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WO2025240517A1 - Composés naphtyridine inhibiteurs de cdk4 - Google Patents

Composés naphtyridine inhibiteurs de cdk4

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Publication number
WO2025240517A1
WO2025240517A1 PCT/US2025/029199 US2025029199W WO2025240517A1 WO 2025240517 A1 WO2025240517 A1 WO 2025240517A1 US 2025029199 W US2025029199 W US 2025029199W WO 2025240517 A1 WO2025240517 A1 WO 2025240517A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
formula
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/029199
Other languages
English (en)
Inventor
Amy Hart
Claude Quesnelle
Kiel LAZARSKI
Rachelle QUACH
Andrew Phillips
Ryan Henry
Donald BACKOS
Sara COULUP
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aleksia Therapeutics Inc
Original Assignee
Aleksia Therapeutics Inc
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Publication date
Application filed by Aleksia Therapeutics Inc filed Critical Aleksia Therapeutics Inc
Priority to PCT/US2025/029229 priority Critical patent/WO2025240539A1/fr
Publication of WO2025240517A1 publication Critical patent/WO2025240517A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Cancer remains a leading cause of death, characterized by uncontrolled cell growth, evasion of cell death, and the ability to invade surrounding tissues.
  • a promising strategy for cancer therapy is the inhibition of cyclin-dependent kinases (CDKs), key regulators of cell cycle progression.
  • 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.
  • CDK4 and CDK6 have been explored as a promising strategy to arrest tumor cell proliferation.
  • small-molecule inhibitors of CDK4/6 have been developed, some of which have shown clinical efficacy in treating hormone receptor-positive (HR+) breast cancer, among other malignancies. These inhibitors work by preventing CDK4 and/or CDK6 from phosphorylating the Rb protein, thereby blocking the transition from G1 to S phase, leading to cell cycle arrest and, in some cases, apoptosis in rapidly dividing cancer cells.
  • CDK4 or CDK6 inhibitors are designed to overcome the limitations of existing therapies, with improved potency, selectivity, and pharmacokinetic properties.
  • CDK4 inhibitor compounds having a naphthyridine or similar isosteric bicyclic heterocycle core composed of two fused 6 membered rings.
  • the core structure of the compounds can be substituted with an amino group, where the amino group is further substituted with a particular substituted heterocycle or cycloalkyl group.
  • compositions comprising the subject CDK4 inhibitor compounds.
  • methods for using compositions of the disclosure in research and as therapeutics are described in greater detail below.
  • CDK4 inhibitor compounds having a bicyclic heterocycle core composed of two fused 6 membered rings.
  • the core is a naphthyridine, or isostere thereof, that is substituted with an amino group, wherein the amino group can be linked to a particular hydroxy-substituted heterocycle or cycloalkyl that is optionally further substituted with a hydrophilic group.
  • the cyclic group is a saturated group such as a piperidinyl.
  • the hydrophilic group is a biologically inert hydrogen bonding group.
  • the CDK4 inhibitor is a classic inhibitor, where the inhibitor compound binds to a target CDK4 and prevents other molecules from binding. Classic inhibitors may not permanently bind to the CDK, i.e., they associate to the kinase and dissociate from the kinase reversibly, for example via hydrogen bonding or Van der Waals interactions.
  • the CDK4 inhibitor is selective for CDK4 over CDK6. In some embodiments, the CDK4 inhibitor is selective for CDK4 over CDK2.
  • X is selected from cyano. In some embodiments, X” is fluoro. In some embodiments, X” is chloro. In some embodiments, X” is bromo. In some embodiments, X” is iodo. In some embodiments, X” is trifluoromethyl. In some embodiments, X” is difluoromethyl. In some embodiments, X” is trifluoromethoxyl. [0011] In some embodiments of the compound of Formula A, one or more of Y 1 -Y 3 is N. In some embodiments, Y 3 is N. In some embodiments, Y 2 is N. In some embodiments Y 1 is N.
  • Y 1 and Y 3 are N. In some embodiments Y 2 and Y 3 are N. In some embodiments Y 1 and Y 2 are N. [0012] In some embodiments of Formula A, the compound is of Formula A’: (A’) or a pharmaceutically acceptable salt thereof. [0013] In some embodiments of Formula A’, X” is selected from cyano. In some embodiments, X” is fluoro. In some embodiments, X” is chloro. In some embodiments, X” is bromo. In some embodiments, X” is iodo. In some embodiments, X” is trifluoromethyl. In some embodiments, X” is difluoromethyl.
  • X is trifluoromethoxyl.
  • X is -OR 31 .
  • R 31 is H.
  • R 31 is -C(O)R 32 , wherein R 32 is optionally substituted (C1-6)alkyl.
  • R 31 is an optionally substituted (C1-6)alkyl (i.e., an R 32 substituent).
  • R 31 is halo(C1-3)alkyl.
  • compound is of Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein: Y 1 is N or CR 1 ; Y 2 is N or CR 2 ; Y 3 is N or CR 3 ; Y 5 is N or CR 5 ; Y 11 is selected from O, S, SO, SO2, CH2, CHR 16 , C(R 16 ) 2 , NH and NR 9 ; R 9 is H, optionally substituted (C 1-6 )alkyl, or Z; each R 16 is independently selected from H, Z, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; m and p are each independently an integer from 0 to 2; Z is a hydrophilic group; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally
  • R 1 is selected from fluoro, chloro, and bromo. In some embodiments, R 1 is fluoro.
  • one or more of Y 1 -Y 3 is N. In some embodiments, Y 3 is N. In some embodiments, Y 2 is N. In some embodiments Y 1 is N. In some embodiments Y 1 and Y 3 are N. In some embodiments Y 2 and Y 3 are N. In some embodiments Y 1 and Y 2 are N. [0018] In some embodiments of Formula I, the compound is of Formula II: (II) or a pharmaceutically acceptable salt thereof.
  • Y 11 is O. In some embodiments of Formulae A, A’, I, or II, Y 11 is S. In some embodiments of Formulae A, A’, I, or II, Y 11 is SO. In some embodiments of Formulae A, A’, I, or II, Y 11 is SO 2 . In some embodiments of Formulae A, A’, I, or II, Y 11 is C(R 16 ) 2 . In some embodiments of Formulae A, A’, I, or II, Y 11 is CHR 16 . In some embodiments of Formulae A, A’, I, or II, Y 11 is CH2.
  • Y 11 is CHR 16 and R 16 is selected from Z, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, hydroxyl, halogen, and CN.
  • Y 11 is NH or NR 9 .
  • Y 11 is NH.
  • Y 11 is NR 9 and R 9 is optionally substituted (C 1- 6)alkyl, or Z.
  • R 9 is optionally substituted (C 1 -C 3 )alkyl.
  • R 9 is Z (e.g., as described herein).
  • Y 11 is N-S(O)R 16A , N-C(O)R 16A , NC(O)OR 16A , N(CH2)zOR 16A , N-OH, N-N(R 16A ) 2 , or NC(O)N(R 16A ) 2 , where R 16A is optionally substituted (C 1-6 )alkyl, and z is 1, 2, 3, 4, 5, or 6.
  • R 16A is optionally substituted (C 1-6 )alkyl
  • z is 1, 2, 3, 4, 5, or 6.
  • Y 11 is NC(O)H, or N(CH 2 ) z OH where z is 1, 2, 3, 4, 5, or 6.
  • Y 11 is N-S(O)CH 3 , N- S(O) 2 CH 3 , N-C(O)CH 3 , NC(O)H, NC(O)OCH 3 , NC(O)OC(CH 3 ) 3 , NCH 2 CH 2 OH, NCH 2 CH 2 OCH 3 , N-OH, N-N(CH 3 ) 2 , NC(O)N(CH 3 ) 2 .
