidine-4- \ / \ / Z\ / ^ carbonitrile9611 HOCI XX?I Z8-(l-(2-hydroxyethyl)-4-methyl- lH-indazol-5-yl)-2-((4- (m ethyl sulfonyl)phenyl)amino)q uinazoline-7-carbonitrile 962HO 2-(4-methyl-5-(2-((4- N-N (m ethyl sulfonyl)phenyl)amino)p yrido[3,4-d]pyrimidin-8-yl)-lH- indazol- 1 -yl)ethan- 1 -ol963HzxXvVk,xXJ O X-s'bAtty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure Name8-(2,4-dimethyl-2H-indazol-5- N-l / H A yi)-2-((4- (m ethyl sulfonyl)phenyl)amino)q uinazoline-7-carbonitrile 964 QCNKJ'NVK, / ..XXI XX?8-(2,4-dimethyl-2H-indazol-5- N-NZyl)-N-(4- (methylsulfonyl)phenyl)pyrido[3 w>,,4-d]pyrimidin-2-amine965 -oHz / X X A A I roc> N II N 1 X i N 1 N 1\ VF~^yoHN-N 3 -fluoro-4-((8-(4-methyl- 1 -(3,3,3 - I trifluoro-2-hydroxy-2- 1001 (trifluoromethyl)propyl)- 1H- JO indazol-5 -yl)pyrido[3,4- T H d]pyrimidin-2- yl)amino)benzenesulfonamide C XXX\^ XNXI z°NH24-((8-(4-methyl-l-(3,3,3-trifluoro-2- hydroxy-2-(trifluoromethyl)propyl)- 1002 lH-indazol-5 -yl)pyrido [3,4- d]pyrimidin-2- yl)amino)benzenesulfonamideAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure NameF7\0HN-methyl-4-((8-(4-methyl-l-(3,3,3- A N-N trifluoro-2-hydroxy-2- [ (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- 1003 JO d]pyrimidin-2- T H yl)amino)benzenesulfonimidamide N y^ y^ N(single enantiomer - relative |l A / N U J, NH",s" stereochemistry)OZ XN HQ Qo.ZI3-fluoro-N-(methyl-d3)-4-((8-(4- x W methyl-1 -(3,3,3 -trifluoro-2- 1004 hydroxy-2-(trifluoromethyl)propyl)- lH-indazol-5 -yl)pyrido [3,4- d]pyrimidin-2- yl)amino)benzenesulfonamide-X3-fluoro-N-methyl-4-((8-(4-methyl- A N-N X 1 -(3,3,3 -trifluoro-2-hydroxy-2- 1005 (trifluoromethyl)propyl)- 1H- JO indazol-5 -yl)pyrido[3,4- 1 H d]pyrimidin-2- N yr yr A yl)amino)benzenesulfonamide UUFXIS^n0z NHAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name2,3-difluoro-4-((8-(4-methyl-l- (3,3,3 -trifluoro-2-hydroxy-2- 1006 (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- d]pyrimidin-2- yl)amino)benzenesulfonamide->-ACM I N-methyl-4-((8-(4-methyl-l-(3,3,3- A N-N L k C zZtrifluoro-2-hydroxy-2- K c / 1007 J0 p, (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- T H d]pyrimidin-2-N^N yl)amino)benzenesulfonamide IZ U- Sxzn0z NHF^ y' °HA N-N i N-(methyl-d3)-4-((8-(4-methyl-l- (3,3,3 -trifluoro-2-hydroxy-2- 1008 J0 (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- T H d]pyrimidin-2- yl)amino)benzenesulfonamide N U\JYZ U1L? n >□o' H °FF'KZ VZ y0'HF1,1, 1,3,3,3 -hexafluoro-2-((5 -(2-((2- fluoro-4-(S- N-N methylsulfonimidoyl)phenyl)amino) pyrido[3,4-d]pyrimidin-8-yl)-4- 1009 jQ methyl- IH-indazol- 1 - T yl)methyl)propan-2-olH NA"NTNy^ (single enantiomer - relative AU stereochemistry)HN"Atty. Docket No.: 39953-62353 (008WO) Cpd. No. Structure NameE V1,1, 1,3,3,3 -hexafluoro-2-((5 -(2-((2- fluoro-4-(S- N-N methylsulfonimidoyl)phenyl)amino) A ipyrido[3,4-d]pyrimidin-8-yl)-4- 1010 methyl- IH-indazol- 1 - yl)methyl)propan-2-ol1 H(single enantiomer - relative t X I X 1 z° stereochemistry)HN' A " COx" O / Z y0H3-fluoro-N-methyl-4-((8-(4-methyl- N-N 1 -(3,3,3 -trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- A i x O / x OT indazol-5 -yl)pyrido[3,4-z? '1011 d]pyrimidin-2- JO yl)amino)benzenesulfonimidamide T HN NT il (single enantiomer - relative 11 A KI k J NHstereochemistry)p ■ 