  • Y 11 is N- S(O) 2 CH3.
  • Y 11 is N-S(O)CH3.
  • Y 11 is N-C(O)CH3.
  • Y 11 is NC(O)H.
  • Y 11 is NC(O)OCH3. In some embodiments, Y 11 is NC(O)OC(CH3)3. In some embodiments, Y 11 is NCH2CH2OH. In some embodiments, Y 11 is NCH2CH2OCH3. In some embodiments, Y 11 is NC(O)N(CH3) 2 . [0022] In some embodiments of Formulae I or II, R 31 is H. In some embodiments, R 31 is - C(O)R 32 , wherein R 32 is optionally substituted (C 1-6 )alkyl. In some embodiments, R 31 is an optionally substituted (C 1-6 )alkyl (i.e., an R 32 substituent).
  • R 32 is an optionally substituted (C 1-6 )cycloalkyl. In some embodiments, R 32 is selected from , , and . In some embodiments, R 32 is selected from , , , , , , , , , , , and . [0023] In some embodiments of Formulae A, A’, I, or II, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 1, 2, 3, 4, or 5, and each R 16 is independently selected from Z, optionally substituted (C1-6)alkyl, optionally substituted (C1- 6)alkoxyl, hydroxyl, halogen, and CN. In some embodiments, each R 16 is independently selected from methyl, methoxy, CF 3 , OCF 3 , hydroxyl, and fluoro. In some embodiments, n is 1 and R 16 is methyl, methoxy, CF 3 , OCF 3 , hydroxyl, or fluoro.
  • R 4 is 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. [0025] In some embodiments of Formulae A, A’, I, or II, R 4 is optionally substituted alkynyl. [0026] In some embodiments of Formulae A, A’, I, or II, R 4 is optionally substituted cycloalkyl.
  • R 4 is optionally substituted cycloalkene.
  • R 4 is optionally substituted heterocycle.
  • R 4 is optionally substituted aryl.
  • R 4 is an optionally substituted heteroaryl.
  • R 4 is a monocyclic group.
  • R 4 is a bicyclic group. In some embodiments of R 4 the bicyclic group is a spirocyclic group. In some embodiments of R 4 , the bicyclic group is a fused bicyclic group. [0033] In some embodiments, R 4 is a spirocyclic group. In some embodiments, R 4 is a heterospirocyclic group.
  • R 4 comprises an amine, (C2- C6)alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, piperazine, pyrrolidine, pyrrole, octahydrocyclopenta[c]pyrrole, pyrazole, azetidine, azepane, 1,4-diazepine, 3-azabicyclo[3.1.0]hexane, 2,7-diazaspiro[4.4]nonan-1-one, 2,7-diazaspiro[4.4]nonane, pyridyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, oxindole, triazole
  • R 4 is optionally substituted amine.
  • the amine is substituted with one or two C1-C6 alkyl groups.
  • R 4 is optionally substituted C2-C3 alkynyl.
  • the alkynyl is substituted with cycloalkyl, aryl, heteroaryl, heterocyclyl, alkyl, or a substituted version thereof.
  • R 4 is optionally substituted cyclobutane.
  • R 4 is optionally substituted cyclopentane. In some embodiments, R 4 is optionally substituted cyclohexane. In some embodiments, R 4 is optionally substituted cyclohexene. In some embodiments, R 4 is optionally substituted cycloheptane. [0038] In some embodiments of Formulae A, A’, I, or II, R 4 is optionally substituted piperidinyl. In some embodiments, R 4 is optionally substituted piperazine. In some embodiments, R 4 is optionally substituted pyrrolidine. In some embodiments, R 4 is optionally substituted pyrrole.
  • R 4 is optionally substituted octahydrocyclopenta[c]pyrrole. In some embodiments, R 4 is optionally substituted pyrazole. In some embodiments, R 4 is optionally substituted azetidine. In some embodiments, R 4 is optionally substituted azepane. In some embodiments, R 4 is optionally substituted 1,4-diazepine. In some embodiments, R 4 is optionally substituted 3-azabicyclo[3.1.0]hexane. In some embodiments, R 4 is optionally substituted 2,7- diazaspiro[4.4]nonan-1-one, 2,7-diazaspiro[4.4]nonane.
  • R 4 is optionally substituted pyridyl. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is optionally substituted pyrimidine. In some embodiments, R 4 is optionally substituted benzisoxazole. In some embodiments, R 4 is optionally substituted indazole. In some embodiments, R 4 is optionally substituted thiazole. In some embodiments, R 4 is optionally substituted dihydropyran. In some embodiments, R 4 is optionally substituted tetrahydropyran. In some embodiments, R 4 is optionally substituted azaindole. In some embodiments, R 4 is optionally substituted indoline.
  • R 4 is optionally substituted oxindole. In some embodiments, R 4 is optionally substituted triazole. In some embodiments, R 4 is optionally substituted oxadiazole. In some embodiments, R 4 is optionally substituted cyclohexanone.
  • R 4 is of Formula 4A: (4A), wherein: X 12 is CH 2 , CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, wherein optionally two geminal R 15 groups can be taken together as a carbonyl; R 25 is H, optionally substituted (C1-6)alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; R 42
  • cycloalkyl optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl
  • R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and r is 0, 1, or 2.
  • q is 0, such that there are no R 15 substituents.
  • q is 1-11, and each R 15 substituent is independently selected from (C1- C3)alkyl, hydroxy, halogen, and nitrile.
  • q is 1 and R 15 is nitrile.
  • q is 1 and R 15 is hydroxy.
  • r is 0.
  • X 12 is NR 25 .
  • X 12 is CHR 15 .
  • X 12 is C(R 15 ) 2 . In some embodiments, X 12 is CH2. In some embodiments, X 12 is O. [0043] In some embodiments of Formula 4A, X 12 is NR 25 and r is 0. In some embodiments of Formula 4A, X 12 is NR 25 and r is 1. In some embodiments of Formula 4A, X 12 is NR 25 and r is 2. [0044] In some embodiments of 4A, R 4 is of formula 4A1: (4A1), wherein R 15 , R 42 , q and r are as described herein. [0045] In some embodiments of 4A1, r is 0. In some embodiments of 4A1, r is 1.
  • R 4 is of formula 4A1a: (4A1a), wherein R 15 , R 42 , q and r are as described herein.
  • q is 0, such that there are no additional R 15 substituents.
  • q is 1-11, and each additional R 15 substituent is independently selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile.
  • q is 1 and the additional R 15 is nitrile.
  • q is 1 and the additional R 15 is hydroxy.
  • q is 1 and the additional R 15 is methyl.
  • R 4 is of formula 4A2: (4A2), wherein, R 15 , R 43 , q and r are as described herein.
  • R 43 is H.
  • R 43 is optionally substituted (C 1 - 3 )alkyl.
  • R 43 is acyl.
  • R 43 is optionally substituted cycloalkyl.
  • R 43 is optionally substituted heterocycle.
  • R 43 is optionally substituted heteroaryl. In some embodiments of 4A2, R 43 is optionally substituted aryl. [0050] In some embodiments of 4A2, q is 0, such that there are no R 15 substituents. In some embodiments, q is 1-11, and each R 15 substituent is independently selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 1 and R 15 is nitrile. In some embodiments, q is 1 and R 15 is hydroxy. In some embodiments, q is 1 and R 15 is halogen. In some embodiments, the halogen is F.
  • q is 1 and R 15 is (C 1 -C 3 )alkyl. In some embodiments, q is 1 and R 15 is methyl. In some embodiments q is 2 and each R 15 is selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile. In some embodiments, q is 2 and each R 15 substituent is halogen. In some embodiments, each halogen is F.