'O' NHkX1,1, 1,3,3,3 -hexafluoro-2-((4- methyl-5-(2-((4-(S- methylsulfonimidoyl)phenyl)amino) pyrido[3,4-d]pyrimidin-8-yl)-lH- 1012indazol- 1 -yl)methyl)propan-2-ol (single enantiomer - relative stereochemistry)1,1, 1,3,3,3 -hexafluoro-2-((4- methyl-5-(2-((4-(S- methylsulfonimidoyl)phenyl)amino) pyrido[3,4-d]pyrimidin-8-yl)-lH- 1013indazol- 1 -yl)methyl)propan-2-ol (single enantiomer - relative stereochemistry)Atty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name1 -imino-5 -((8-(4-methyl- 1 -(3,3,3 - trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- 1014 d]pyrimidin-2-yl)amino)-2,3- dihydrobenzo[b]thiophene 1 -oxide (single enantiomer - relative ZI ZIstereochemistry)\ I I / \?xo O1 -imino-5 -((8-(4-methyl- 1 -(3,3,3 - trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- 1015 d]pyrimidin-2-yl)amino)-2,3- dihydrobenzo[b]thiophene 1 -oxide (single enantiomer - relative stereochemistry)N-methyl-4-((8-(4-methyl-l-(3,3,3- trifluoro-2-hydroxy-2- A N-N k (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- 1016 d]pyrimidin-2- JO yl)amino)benzenesulfonimidamide 1 H(single enantiomer - relative (XJ X1"NHstereochemistry)3-fluoro-N-methyl-4-((8-(4-methyl- / y0HN-N 1 -(3,3,3 -trifluoro-2-hydroxy-2- A k (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- 1017J0 d]pyrimidin-2- yl)amino)benzenesulfonimidamide T Hfl I V | ll NH (single enantiomer - relative k-^k^-N A Jk / / stereochemistry)ou'NHAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name3 -fluoro-4-((8-(7 -fluoro-4-methyl- 1 - (3,3,3 -trifluoro-2-hydroxy-2- 1018 (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- d]pyrimidin-2- yl)amino)benzenesulfonamideVF4 AFF / \'OHM CN-N T 3-fluoro-4-((8-(4-(methyl-d3)-l- A i k C / z(3,3,3 -trifluoro-2-hydroxy-2- 1019 K C / (trifluoromethyl)propyl)- 1H- □JU indazol-5 -yl)pyrido[3,4- D'T T H d]pyrimidin-2- D / k / N. yl)amino)benzenesulfonamide IZ u.[l A KI 11 A PNH2F VF-A Z~ FFZY'°HN-N 3-fluoro-4-((8-(4-(methyl-d3)-l- (3,3,3 -trifluoro-2-hydroxy-2- 1020 (trifluoromethyl)propyl)- 1H- □JO indazol-5 -yl-3 -d)pyrido [3,4- d]pyrimidin-2-D DN V A, yl)amino)benzenesulfonamide U A KI 1 A 9NH2Z y0HN-methyl-4-((8-(4-methyl-l-(3,3,3- N-N trifluoro-2-hydroxy-2- A £ (trifluoromethyl)propyl)- 1H- 1021 indazol-5 -yl)pyrido[3,4- JO d]pyrimidin-2- 1 H yl)amino)benzenesulfonimidamide N nT HA KI L 1 NHSx.c0<NHAtty. Docket No.: 39953-62353 (008WO)Cpd. No. Structure Name1,1, 1,3,3,3 -hexafluoro-2-((5 -(2-((2- fluoro-4-(S- 1022 methylsulfonimidoyl)phenyl)amino) pyrido[3,4-d]pyrimidin-8-yl)-4- A ' methyl- IH-indazol- 1 - yl)methyl)propan-2-olZI n" W-X / N-N 3-fluoro-N-methyl-4-((8-(4-methyl- A i l-(3,3,3-trifluoro-2-hydroxy-2- 1023 (trifluoromethyl)propyl)- 1H- indazol-5 -yl)pyrido[3,4- T H d]pyrimidin-2- N il yl)amino)benzenesulfonimidamide U A M k 11 NHd- aF VF-V <FZ y0HN-NA i 1,1, 1,3,3,3 -hexafluoro-2-((4- methyl-5-(2-((4-(S- 1024 methylsulfonimidoyl)phenyl)amino)JO pyrido[3,4-d]pyrimidin-8-yl)-lH- 1 H indazol- 1 -yl)methyl)propan-2-ol t X I X i pHNt VFX y°HN-N 1 -imino-5 -((8-(4-methyl- 1 -(3,3,3 - A trifluoro-2-hydroxy-2- 1025 (trifluoromethyl)propyl)- 1H- JO indazol-5 -yl)pyrido[3,4- T H d]pyrimidin-2-yl)amino)-2,3- dihydrobenzo[b]thiophene 1 -oxide V r ¥ YV>¥V YAs<HNX°Atty. Docket No.: 39953-62353 (008WO)

[0311] It is understood that any of the compounds shown herein (e.g., Table 3 or Table 8) may be present in a salt form. In some cases, the salt form of the compound is a pharmaceutically acceptable salt (e.g., Table 3 or Table 8). It is understood that isotopically labelled derivatives of any of the compounds shown herein (e.g., Table 3 or Table 8) are included in the present disclosure. It is further understood by those of skill in the art that the compounds of the present disclosure can be prepared as isotopologues or isotopomers (e.g., Table 3 or Table 8) through conventional methods and through those exemplified herein.

[0312] “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.

[0313] 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 5-6 may be present in a prodrug form.

[0314] 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.

[0315] 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,nC,13C,14C,15N,18F,31P,32P,35S,36C1, 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 emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or inAtty. Docket No.: 39953-62353 (008WO)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.

[0316] 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.

[0317] Isotopologue - Isotopic analogue. An isotopologue refers to a molecule that contains one or more isotopic substitutions, where isotopes of the same element are replaced with each other. Isotopologues have the same chemical formula but differ in the distribution of isotopes within the molecule. These substitutions can occur in different positions or in different isotopic ratios, leading to variations in the physical and chemical properties of the molecule. For example, a, a, a-tri deuterotoluene is an isotopologue of toluene and vice versa. See below.

[0318] Isotopomer - Isotopic isomer. Isotopomer refers to a specific isotopic species of a molecule. Unlike isotopologues, isotopomers have the same isotopic substitutions but differ in the arrangement or connectivity of the isotopes within the molecule. This means that isotopomers have the same isotopic composition but vary in their structural isomers. For example, a, a, a-tri deuterotoluene and a,a-dideutero-2-deuterotoluene are isotopomers, see below.

[0319] Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N. Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society ofAtty. Docket No.: 39953-62353 (008WO)Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0320] Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.

[0321] In some embodiments, a radionuclide is incorporated in the compounds of this disclosure to provide radio-labeled compounds, where the particular radionuclide selected will depend on the specific application of that radio-labeled compound. For example, for in vitro labeling and competition assays, compounds that incorporate3H,14C,82Br,125I,131I or35S can be useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br or77Br can be useful.

[0322] It is understood that a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of3H,14C,125I,35S and82Br.

[0323] The present disclosure can further include synthetic methods for incorporating radio-isotopes into compounds of the disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of disclosure.

[0324] In some embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of any one of Formulas I-XIIB, or exemplary compounds of Tables 1-3 and 8. 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, R33, R34, R35, R36, R37, R38, R39, R40, R, R’, and R” etc. For example, when 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.Atty. Docket No.: 39953-62353 (008WO)4.2 Pharmaceutical Compositions

[0325] Also provided herein is a pharmaceutical composition comprising the subject CDK2 inhibitor compounds and a pharmaceutically acceptable carrier or excipient.

[0326] 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 different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like.

[0327] 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.

[0328] 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.

[0329] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope ofAtty. Docket No.: 39953-62353 (008WO)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.

[0330] A pharmaceutically acceptable carrier, diluent or excipient for therapeutic use are well known in the pharmaceutical art, arid 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, 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

[0331] Also provided herein are methods for using the subject CDK inhibitor compounds and pharmaceutical compositions in research and as therapeutics. Also provided herein is the use of a compound of the present disclosure in the treatment of a disease or disorder and / or the use of a compound in the manufacture of a medicament for the treatment of a disease or disorder.4.4.1 Methods of Inhibiting CDK

[0332] As illustrated in the working examples the subject compounds can inhibit cyclin-dependent kinases such as CDK2. 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 aAtty. Docket No.: 39953-62353 (008WO)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).

[0333] 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.

[0334] Accordingly, in some embodiments there is provided a method of inhibiting cyclin-dependent kinase (e.g., CDK2), 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.

[0335] 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 cases, the sample is a cellular sample.

[0336] In certain embodiments the CDK (e.g., CDK2) inhibitor is a compound as defined herein. In some embodiments, the CDK (e.g., CDK2) inhibitor is an inhibitor according to any one of Formulas I-XIIB, or exemplary compounds of Tables 1-4, or a pharmaceutically acceptable salt thereof.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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 CDK2Atty. Docket No.: 39953-62353 (008WO)over CDK4, and / or CDK6. In some embodiments, the subject compounds selectively inhibit CDK2 over CDK1.