  • R 4 is of any one of formulae 4A2a-4A2c: (4A2a) (4A2b), or (4A2c) wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl; and each R 15 is independently selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile.
  • r is 0. In some embodiments of any one of Formulae 4A2a-4A2c, r is 1. In some embodiments of any one of Formulae 4A2a- 4A2c, r is 2.
  • R 4 is of Formula 4A2a’: (4A2a’), wherein: X 12 is CH 2 , CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 or NR 25 ; R 15 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R 25 is H, optionally substituted (C1-6)alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and
  • R 15 is selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile. In some embodiments, R 15 is nitrile. In some embodiments, R 15 is hydroxy. In some embodiments, R 15 is halogen. In some embodiments, the halogen is F. In some embodiments, R 15 is (C 1 -C 3 )alkyl. In some embodiments, R 15 is methyl. In some embodiments, R 15 is nitrile. [0055] In some embodiments of Formula 4A2a’, r is 0. In some embodiments of Formula 4A2a’, r is 1. In some embodiments r is 2.
  • X 12 is NR 25 . In some embodiments of Formula 4A2a’, X 12 is NR 43 . In some embodiments of Formula 4A2a’, X 12 is CHR 15 . In some embodiments of Formula 4A2a’, X 12 is CHR 42 . In some embodiments of Formula 4A2a’, X 12 is C(R 15 ) 2 . In some embodiments, X 12 is CH2. In some embodiments, X 12 is O. [0057] In some embodiments of Formula 4A2a’, X 12 is NR 25 and r is 0. In some embodiments of Formula 4A2a’, X 12 is NR 25 and r is 1.
  • X 12 is NR 25 and r is 2. [0058] In some embodiments of Formula 4A2a’, X 12 is NR 43 and r is 0. In some embodiments of Formula 4A2a’, X 12 is NR 43 and r is 1. In some embodiments of Formula 4A2a’, X 12 is NR 43 and r is 2.
  • R 4 is of formulae 4A2a”: (4A2a”) wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl; and each R 15 is independently selected from (C 1 -C 3 )alkyl, hydroxy, halogen, and nitrile.
  • R 4 is of Formula 4B: (4B), wherein: X 1 is O, NR 25 , or C(R 26 ) 2 ; R 16 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; each R 26 is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted ary
  • X 1 is C(R 26 ) 2 .
  • each R 26 is H (i.e., X 1 is CH2).
  • X 1 is O.
  • X 1 is NR 25 .
  • s is 0, such that there are no R 16 substituents.
  • s is 1-9, and each R 16 substituent is independently selected from (C 1 - C 3 )alkyl, hydroxy, halogen, and nitrile.
  • q is 1 and R 16 is nitrile.
  • q is 1 and R 16 is hydroxy.
  • R 4 is of Formula 4C: (4C), wherein: R 17 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, wherein optionally two geminal R 15 groups can be taken together as a carbonyl; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and u is 0, 1, or 2.
  • t is 0, such that there are no R 17 substituents.
  • t is 1-10, and each R 17 substituent is independently selected from (C 1 - C 3 )alkyl, hydroxy, halogen, and nitrile.
  • t is 1 and R 17 is nitrile.
  • t is 1 and R 17 is hydroxy.
  • u is 0. In some embodiments of Formula 4C, u is 1. In some embodiments of Formula 4C, u is 2.
  • R 4 is of Formula 4D: (4D), wherein: X 14 is CH 2 , CHR 15 , CHR 42 , C(R 15 ) 2 , O, NR 43 , or NR 25 ; R 17 is 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, wherein optionally two geminal R 15 groups can be taken together as a carbonyl; each R 25 is selected from H, (C 1 - 6 )alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted aryl;
  • X 14 is NR 25
  • R 17 is an optional substituent selected from optionally substituted alkyl, carbonyl, carboxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile.
  • two geminal R 17 s can optionally be taken together as a carbonyl.
  • X 14 is CHR 15 .
  • X 14 is C(R 15 ) 2 .
  • X 14 is CH2.
  • X 14 is O, and R 17 is an optional substituent selected from optionally substituted alkyl, carboxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile.
  • R 17 is an optional substituent selected from optionally substituted alkyl, carboxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile.
  • X 14 is NR 25 and r is 0.
  • X 12 is NR 25 and r is 1.
  • X 14 is NR 25 and r is 2.
  • X 14 is CHR 15 and r is 0.
  • X 14 is CHR 15 and r is 1.
  • R 4 is of formula 4D1: (4D1), wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl; R 17 is optionally substituted alkyl, carbonyl, carboxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, wherein optionally two geminal
  • R 43 is H. In some embodiments of 4D1, R 43 is optionally substituted (C 1 - 3 )alkyl. In some embodiments of 4D1, R 43 is acyl. In some embodiments of 4D1, R 43 is optionally substituted cycloalkyl. In some embodiments of 4D1, R 43 is optionally substituted heterocycle. In some embodiments of 4D1, R 43 is optionally substituted heteroaryl. In some embodiments of 4D1, R 43 is optionally substituted aryl. [0073] In some embodiments of 4D1, k is 0, such that there are no R 17 substituents.
  • k is 1-8, and each R 17 substituent is independently selected from (C 1 -C 3 )alkyl, and nitrile. In some embodiments, k is 1 and R 17 is nitrile. In some embodiments, k is 1 and R 17 is (C 1 -C 3 )alkyl. In some embodiments, k is 1 and R 17 is methyl. In some embodiments k is 2 and each R 17 is selected from (C 1 -C 3 )alkyl, , and nitrile.
  • R 4 is one of Formula 4D1a or 4D1b: (4D1a), or (4D1b), wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl; and each R 17 is independently (C 1 -C 3 )alkyl or nitrile; or two geminal R 17 groups can optionally be taken together as a carbonyl.
  • R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted
  • r is 0. In some embodiments of Formula 4D1a or 4D1b, r is 0. In some embodiments of Formula 4D1a or 4D1b, r is 1. In some embodiments of Formula 4D1a or 4D1b, r is 2. [0075] In some embodiments of 4D, R 4 is of Formula 4D1c: (4D1c), wherein: R 43 is as described herein; and each R 17 is independently selected from (C 1 -C 3 )alkyl, and nitrile. [0076] In some embodiments of Formula 4D1c, r is 0. In some embodiments of Formula 4D1c, r is 1. In some embodiments of Formula 4D1c, r is 2.
  • each R 17 is selected from (C 1 -C 3 )alkyl, and nitrile. In some embodiments of Formula 4D1a or 4D1c, R 17 is nitrile. In some embodiments of Formula 4D1a or 4D1c, R 17 is (C 1 -C 3 )alkyl. In some embodiments of Formula 4D1a or 4D1c, R 17 is methyl. In some embodiments of Formula 4D1a, R 17 is carbonyl.
  • R 26 is H. In some embodiments, R 26 is optionally substituted alkyl.
  • X 4 is N. In some embodiments of Formula 4E, X 4 is CR 26 . In some embodiments, R 26 is H. In some embodiments, R 26 is optionally substituted alkyl.
  • X 2 is NR 25 , X 3 is CR 26 and X 4 is CR 26 . In some embodiments of Formula 4E, X 2 is NR 25 , X 3 is N and X 4 is CR 26 . In some embodiments of Formula 4E, X 2 is O, X 3 is CR 26 and X 4 is N.
  • v is 0, such that there are no R 18 substituents.
  • v is 1-3, and each R 18 substituent is independently selected from (C1-3)alkyl, hydroxy, halogen, and nitrile.
  • v is 1 and R 18 is (C1-3)alkyl.
  • the (C1-3)alkyl is methyl.