[0341] In some embodiments, the subject compounds inhibit CDK (e.g., CDK2), 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 IC50 or EC50 value, respectively. In certain embodiments, the subject compounds have an IC50 value (or EC50 value) of 10 pM or less, such as 3 pM or less, 1 pM 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.

[0342] As summarized above, aspects of the disclosure include methods of inhibiting CDK (e.g., CDK2). A subject compound (e.g., as described herein) may inhibit at activity of CDK (e.g., CDK2) 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 IC50 of 1 x 106M 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).

[0343] 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).

[0344] 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.

[0345] 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.

[0346] 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.Atty. Docket No.: 39953-62353 (008WO)

[0347] In another embodiment of the subject method, the sample is known to contain the CDK(s) of interest.

[0348] 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) 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. In certain instances, the method includes contacting the cell with a CDK (e.g., CDK2) inhibitor compound (e.g., as described herein) and contacting the cell with a chemotherapeutic agent. Any convenient cancer cells can be targeted.

[0349] In some embodiments, there is provided a method of inhibiting CDK (e.g., CDK2) in a subject, comprising administering to the subject a compound or a pharmaceutical composition, as described herein, to inhibit CDK (e.g., CDK2) in the subject.4.4.2 Methods of Treatment

[0350] Compounds of the present disclosure can inhibit CDK (e.g., CDK2) 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) 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.

[0351] Such diseases or disorders associated with CDK (e.g., CDK2) 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) 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).

[0352] In certain embodiments the CDK (e.g., CDK2) inhibitor is an inhibitor as defined herein. In some embodiments, the CDK inhibitor is an inhibitor according to any one of Formulas I-XIIB, or exemplary compounds of Tables 1-4, or a pharmaceutically acceptable salt thereof.Atty. Docket No.: 39953-62353 (008WO)

[0353] 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 is 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.Atty. Docket No.: 39953-62353 (008WO)4.4 Utility

[0359] The subject methods and compositions, e.g., as described above, can be used in any application where CDK (e.g., CDK2) 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.

[0360] 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

[0361] When describing the embodiments of the present disclosure, the following terms have the following meanings unless otherwise indicated.

[0362] It will be understood by those within the art that, in general, terms used herein, and especially in 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 otherAtty. Docket No.: 39953-62353 (008WO)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 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, 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.”

[0363] 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.

[0364] As will be understood by one skilled in the art, for any and all purposes, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of subranges 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.

[0365] 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 ofAtty. Docket No.: 39953-62353 (008WO)enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] 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.Atty. Docket No.: 39953-62353 (008WO)

[0370] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized 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)).

[0371] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0372] 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.

[0373] The term “cyclopropylenyl” refers to a divalent cyclopropyl group of thefollowing structure:.

[0374] 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.: 39953-62353 (008WO)

[0375] A dash (“-”) that 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.

[0376] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, C4, C5, Ce, 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.

[0377] 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 Cl-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.

[0378] 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 2 8 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.

[0379] 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.: 39953-62353 (008WO)as Ci-8 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 methyl- 1 -pentyl, 4-m ethyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l-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.

[0380] 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.

[0381] The term “alkylene” as used herein refers to a divalent alkyl radical.Representative examples of Cl -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 -dimethylpentyl ene, n-heptylene, n-octylene, n-nonylene and n-decylene.

[0382] 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-m ethyl- 1 -butynyl, 4-propyl-2-pentynyl, and 4 butyl 2 hexynyl.

[0383] 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.

[0384] 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.: 39953-62353 (008WO)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.

[0385] The term “heteroaryl” refers to a group having 5 to 10 ring atoms, 5, 6, or 9 ring atoms; having 6, 10, or 14K 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]-l,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.

[0386] The term “cyano” as used herein refers to CN.

[0387] 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.: 39953-62353 (008WO)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.

[0388] The terms “halo” or “halogen” as used herein refer to -F, -Cl, -Br, and / or -I.

[0389] “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.

[0390] 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, alkyl carbonyl, 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-lH,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H-spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro- lH-pyrrolo[2, 1-c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H-thiopyranyl 1,1 -di oxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0391] 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.: 39953-62353 (008WO)

[0392] As used herein, the term “partially unsaturated” refers to a ring moiety that 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.

[0393] 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.

[0394] 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 leastandaddition, in a polycyclic ring system, substituents may, unless otherwise indicated, replace a R1hydrogen on any individual ring (e.g.,Atty. Docket No.: 39953-62353 (008WO)R1ca"'6o "to Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at 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."

[0395] 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.

[0396] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o-4R°; -0(CH2)O-4C(0)OR°; -0(CH2)O-40R°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh, which may be substituted with R°, -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)o-4N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(R0)C(0)N(R°)2; -N(RO)C(S)N(R°)2; -(CH2)O-4N(R0)C(S)N(R°)2; -(CH2)O-4N(R0)C(0)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)N(RO)2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; -(CH2)o-4C(0)OR°; -(CH2)o-4C(0)SR°; -(CH2)o-4C(0)OSi(R0)3; -(CH2)o-40C(0)R°; -OC(0)(CH2)o-4SR°; -SC(S)SR°; -(CH2)o-4SC(O)R°; -(CH2)O-4C(0)N(R°)2; -C(S)N(RO)2; -C(S)SR°; -SC(S)SR°; -(CH2)O-4OC(O)N(RO)2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O-4SSRO; -(CH2)O-4S(0)2R0; -(CH2)O-4S(0)2OR0; -(CH2)O-40S(0)2R0; -S(O)2NRO; -(CH2)O-4S(O)RO; -N(RO)S(O)2N(R°)2; -N(RO)S(O)2R°; -N(0R°)R°; -C(NH)N(RO)2; -P(ORO)2; -P(O)(R°)2; -OP(O)(RO)2; -OP(O)(ORO)2; -SiR°3; -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CFUPh, -0(CH2)o-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated,Atty. Docket No.: 39953-62353 (008WO)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.

[0397] 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)o-2OH; -(CH2)o-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)o-2SR*; -(CH2)O.2SH; -(CH2)O.2NH2; -(CH2)O-2NHR*; -(CH2)O-2NR*2; -NO2, -SiR*3; -OSiR*3; -C(O)SR*; -(Ci-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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, 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 =0 and =S.

[0398] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0; =S; =NNR#2; =NNHC(0)R#2;=NNHC(0)0R#2; =NNHS(O)2R#2; =NR#; =N0R#; -O(C(R#2))2.3O-; or -S(C(R#2))2.3S-; wherein each independent occurrence of R#is selected from hydrogen, Ci-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, Ci-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.

[0399] 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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5- to 6-memberedAtty. Docket No.: 39953-62353 (008WO)saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0400] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R', -NR'2, -C(O)Rf, -C(O)ORf, -C(O)C(O)RT, -C(O)CH2C(O)RT, -S(O)2RT, -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, Cl -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.

[0401] 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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0402] 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. ForN HN jexample the following structure:His intended to encompass bothHand

[0403] The term “oxo”, as used herein, means an oxygen that is double bonded to a carbon atom thereby forming a carbonyl.

[0404] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH.

[0405] 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.: 39953-62353 (008WO)groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0406] 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.

[0407] 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.

[0408] 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.

[0409] 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.: 39953-62353 (008WO)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.

[0410] 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.

[0411] 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.

[0412] 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.: 39953-62353 (008WO)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.

[0413] 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.

[0414] 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.

[0415] 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.: 39953-62353 (008WO)pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0416] 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.

[0417] 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.

[0418] 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., l,l’-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.: 39953-62353 (008WO)

[0419] 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, de-acetone, de-DMSO. A solvate can be in a liquid or solid form.

[0420] 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.

[0421] Chemical names were generated using PerkinElmer ChemDraw® Professional, version 17.

[0422] 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.

[0423] 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.

[0424] 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.: 39953-62353 (008WO)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.

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.: 39953-62353 (008WO)

[0431] Definitions of other terms and concepts appear throughout the detailed description.

[0432] The following example(s) is / are offered by way of illustration and not b...

Claims

1. Atty. Docket No.: 39953-62353 (008WO)2.WHAT IS CLAIMED IS:

1. A compound of Formula I:4.Y2YVR45.Y Y56.RANAN.R67.I8.H10.

11. (I)12.or a pharmaceutically acceptable salt thereof, wherein:13.Y1is N or CR1;14.Y2is N or CR2;15.Y3is N or CR3;16.Y5is N or CR5;17.R'-R R5and R7are independently selected from H, optionally substituted (Cn e)alkyl, halo(Ci-6)alkyl, -COR30, -OR30, halogen, and CN, wherein R30is H or optionally substituted (Ci-6)alkyl;18.R4is optionally substituted heteroaryl (e.g., optionally substituted fused bicyclic heteroaryl), optionally substituted aryl, or substituted alkynyl; and19.r Y20.6vV21.R22.