  • v is 1 and R 18 is halogen.
  • the halogen is Cl or F.
  • R 4 is selected from one of the following structures: , , , , , , and .
  • R 4 is selected from: or wherein R 25 , R 18 and v are as defined herein. [0086] In some embodiments of Formula 4E, R 4 is selected from: or wherein R 25 , R 18 and v are as defined herein. [0087] In some embodiments of Formula 4E, R 4 is selected from: or wherein R 25 , R 18 and v are as defined herein.
  • R 25 is of structure: wherein R 33 – R 37 are independently selected from H, CH3, CF 3 , CHF2, CH2F, CH3, OH, OCH3, and halogen, and/or any two of R 33 – R 37 (e.g., R 36 and R 37 , or R 33 and R 34 ) are cyclically linked and together with the carbon atom(s) to which they are attached provide an optionally substituted cycloalkyl (e.g., cyclopropyl or cyclobutyl).
  • at least one of R 33 -R 37 is a halogen
  • the halogen is F.
  • the halogen is Cl.
  • one or two of R 33 -R 35 are CF 3 . In some embodiments, one of R 33 -R 35 is CF 3 . In some embodiments, two of R 33 -R 35 are CF 3 . In some embodiments, one or two of R 33 -R 35 are OH. In some embodiments, one of R 33 -R 35 is OH. In some embodiments, two of R 33 -R 35 are OH. In some embodiments, one or both of R 36 -R 37 are H. In some embodiments, R 36 is H, and R 37 is selected from CF 3 , CHF2, CH2F, OH, OCH3, and halogen. In some embodiments, both R 36 and R 37 are H .
  • R 25 is of structure: .
  • R 25 is of structure: .
  • the compound is: wherein R 18 and v are as defined herein.
  • the compound is: wherein R 18 and v are as defined herein.
  • the compound is: wherein R 18 and v are as defined herein.
  • the compound is: wherein R 18 and v are as defined herein.
  • At least one R 26 group is optionally substituted alkyl.
  • X 9 is C(R 26 ) 2
  • X 10 is NR 25
  • X 10 is NR 25
  • y is 0, such that there are no R 24 substituents.
  • y is 1-3, and each R 24 substituent is independently selected from (C 1 - C3)alkyl, hydroxy, halogen, and nitrile.
  • y is 1 and R 24 is (C 1 -C 3 )alkyl.
  • y is 1 and R 24 is halogen.
  • the halogen is Cl or F.
  • the compound is selected from: , or wherein R 24 , R 25 , R 29 , R 30 , and y are as defined herein.
  • R 29 and R 30 are each independently H, or optionally substituted (C1-3)alkyl.
  • one of R 29 and R 30 is H, and the other is optionally substituted (C1-3)alkyl.
  • both R 29 and R 30 are H.
  • both R 29 and R 30 are optionally substituted (C1-3)alkyl.
  • R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group.
  • the spirocyclic group is optionally substituted spirocyclopropyl.
  • the spirocyclic group is optionally substituted spirocyclobutyl.
  • the compound is selected from: , and wherein R 24 , R 25 , and y are as defined herein.
  • R 4 is of Formula 4G: (4G), wherein: X 8 is N or CR 26 ; R 21 and R 22 are each independently optionally substituted (C1-C6)alkyl; and R 26 is 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.
  • X 8 is N.
  • X 8 is CR 26 .
  • R 26 is H. In some embodiments, R 26 is optionally substituted alkyl.
  • R 21 and R 22 are each a (C 1 -C 6 )alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl. In some embodiments of Formula 4G, R 21 and R 22 are the same. In some embodiments of Formula 4G, R 21 and R 22 are different.
  • X 8 is N and R 21 and R 22 are each a different C 1 -C 6 alkyl.
  • R 21 is methyl and R 22 is isopropyl. In some embodiments, R 21 is methyl and R 22 is ethyl. In some embodiments, R 21 is methyl and R 22 is propyl. In some embodiments, R 21 is methyl and R 21 is butyl. In some embodiments, R 21 is methyl and R 22 is t- butyl. [00108] In some embodiments of Formula 4G, X 8 is CR 26 and R 21 and R 22 are the same. In some embodiments, R 21 and R 22 are both methyl. In some embodiments, R 21 and R 22 are both ethyl. In some embodiments, R 21 and R 22 are both propyl.
  • R 4 is of Formula 4H: (4H), wherein: R 27 and R 28 are each independently H, or optionally substituted (C 1 -C 6 )alkyl; or R 27 and R 28 together with the nitrogen atom to which they are attached form an optionally substituted cyclic group.
  • R 27 is H.
  • R 27 is optionally substituted (C1-C6)alkyl.
  • R 28 is H.
  • R 28 is optionally substituted (C1-C6)alkyl.
  • R 27 and R 28 are different.
  • R 27 and R 28 are the same. [00111] In some embodiments of Formula 4H, R 27 and R 28 together 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.
  • R 4 is of Formula 4I: (4I), wherein: R 23 is H, optionally substituted (C1-C6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl.
  • R 23 is H.
  • R 23 is optionally substituted (C 1 -C 6 )alkyl.
  • R 23 is methyl, ethyl or propyl.
  • R 23 is optionally substituted cycloalkyl.
  • the cycloalkyl selected from cyclobutene, cyclopentane or cyclohexane.
  • R 23 is optionally substituted cycloalkene.
  • R 23 is optionally substituted heterocyclyl.
  • R 23 is optionally substituted heteroaryl.
  • R 23 is and optionally substituted aryl.
  • R 23 is of Formula 4F (4F). [00116] In some embodiments of Formula 4I, R 23 is selected from one of the following structures: , , , and wherein R 24 , R 43 , R 29 , R 30 , and y are as defined herein.
  • R 4 is of any one of Formulae 4J-4L: (4J), (4K), (4L), wherein: X 5 is N or CR 26 ; R 19 is 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; R 26 is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and w is 0 to 4.
  • X 5 is N. In some embodiments of Formula 4J, X 5 is CR 26 . In some embodiments, R 26 is H. In some embodiments, R 26 is optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R 26 is nitrile. In some embodiments, R 26 is amino. In some embodiments, R 26 is hydroxy. [00119] In some embodiments of Formula 4J, w is 0, such that there are no R 19 substituents.
  • w is 1-4, and each R 19 substituent is independently selected from optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy, amino, hydroxy, halogen, and nitrile.
  • w is 1 and R 19 is C 1 -C 3 alkyl.
  • w is 1 and R 19 is C 1 -C 3 alkyl substituted with hydroxy or alkoxy.
  • w is 1 and R 19 is C 1 -C 3 alkoxy.
  • R 19 is -OCF 3 .
  • w is 1 and R 19 is nitrile.
  • w is 1 and R 19 is nitrile. In some embodiments, w is 1 and R 19 is hydroxy.
  • X 5 is N. In some embodiments of Formula 4K, X 5 is CR 26 . In some embodiments, R 26 is H. In some embodiments, R 26 is optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R 26 is nitrile. In some embodiments, R 26 is amino. In some embodiments, R 26 is hydroxy. [00121] In some embodiments of Formula 4K, w is 0, such that there are no R 19 substituents.
  • w is 1-4, and each R 19 substituent is independently selected from optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy, amino, hydroxy, halogen, and nitrile.
  • w is 1 and R 19 is C 1 -C 3 alkyl.
  • w is 1 and R 19 is C 1 -C 3 alkyl substituted with hydroxy or alkoxy.
  • w is 1 and R 19 is C 1 -C 3 alkoxy.
  • R 19 is -OCF 3 .
  • w is 1 and R 19 is nitrile.
  • w is 1 and R 19 is nitrile. In some embodiments, w is 1 and R 19 is hydroxy.