23. is, wherein:24.a) Y6, Y7, Y9, and Y10are independently CR12or N, wherein at least three of Y6, Y7, Y9, and Y10are CR12,25.each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, and26.OKX1127.v s"28.'Y29.Z is '1230., wherein:31.X11is selected from O, NH and N(Ci-6)alkyl,32.Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2- e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,33.R9is H or optionally substituted (Ci-6)alkyl, and Atty. Docket No.: 39953-62353 (008WO)34.R10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl;35.or36.b) Y6, Y9, and Y10are independently CR12or N, wherein at least two of Y6, Y9, and Y10are CR12,37.Y7is C, and Z and Y7are cyclically linked and together with the carbon atom to which they are attached provide a 4- to 7-membered (e.g., 4-, 5-, 6- or 7- membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, - S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-, wherein each R32is independently H or optionally substituted (Ci-6)alkyl; and38.each R12is independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN.39.The compound of claim 1, wherein:40.X4'X41.I S42.(L 4(R18)V.43.> _ _ p2344.R45. 46.4is or I, wherein:47.X2is selected from NR25, C(R26)2, C=O, O and S,48.X3and X4are independently selected from N and CR26,49.v is 0, 1, 2, or 3,50.each R18is independently selected from optionally substituted (Ci_6)alkyl, optionally substituted amino, optionally substituted (Ci-6)alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted (C3-s)cycloalkyl, and CN,51.R25is selected from H, optionally substituted alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl and optionally substituted aryl,52.each R26is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, Atty. Docket No.: 39953-62353 (008WO)53.halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, and54.R23is selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl;56. 58.X11is selected from O, NH and N(Ci-6)alkyl,59.Y12is selected from -NR9R10, (Ci-6)alkyl (e.g., (C3-6)cycloalkyl), (C2-e)alkenyl, (C2-e)alkynyl, cycloalkyl, heterocyclyl, and a substituted version thereof,60.R9is H or optionally substituted (Ci-6)alkyl,61.R10is selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (C3-s)cycloalkyl, and optionally substituted heterocyclyl,62.ring B is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) carbocyclic or heterocyclic ring optionally comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, -S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-,63.Ri2a, R12b, R12C, and R12dare independently selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Ci-6)alkoxy, hydroxy, halogen, and CN, m is 0, 1, 2, 3 or 4,64.each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked to provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused), and65.R32is H or optionally substituted (Ci-6)alkyl.

3. The compound of claim 2, wherein R6is68.

69. Atty. Docket No.: 39953-62353 (008WO)4. The compound of claim 3, wherein R6is71.O X11C) X72.'■V'1173.Y12yys>1274.Y y^R75.R12a p12ai2b77.

78. orK5. The compound of any one of claims 2 to 4, wherein X11is O.

6. The compound of any one of claims 2 to 4, wherein X11is NH.

7. The compound of any one of claims 2 to 6, wherein Y12is -NR9R10.

8. The compound of any one of claims 2 to 6, wherein Y12is (Ci-6)alkyl.

9. The compound of any one of claims 2 to 6, wherein Y12is optionally substituted (C3- 7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

10. The compound of claim 2, wherein R6is:

86. 88.wherein ring B is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) heterocyclic ring comprising a group selected from -S(O)2-, -S(O)(=NR32)-, -C(O)-, -S(O)2NR32-, -S(O)(=NR32)NR32-, -S(O)2NR32C(O)-, -C(O)NR32-, - OC(O)NR32-, and -C(O)NR32C(O)-.

11. The compound of claim 10, wherein R6is91. 93.wherein: Atty. Docket No.: 39953-62353 (008WO)94.n is 0, 1, 2, or 3;95.Y13is NR32, or C(R31)2; and96.R32is H or optionally substituted (Ci-6)alkyl.

12. The compound of claim 11, wherein R6is98.R31R31RO331199._v11100.S?x101.II o102.R12b104.

105. R12a106.wherein each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked and together with the carbon atom to which they are attached provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused).

13. The compound of claim 12, wherein R6is109.

14. The compound of any one of claims 11 to 13, wherein X11is O.

15. The compound of any one of claims 11 to 13, wherein X11is NH.

16. The compound of any one of claims 2 to 15, wherein R12a, R12b, R12c, and R12d, if present, are independently selected from hydrogen, halogen, hydroxy, optionally substituted (Ci-6)alkyl, and optionally substituted (Ci-6)alkoxy.

17. The compound of claim 16, wherein R12aand R12bare fluoro.

18. The compound of any one of claims 2 to 17, wherein R4is:

117.

118. Atty. Docket No.: 39953-62353 (008WO)19. The compound of claim 18, wherein R4is selected from:

121.

20. The compound of claim 19, wherein R4is selected from:

125.

21. The compound of claim 19, wherein R4is selected from:

129.

22. The compound of claim 20, wherein R4is selected from:

133. 135.wherein:136.R18ais selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Cn e)alkoxy, hydroxy, and halogen.

23. The compound of any one of claims 19 to 22, wherein R25is H, or optionally substituted alkyl (e.g., optionally substituted (Ci-6)alkyl).