  • X 5 is N. In some embodiments of Formula 4L, X 5 is CR 26 . In some embodiments, R 26 is H. In some embodiments, R 26 is optionally substituted alkyl, amino, hydroxy, halogen, or nitrile. In some embodiments, R 26 is nitrile. In some embodiments, R 26 is amino. In some embodiments, R 26 is hydroxy. [00123] In some embodiments of Formula 4L, w is 0, such that there are no R 19 substituents.
  • w is 1-4, and each R 19 substituent is independently selected from optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy, amino, hydroxy, halogen, and nitrile.
  • w is 1 and R 19 is C 1 -C 3 alkyl.
  • w is 1 and R 19 is C 1 -C 3 alkyl substituted with hydroxy or alkoxy.
  • w is 1 and R 19 is C 1 -C 3 alkoxy.
  • R 19 is -OCF 3 .
  • w is 1 and R 19 is nitrile.
  • X 6 is C(R 26 ) 2 . In some embodiments each R 26 is H. In some embodiments, at least one R 26 group is optionally substituted alkyl. In some embodiments of Formula 4M, X 6 is O. In some embodiments of Formula 4M, X 6 is NR 25 . In some embodiments, R 25 is H. In some embodiments, R 25 is C 1 -C 3 alkyl. In some embodiments of Formula 4M, X 2 is S. [00126] In some embodiments of Formula 4M, X 7 is N. In some embodiments of Formula 4M, X 7 is CR 26 . In some embodiments, R 26 is H.
  • R 26 is optionally substituted alkyl.
  • X 6 is NR 25 and X 7 is CR 26 .
  • X 2 is S and X 7 is N.
  • x is 0, such that there are no R 20 substituents.
  • x is 1 or 2, and each R 20 substituent is independently selected from C 1 -C 3 alkyl, hydroxy, halogen, and nitrile.
  • x is 1 and R 20 is C 1 -C 3 alkyl.
  • the compound is: .
  • R 4 is of Formula 4N: (4N), wherein: X 12 is CH2, CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is 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; R 25 is H, optionally substituted (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; and q is 0, 1,
  • R 4 is of Formula 4O: (4O), wherein: X 12 is CH2, CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, wherein optionally two geminal R 15 groups can be taken together as a carbonyl; R 25 is H, optionally substituted (C 1 - 6 )alkyl, formyl acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; and
  • R 4 is of Formula 4P: (4P), wherein: X 12 is CH 2 , CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is an optional substituent, and as valency permits, is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile, wherein optionally two geminal R 15 groups can be taken together as a carbonyl; R 25 is H, optionally substituted (C1-6)alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optional
  • R 4 is of Formula 4Q: (4Q), wherein: X 12 is CH2, CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R 25 is H, optionally substituted (C 1 - 6 )alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • R 4 is of Formula 4R: (4R), wherein: X 12 is CH2, CHR 15 , C(R 15 ) 2 , O, CHR 42 , NR 43 , or NR 25 ; R 15 is an optional substituent selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxy, carboxy, carboxamide, halogen, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; R 25 is H, optionally substituted (C1-6)alkyl, formyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • Formulae A, A’, I, or II comprises a hydrophilic group (Z).
  • Z comprises a hydrophilic moiety that is substantially biologically inert.
  • Y 11 is NR 9 , and R 9 is Z.
  • Y 11 is C(R 16 ) 2 , or CHR 16 , and at least one R 16 group is Z.
  • Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, and any combination thereof.
  • Z comprises a sulfonyl.
  • Z comprises a sulfone.
  • Z comprises a sulfimide.
  • Z comprises a sulfoximine.
  • Z comprises a sulfonimidamide. In some embodiments, Z comprises a sulfonate. In some embodiments, Z comprises a carboxamide. In some embodiments, Z comprises a carboxy. In some embodiments, Z comprises a hydroxy or a hydroxyalkyl. In some embodiments, Z comprises an aldehyde. In some embodiments, Z comprises an ester. In some embodiments, Z comprises an alkoxy. In some embodiments, Z comprises a nitrile. In some embodiments, Z comprises a halogen.
  • Z is alkylsulfonyl, cycloalkylsulfonyl, or heterocyclylsulfonyl. In some embodiments, Z is alkylsulfonyl. In some embodiments, Z is cycloalkylsulfonyl. In some embodiments, Z is heterocyclylsulfonyl. [00139] In some embodiments of Formulae A, A’, I, or II, Z is alkylsulfoximine, cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, or alkylsulfonamide.
  • 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.
  • Z comprises -S(O)R 16A , - C(O)R 16A , -C(O)H, -C(O)OR 16A , -(CH2)zOH, -(CH2)zOR 16A , -OH, -N(R 16A ) 2 , -C(O)N(R 16A ) 2 , where R 16A is optionally substituted (C 1-6 )alkyl, and z is 1, 2, 3, 4, 5, or 6.
  • Z comprises -S(O)CH 3 , -C(O)CH 3 , -C(O)H, -C(O)OCH 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , -OH, -N(CH 3 ) 2 , -C(O)N(CH 3 ) 2 .
  • Z is selected from a sulfone, a sulfonate, carboxy, ester, hydroxy, hydroxyalkyl, aldehyde, and an optionally substituted carboxamide.
  • Z is a sulfone.
  • Z is a sulfonate. In some embodiments, Z is an optionally substituted carboxamide. In some embodiments, Z is a carboxy group. In some embodiments, Z is a hydroxy or a hydroxyalkyl group. In some embodiments, Z is an aldehyde. In some embodiments, Z is an ester.
  • Z is of one of Z1-Z6: ( Z1), (Z2), (Z3), (Z4), (Z5), or (Z6), wherein: Y 9 is absent, -O-, -NR 9 -, -(C 1-6 )alkylene-O-, -(C 1-6 )alkylene-NR 9 -; X 11 is absent, O, or NH; R 11 is selected from halogen, R 8 , -NR 9 R 10 , (C1-6)alkyl, cycloalkyl, heterocyclyl, and substituted versions thereof; R 8 is (C1-6)alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof; each R 9 is independently H or optionally substituted (C 1-6 )alkyl; each R 10 is independently H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 3- 8 )cycloal
  • Z is of the Formula Z1A: (Z1A), wherein: R 11 is -NR 9 R 10 , optionally substituted (C1-6)alkyl.
  • R 11 is (C1-6)alkyl.
  • R 11 is -NR 9 R 10 .
  • Z is of the Formula Z1B: (Z1B), wherein: X 11 is O, or NH; and R 8 is (C 1-6 )alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof.
  • X 11 is O.
  • X 11 is NH.
  • R 8 is (C 1-6 )alkyl. In some embodiments of Z1B, R 8 is methyl. In some embodiments of Z1B, R 8 is trifluoromethyl. In some embodiments of Z1B, R 8 is difluoromethyl. In some embodiments of Z1B, R 8 is optionally substituted (C3-7)cycloalkyl. In some embodiments of Z1B, R 8 is optionally substituted (C3-7)heterocyclyl. In some embodiments of Z1B, R 8 is (C3-4)cycloalkyl. In some embodiments of Z1B, R 8 is (C2-4)heterocyclyl.
  • R 8 is a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from N, O, and S. In some embodiments of Z1B, R 8 is . In some embodiments of Z1B, R 8 is . [00147] In some embodiments of Z1B, X 11 is NH, and R 8 is (C 1-6 )alkyl. In some embodiments of Z1B, X 11 is NH, and R 8 is cycloalkyl. In some embodiments of Z1B, X 11 is NH, and R 8 is heterocyclyl. [00148] In some embodiments of Z1B, X 11 is O, and R 8 is (C1-6)alkyl.
  • Z is of the Formula Z1C: (Z1C), wherein: X 11 is O, or NH; R 9 is H or optionally substituted (C1-6)alkyl; and R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 3-8 )cycloalkyl, or optionally substituted heterocyclyl.
  • Z1C is O. In some embodiments of Z1C, X 11 is NH.
  • R 9 is H. In some embodiments of Z1C, R 9 is (C 1-6 )alkyl. In some embodiments of Z1C, R 10 is H. In some embodiments of Z1C, R 10 is (C1-6)alkyl. In some embodiments of Z1C, R 10 is optionally substituted cycloalkyl. In some embodiments of Z1C, R 10 is optionally substituted heterocyclyl. In some embodiments of Z1C, R 9 is H, and R 10 is (C1- 6)alkyl. In some embodiments of Z1C, R 9 is H, and R 10 H.
  • X 11 is NH, R 9 is H and R 10 is (C 1-6 )alkyl. In some embodiments of Z1C, X 11 is NH, R 9 is H and R 10 is methyl. In some embodiments of Z1C, X 11 is NH, R 9 is H and R 10 is ethyl. [00152] In some embodiments of Z1C, X 11 is O, R 9 is H and R 10 is (C 1-6 )alkyl. In some embodiments of Z1C, X 11 is O, R 9 is H and R 10 is methyl. In some embodiments of Z1C, X 11 is O, R 9 is H and R 10 is ethyl.
  • Z is of the Formula Z4A: (Z4A), wherein: R 9 is H; and R 10 is -SO 2 R 38 ; and R 38 is optionally substituted alkyl, or amino.
  • R 38 is (C1-6)alkyl.
  • R 18 is methyl.
  • R 38 is ethyl.
  • Z is of the Formula Z3: (Z3) wherein: R 52 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and t is 0, 1, or 2.
  • R 52 is (C 1-6 )alkyl.
  • t is 1. In some embodiments of Z3, t is 2. In some embodiments of Z3, t is 0.
  • Z3 is of the Formula Z3A: (Z3A), wherein R 52 is H.
  • Z is of the Formula Z5: (Z5), wherein q is 0, 1, or 2.
  • Z5 is 0. In some embodiments of Z5, q is 1. In some embodiments of Z5, q is 2.
  • Z is of the Formula Z6: (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. [00162] In some embodiments of Formula I, Z is of the formula Z1, wherein R 51 is optionally substituted alkyl or amino. In some embodiments, Z is Z1, and R 51 is amino. In some embodiments, Z is Z1 and R 51 is optionally substituted alkyl.
  • Z is an alkylsulfone.
  • Z is an alkylsulfone of Formula Z1D: (Z1D) wherein R 53 is H or optionally substituted C1-C6 alkyl.
  • R 53 is H.
  • R 13 is C 1 -C 3 alkyl.
  • Z is a group of Formula Z4, wherein; R 9 is H; and R 10 is of the formula -SO 2 R 38 ; and R 38 is optionally substituted alkyl, or amino.
  • Z is a carboxamide of Formula Z4, R 10 is -SO2R 38 , and R 38 is methyl. In some embodiments, Z is a carboxamide of Formula Z4, R 10 is of the formula -SO2R 38 , and R 38 is amino. [00165] In some embodiments of Formulae A, A’, I, or II, Z is a 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 -CH 2 OH. In some embodiments, p is 2, such that Z6 is CH 2 CH 2 OH.
  • Z is a group of formula Z3, where R 52 is H (i.e., Z is -CO 2 H).
  • R 52 is H (i.e., Z is -CO 2 H).
  • Z is a carboxamide of Formula Z4, R 10 is -SO2R 38 .
  • Z is of Formula Z3, wherein R 52 is optionally substituted (C1-6)alkyl or a heterocyclyl. In some embodiments, Z is of Formula Z3, where R 52 is a heterocycle.
  • two or more of Y 1 -Y 3 are CR 1 , CR 2 and CR 3 respectively. In some embodiments of the compound of Formula I, Y 1 -Y 3 are CR 1 , CR 2 and CR 3 respectively. In some embodiments, each of R 1 -R 3 are H. In some embodiments, at least one of R 1 -R 3 is not H. In some embodiments, Y 2 is CR 2 , and R 2 is not H. In some embodiments R 2 is selected from optionally substituted alkyl, alkyl halide, or -COR 30 , where R 30 is H or C1-6 alkyl.
  • Y 3 is N and Y 1 and Y 2 are each CR 1 and CR 2 respectively. In some embodiments of the compound of Formula I, Y 1 is N and Y 2 and Y 3 are each CR 2 and CR 3 respectively. In some embodiments of the compound of Formula I, Y 2 is N and Y 1 and Y 3 are each CR 1 and CR 3 respectively.
  • Y 5 is CR 5 . In some embodiments, R 5 is selected from H, CH 3 , CF 3 , and halogen. In some embodiments, R 5 is CH 3 . In some embodiments, R 5 is CF 3 .
  • R 5 is halogen. In some embodiments, R 5 is F or Cl. In some embodiments, R 5 is H.
  • Y 5 is N. [00173] In some embodiments of Formulae A, A’, I, or II, R 7 is selected from H, CH 3 , CF 3 , and halogen. In some embodiments R 7 is CH 3 . In some embodiments R 7 is CF 3 . In some embodiments R 7 is halogen. In some embodiments R 7 is F or Cl. In some embodiments, R 7 is H. [00174] In some embodiments of Formulae A, A’, I, or II, Y 1 is CR 1 .
  • R 1 is selected from H, CH3, CF 3 , and halogen. In some embodiments, R 1 is CH3. In some embodiments, R 1 is CF 3 . In some embodiments, R 1 is halogen. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 is H. [00175] In some embodiments of Formulae A, A’, I, or II, Y 1 is N. [00176] In some embodiments of Formulae A, A’, I, or II, Y 2 is CR 2 .
  • R 2 is CH3.
  • R 2 is CF 3 .
  • R 2 is -CHF2.
  • R 2 is -CH2Cl.
  • R 2 is halogen.
  • R 2 is F or Cl.
  • R 2 is -(CH2)zOH, where z is 1.
  • R 2 is - (CH 2 ) z OH, where z is 2. In some embodiments, R 2 is -(CH 2 ) z OH, where z is 3. In some embodiments, R 2 is H. [00177] In some embodiments of Formulae A, A’, I, or II, Y 2 is N. [00178] In some embodiments of Formula I, the compound is of Formula IA: (IA) where R 1 , R 2 , R 4 , R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IB: (IB) where R 1 , R 2 , R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IC: (IC) where R 1 -R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula ID: (ID) where R 1 -R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IE: (IE) where R 2 -R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IF: (IF) where R 2 -R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IG: (IG) where R 2 , R 4 , R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IH: (IH) where R 2 , R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IJ: (IJ) where R 1 , R 4 , R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IK: (IK) where R 1 , R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IL: (IL) where R 1 , R 3 , R 4 , R 5 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • the compound is of Formula IM: (IM) where R 1 , R 3 , R 4 , R 7 , R 16 , R 31 , Y 11 , m, n and p are as defined herein.
  • m is 0 and p is 0.
  • m is 1 and p is 0.
  • m is 2 and p is 0. [00193] In some embodiments of Formulae IA-IM, m is 0 and p is 1. [00194] In some embodiments of Formulae IA-IM, m is 1 and p is 1. [00195] In some embodiments of Formulae IA-IM, m is 2 and p is 1. [00196] In some embodiments of Formulae IA-IM, m is 0 and p is 2. [00197] In some embodiments of Formulae IA-IM, m is 1 and p is 2. [00198] In some embodiments of Formulae IA-IM, m is 2 and p is 2. [00199] In some embodiments of Formulae IA-IM, m is 1 and p is 1 and the compound is of Formulae IIIA-IIIM: (IIIA), (IIIB), (IIIC),
  • the compound is also a diastereoisomer of the structure of Formula II.