24. The compound of any one of claims 19 to 23, wherein R25is:Atty. Docket No.: 39953-62353 (008WO)140. 142.wherein:143.R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and144.g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

25. The compound of any one of claims 2 to 17, wherein R4is146.

147. R2326. The compound of claim 25, wherein R4is150. 152.wherein:153.w is 0, 1, 2, 3, 4 or 5;154.each R19is 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.

27. The compound of claim 26, wherein w is 1 or 2, and each R19is independently selected from halogen, CF3, (Ci-3)alkyl, hydroxyl, (Ci-3)alkoxyl, and CN.

28. The compound of claim 25, wherein R23is an optionally substituted fused bicyclic heteroaryl group.

29. The compound of claim 28, wherein R4is159.

160. Atty. Docket No.: 39953-62353 (008WO)161.wherein:162.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;163.R25is H, or optionally substituted (Ci-e)alkyl;164.R29and R30are each independently H, or optionally substituted (Ci-e)alkyl, or R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkane or heterocycle; and165.y is 0, 1, 2, or 3.

30. The compound of claim 29, wherein R29and R30are each independently optionally substituted (Ci-6)alkyl.

31. The compound of claim 30, wherein R29and R30are each independently (Ci-3)alkyl.

32. The compound of claim 31, wherein R29and R30are each methyl.

33. The compound of claim 31, wherein R29and R30are each ethyl.

34. The compound of claim 29, wherein R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., (C3-7)spirocycloalkyl, such as spirocyclopropyl).

35. The compound of any one of claims 1 to 34, wherein:172.Y1is CR1; and173.Y2is CR2.

36. The compound of any one of claims 1 to 35, wherein Y3is N.

37. The compound of any one of claims 1 to 35, wherein Y3is CR3.

38. The compound of any one of claims 1 to 37, wherein the compound is of any one of Formulae IA-IM:Atty. Docket No.: 39953-62353 (008WO)178.

179.

39. The compound of any one of claims 1 to 38, wherein R3is CN.

40. The compound of any one of claims 1 to 38, wherein R3is H.

41. The compound of any one of claims 1 to 40, wherein R1, R2, R5and R7are each H.

42. The compound of claim 2, wherein the compound is of the formula:

184.

185. Atty. Docket No.: 39953-62353 (008WO)186.or a pharmaceutically acceptable salt thereof.

43. The compound of claim 42, wherein R4is selected from:

189.

44. The compound of claim 43, wherein R4is selected from:

193. 195.wherein:196.R18ais selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Cn e)alkoxy, hydroxy, and halogen.

45. The compound of any one of claims 42 to 44, wherein R25is H, or optionally substituted alkyl (e.g., optionally substituted (Ci-6)alkyl).

46. The compound of any one of claims 42 to 45, wherein R25is:199.D35 p33201. 203.wherein:204.R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and205.g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

47. The compound of claim 42, wherein the compound is of the formula:Atty. Docket No.: 39953-62353 (008WO)208. 210.or a pharmaceutically acceptable salt thereof, wherein:211.R18ais selected from H, optionally substituted (Ci-3)alkyl, optionally substituted (Cn 3)alkoxy, hydroxy, and halogen;212.R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and213.R12aand R12bare independently selected from hydrogen, halogen (e.g., fluoro), hydroxy, optionally substituted (Ci-3)alkyl, and optionally substituted (Ci-3)alkoxy.

48. The compound of claim 47, wherein:215.R12ais fluoro; and216.R12bis hydrogen or fluoro.

49. The compound of claim 47, wherein:218.R12ais fluoro; and219.R12bis hydrogen.

50. The compound of claim 47, wherein:221.R12ais fluoro; and222.R12bis fluoro.

51. The compound of any one of claims 47 to 50, wherein R18ais (Ci-3)alkyl52. The compound of any one of claims 47 to 51, wherein R18ais methyl.

53. The compound of any one of claims 47 to 52, wherein:226.R33is OH;227.R34and R35are each methyl; and Atty. Docket No.: 39953-62353 (008WO)228.R36and R37are each H.

54. The compound of any one of claims 47 to 52, wherein:230.R33is OH;231.R34and R35are each CF3; and232.R36and R37are each H.

55. The compound of claim 2, wherein the compound is of the formula:

235. 237.or a pharmaceutically acceptable salt thereof.

56. The compound of claim 55, wherein w is 0.

57. The compound of claim 55, wherein w is 1 or 2, and each R19is independently selected from halogen, CF3, (Ci-3)alkyl, hydroxyl, (Ci-3)alkoxyl, and CN.

58. The compound of any one of claims 55 to 57, wherein R29and R30are each independently optionally substituted (Ci-6)alkyl.