  • Y 11 is NR 9 .
  • R 9 is H.
  • R 9 is optionally substituted (C 1-6 )alkyl.
  • R 9 is Z (e.g., as described herein).
  • Y 11 is O. [00203] In some embodiments of Formulae IA-IM, and IIIA-IIIM, Y 11 is S. [00204] In some embodiments of Formulae IA-IM, and IIIA-IIIM, Y 11 is SO. [00205] In some embodiments of Formulae IA-IM, and IIIA-IIIM, Y 11 is SO2. [00206] In some embodiments of Formulae IA-IM, and IIIA-IIIM, Y 11 is CH2, CHR 16 or C(R 16 ) 2 .
  • the compound is of Formula II: (II), or a pharmaceutically acceptable salt thereof, wherein Y 1 -Y 3 , Y 5 , R 4 , R 7 , R 16 , R 31 , Y 11 , n, m and p are as defined herein.
  • m is 0 and p is 0.
  • m is 1 and p is 0.
  • m is 2 and p is 0.
  • m is 0 and p is 1.
  • m is 1 and p is 1.
  • m is 2 and p is 1.
  • m is 0 and p is 2. In some embodiments of Formula II, m is 1 and p is 2. In some embodiments of Formula II, m is 2 and p is 2. [00209] In some embodiments of Formula II, Y 11 is NR 9 . In some embodiments, R 9 is H. In some embodiments, R 9 is optionally substituted (C 1-6 )alkyl. In some embodiments, R 9 is Z (e.g., as described herein). In some embodiments of Formula II, Y 11 is O. In some embodiments of Formula II, Y 11 is S. In some embodiments of Formula II, Y 11 is SO. In some embodiments of Formula II, Y 11 is SO 2 .
  • Y 11 is CH 2 , CHR 16 or C(R 16 ) 2 .
  • one or more of Y 1 -Y 3 is N.
  • Y 3 is N.
  • Y 2 is N.
  • Y 1 is N.
  • Y 1 and Y 3 are N.
  • Y 2 and Y 3 are N.
  • Y 1 and Y 2 are N.
  • two or more of Y 1 -Y 3 are CR 1 , CR 2 and CR 3 respectively.
  • Y 1 -Y 3 are CR 1 , CR 2 and CR 3 respectively. In some embodiments, each of R 1 -R 3 are H. In some embodiments, at least one of R 1 -R 3 is not H. In some embodiments, Y 2 is CR 2 , and R 2 is not H. In some embodiments R 2 is selected from optionally substituted alkyl, alkyl halide, or -COR 30 , where R 30 is H or C1-6 alkyl. [00212] In some embodiments of the compound of Formula II, Y 3 is N and Y 1 and Y 2 are each CR 1 and CR 2 respectively.
  • Y 1 is N and Y 2 and Y 3 are each CR 2 and CR 3 respectively. In some embodiments of the compound of Formula II, Y 2 is N and Y 1 and Y 3 are each CR 1 and CR 3 respectively.
  • Y 5 is CR 5 . In some embodiments, R 5 is H.
  • Y 5 is N.
  • n is 1-9, such that the ring includes one or more R 11 substituents. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments n is 4.
  • n is 5. In some embodiments, R 11 is selected from C1-3 alkyl. In some embodiments, R 11 is methyl. In some embodiments, R 11 is trifluoromethyl. [00216] In some embodiments of Formula II, n is 0.
  • the compound is of the Formula IVA: (IVA) or a pharmaceutically acceptable salt thereof, wherein: X 11 is absent, O, or NH; R 11 is selected from R 8 , and -NR 9 R 10 ; R 8 is (C 1-6 )alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C 1-6 )alkyl; R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; each R 16 is independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,
  • R 8 is methyl or trifluoromethyl. [00219] In some embodiments of Formula IVA, R 8 is methyl. [00220] In some embodiments of Formula IVA, R 8 is trifluoromethyl.
  • the compound is of the Formula IVB: (IVB) or a pharmaceutically acceptable salt thereof, wherein: each R 16 is independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C 1-6 )alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; and R 1 -R 2 , R 5 and R 7 are independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxyl, halo(C1-6)alkyl, -COR 30 , -OR 30 , halogen, and CN.
  • each R 16 is independently selected from H, optionally substituted (C1-6)alkyl,
  • the compound is of Formula IVC: (IVC) or a pharmaceutically acceptable salt thereof, wherein: each R 16 is independently selected from H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; and R 1 -R 2 , R 5 and R 7 are independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, halo(C 1-6 )alkyl, -COR 30 , -OR 30 , halogen, and CN.
  • each R 16 is independently selected from H, optionally substituted (C1-6)al
  • cycloalkyl optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl
  • R 4 is of formula 4A, 4A1, 4A1a, 4A2, 4A2a, 4A2a’, 4A2a”, 4A2b, or 4A2c (as described herein).
  • R 4 is of formula 4A, 4A1, 4A1a, 4A2, 4A2a, 4A2a’, 4A2a”, 4A2b, or 4A2c, and r is 0.
  • R 4 is of formula 4A, 4A1, 4A1a, 4A2, 4A2a, 4A2a’, 4A2a”, 4A2b, or 4A2c, and r is 1.
  • R 4 is of formula 4A, 4A1, 4A1a, 4A2, 4A2a, 4A2a’, 4A2a”, 4A2b, or 4A2c, and r is 2. [00225] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4B. [00226] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4C. In some embodiments, R 4 is of formula 4C, and u is 0. In some embodiments, R 4 is of formula 4C, and u is 1. In some embodiments, R 4 is of formula 4C, and u is 2.
  • R 4 is of formula 4D, 4D1, 4D1a, 4D1b, or 4D1c (as described herein). In some embodiments, R 4 is of formula 4D, 4D1, 4D1a, 4D1b, or 4D1c, and r is 0. In some embodiments, R 4 is of formula 4D, 4D1, 4D1a, 4D1b, or 4D1c, and r is 1. In some embodiments, R 4 is of formula 4D, 4D1, 4D1a, 4D1b, or 4D1c, and r is 2.
  • R 4 is of formula 4E. [00229] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4F. [00230] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4G. [00231] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4H. [00232] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4I. [00233] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4J.
  • R 4 is of formula 4K. [00235] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4L. [00236] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4M. [00237] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4N. [00238] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4O. [00239] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4P.
  • R 4 is of formula 4Q. [00241] In some embodiments of Formulae IVA, IVB, or IVC, R 4 is of formula 4R. [00242] In some embodiments, R 4 is . [00243] In some embodiments, R 4 is . [00244] In some embodiments, R 4 is . [00245] In some embodiments, R 4 is . [00246] In some embodiments, R 4 is . [00247] In some embodiments, R 4 is .
  • R 4 is or comprises a group selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4 is or comprises . In some embodiments, R 4
  • the compound is of the Formula VA: (VA) or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula VA, r is 1. In some embodiments of Formula VA, r is 2.
  • the compound is of the Formula VIA: (VIA) or a pharmaceutically acceptable salt thereof, wherein: R 42 is H, optionally substituted (C 1 - 6 )alkyl, acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted sulfonamide, optionally substituted sulfonyl, optionally substituted amine, optionally substituted aminde, optionally substituted carbocycle (e.g.