59. The compound of claim 58, wherein R29and R30are each independently (Ci-3)alkyl.

60. The compound of claim 59, wherein R29and R30are each methyl.

61. The compound of claim 59, wherein R29and R30are each ethyl.

62. The compound of any one of claims 55 to 57, wherein R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., (C3-7)spirocycloalkyl, e.g., spirocyclopropyl).Atty. Docket No.: 39953-62353 (008WO)63. The compound of any one of claims 5 to 62, wherein X11is O.

64. The compound of any one of claims 55 to 62, wherein X11is NH.

65. The compound of any one of claims 5 to 64, wherein Y12is -NR9R10.

66. The compound of any one of claims 55 to 64, wherein Y12is -NH2, -NH(Ci-6)alkyl (e.g., -NH(Ci-3)alkyl, such as -NHCH3, -NHCD3, or -NHCH2CH3), or -N[(Ci-6)alkyl]2(e.g., -N[(Ci-3)alkyl]2).

67. The compound of any one of claims 55 to 64, wherein Y12is (Ci-6)alkyl (e.g., (Cn3)alkyl).

68. The compound of any one of claims 55 to 64, wherein Y12is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.

69. The compound of claim 1, wherein the compound is of the formula:

253. 255.or a pharmaceutically acceptable salt thereof.

70. The compound of claim 69, wherein R4is selected from:

258.

71. The compound of claim 70, wherein R4is selected from:Atty. Docket No.: 39953-62353 (008WO)262. 264.wherein:265.R18ais selected from H, optionally substituted (Ci-6)alkyl, optionally substituted (Cn e)alkoxy, hydroxy, and halogen.

72. The compound of any one of claims 69 to 71, wherein R25is H, or optionally substituted alkyl (e.g., optionally substituted (Ci-6)alkyl).

73. The compound of any one of claims 69 to 72, wherein R25is:

269. 271.wherein:272.R33- R37are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and273.g and h are independently 1, 2, 3, 4 or 5 (e.g., 1, or 2).

74. The compound of claim 2, wherein the compound is of one of the following formulas:

276.

277. or a pharmaceutically acceptable salt thereof.

75. The compound of claim 74, wherein y is 0.

76. The compound of claim 74, wherein y is 1.Atty. Docket No.: 39953-62353 (008WO)77. The compound of claim 74, wherein y is 2.

78. The compound of claim 74 or 77, and each R24is independently selected from halogen, CF3, (Ci-3)alkyl, hydroxyl, (Ci-3)alkoxyl, and CN.

79. The compound of any one of claims 78 to 80, wherein R29and R30are each independently optionally substituted (Ci-6)alkyl.

80. The compound of claim 79, wherein R29and R30are each independently (Ci-3)alkyl.

81. The compound of claim 80, wherein R29and R30are each methyl or ethyl.

82. The compound of any one of claims 76 to 78, wherein R29and R30together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., (C3-7)spirocycloalkyl, e.g., spirocyclopropyl).

83. The compound of any one of claims 76 to 82, wherein R6is288. 289.R12a290.wherein each R31is independently H or optionally substituted (Ci-6)alkyl, or two R31groups are cyclically linked to provide an optionally substituted (C3-7)cycloalkyl (e.g., spirocyclic or fused).

84. The compound of claim 83, wherein R6is293.

85. The compound of any one of claims 69 to 84, wherein X11is O.Atty. Docket No.: 39953-62353 (008WO)86. The compound of any one of claims 69 to 84, wherein X11is NH.

87. The compound of any one of claims 2 to 80, wherein R12a, R12b, R12c, and R12d, if present, are independently selected from hydrogen, halogen, hydroxy, optionally substituted (Ci-6)alkyl, and optionally substituted (Ci-6)alkoxy.

88. The compound of claim 81, wherein:299.R12ais fluoro; and300.R12bis hydrogen or fluoro.

89. The compound of any one of claims 1 to 88, wherein Y5is N.

90. The compound of any one of claims 1 to 88, wherein Y5is CR5.

91. The compound of claim 90, wherein R5is H.

92. The compound of claim 1, wherein the compound is a compound of any one of Tables 3 or 8, or a pharmaceutically acceptable salt thereof.

93. A pharmaceutical composition comprising a compound of any one of claims 1 to 92 and a pharmaceutically acceptable excipient.

94. 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 92 effective to inhibit the CDK.

95. A method of inhibiting CDK in a subject, comprising administering to a subject a compound of any one of claims 1 to 92, or a pharmaceutical composition according to claim 93, to inhibit CDK in the subject.

96. The method of claim 94 or 95, wherein the CDK is CDK2.Atty. Docket No.: 39953-62353 (008WO)97. 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 92, or a pharmaceutical composition of claim 93.

98. The method of claim 97, wherein the disease or disorder associated with CDK2 is cancer.

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