  • the compound is of Formula VIIA: (VIIA) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula IXA: (IXA) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XA: (XA) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XIA:
  • XIA or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula XIA, r is 1. In some embodiments of Formula XIA, r is 2. [00258] In some embodiments of Formula IVA, the compound is of Formula XIIA: (XIIA) or a pharmaceutically acceptable salt thereof. [00259] In some embodiments of Formula IVA, the compound is of Formula XIIIA: (XIIIA) or a pharmaceutically acceptable salt thereof. [00260] In some embodiments of Formula IVA, the compound is of Formula XIVA: (XIVA) or a pharmaceutically acceptable salt thereof.
  • R 11 is -CH3, -CHF2, or -CF 3 .
  • the compound is of Formula VB: (VB) or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula VB, r is 1. In some embodiments of Formula VB, r is 2.
  • the compound is of the Formula VIB: (VIB) or a pharmaceutically acceptable salt thereof, wherein: R 42 is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted amine, optionally substituted carbocycle (e.g. cycloalkyl), optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl.
  • R 42 is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted amine,
  • the compound is of the Formula VIIB: (VIIB) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula IXB: (IXB) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XB:
  • the compound is of Formula XIB: (XIB) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XIB: (XIB) or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula XIB, r is 1. In some embodiments of Formula XIB, r is 2.
  • the compound is of Formula XIIIB: (XIIA) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XIVB:
  • the compound is of Formula XVB: (XVB) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula VC: (VC) or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula VC, r is 1. In some embodiments of Formula VC, r is 2.
  • the compound is of Formula VIC: (VIC) or a pharmaceutically acceptable salt thereof, wherein: R 42 is H, optionally substituted (C 1 - 6 )alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted amine, optionally substituted carbocycle (e.g. cycloalkyl), optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl.
  • R 42 is H, optionally substituted (C 1 - 6 )alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide,
  • the compound is of Formula VIIC: (VIIC) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula VIIIC: (VIIIC) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula IXC: (IXC) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XC: (XC) or a pharmaceutically acceptable salt thereof.
  • r is 0. In some embodiments of Formula XC, r is 1. In some embodiments of Formula XC, r is 2.
  • the compound is of Formula XIIC: (XIIC) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XIIIC: (XIIIC) or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula XIVC: (XIVC) or a pharmaceutically acceptable salt thereof.
  • R 42 is an optionally substituted carboxamide.
  • R 42 is or wherein: L 1 and L 3 are independently an optional linker selected from a bond, -CONR 45 -, - NR 46 CO-, -NR 46 -, -O-, -NR 46 COCR 45 2 -, -CO-, -SO 2 NR 45 -, -NR 46 SO 2 -, -SO 2 -, -CONR 46 CR 45 2 -, - NR 46 (CR 45 2 ) i -, optionally substituted methylene, and optionally substituted ethylene; Ring B and Ring D are independently an optionally substituted cyclic group (e.g., a saturated, partially saturated, or unsaturated monocyclic, bicyclic, or spirocyclic group that is a carbocycle, heterocycle, heteroaryl, and/or aryl); R 45 is H or optionally substituted (C1-6
  • R 46 is H, optionally substituted (C 1 - 6 )alkyl, or optionally substituted carbocycle; each R 51 and each R 52 is independently selected from H, optionally substituted (C 1 - 6 )alkyl, (C 1 - 6 )haloalkyl, optionally substituted (C 1 - 6 )alkoxyl, halogen, hydroxyl, carboxy, CN, NO2, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted (C1- 6)alkylamino, optionally substituted (C1-6)dialkylamino, optionally substituted sulfonamide, optionally substituted sulfonyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; j is an integer from 0 to 6; h is
  • Ring B and Ring D are connected via a sigma bond. In some embodiments, Ring B and Ring D are connected via a spirocyclic ring junction (e.g., a quaternary carbon atom). [00287] In some embodiments, R42 is selected from:
  • R 42 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . [00290] In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 . In some embodiments, R 42 . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is .
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is
  • R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . In some embodiments, R 42 is . [00291] In some embodiments of Formula I, the compound is of Formula B, (B) or a pharmaceutically acceptable salt thereof, wherein: Y 1 is N or CR 1 ; Y 2 is N or CR 2 ; Y 3 is N or CR 3 ; R 11 is an optionally substituted (C1-6)alkyl or (C1-6)haloalkyl (e.g., CH3 or CF 3 ); L 1 is an optional linker selected from -CONR 45 -, -NR 46 CO-, -NR 46 -, -O-, -NR 46 COCR 45 2- , -CO-, -SO2NR 45 -, -NR 46 SO2-, -SO2-, -CONR 46 CR 45 2-, -NR 46 (CR 45 2)i-, optionally substituted methylene, and optionally substituted ethylene; each R 15
  • R 46 is H, optionally substituted (C1-6)alkyl, optionally substituted heterocycle, or optionally substituted carbocycle; each R 16 is independently selected from H, Z, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxyl, hydroxyl, halogen, and CN; R 1 -R 3 , R 5 and R 7 are independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, halo(C 1-6 )alkyl, hydroxyl, halogen, and CN; R 116 is selected from H, optionally substituted (C 1-3 )alkyl, optionally substituted (C 1- 3 )alkoxyl, hydroxyl, halogen, CN, optionally substituted (C 3 - 5 )
  • R 116 is fluoro or chloro.
  • nm is 1 or 2.
  • np is 1 or 2.
  • the compound is of Formula B2: (B2) or a pharmaceutically acceptable salt thereof.
  • L 1 is a bond.
  • L 1 is a linker selected from -CONR 45 -, -NR 46 CO-, -NR 46 -, -O-, -NR 46 COCR 45 2-, -CO-, -SO2NR 45 -, -NR 46 SO2-, -SO2-, -CONR 46 CR 45 2-, -NR 46 (CR 45 2)i-, optionally substituted methylene, and optionally substituted ethylene.
  • L 1 is -NR 46 CO-.
  • L 1 is -NR 46 -.
  • L 1 is -O-.
  • L 1 is -NR 46 COCR 45 2-.
  • L 1 is -CO-.
  • L 1 is -SO 2 NR 45 -. In some embodiments, L 1 is -NR 46 SO 2 -. In some embodiments, L 1 is -SO 2 -. In some embodiments, L 1 is -CONR 46 CR 45 2 -. In some embodiments, Y 1 is CH, Y 2 is CH, Y 3 is N, Y 5 is N or CH. In some embodiments, Y 1 is CH. In some embodiments, Y 2 is CH. In some embodiments, Y 3 is N. In some embodiments, Y 5 is N or CH. In some embodiments, Y 5 is CH. In some embodiments, Y 5 is N.
  • each R 15 is independently halogen, (C 1-6 )alkyl, or (C 1- 6)haloalkyl. In some embodiments, each R 15 is independently fluoro, chloro, or bromo. In some embodiments, each R 15 is independently fluoro.
  • each R 15 is independently (C1-6)alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl). In some embodiments, each R 15 is independently (C1-6)haloalkyl. In some embodiments, q is 1, 2, 3, or 4. [00301] In some embodiments, R 46 is H, optionally substituted (C 1-6 )alkyl, (C 1-6 )haloalkyl, or optionally substituted 3- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O, and S.
  • R 116 is H, optionally substituted (C 1-3 )alkyl, optionally substituted (C1-3)alkoxyl, hydroxyl, halogen, CN, and (C3-5)cycloalkyl.
  • the compound is of the Formula VIIIA: (VIIIA) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycl
  • the compound is of Formula VIIIA”: (VIIIA”) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl,
  • R 11 is -CH 3 , CHF 2 , or -CF 3 . In some embodiments, R 11 is -CH 3 . In some embodiments, R 11 is -CHF 2 . In some embodiments, R 11 is -CF 3 . [00306] In some embodiments of Formula VB, the compound is of Formula VIIIB:
  • R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • the compound is of Formula VIIIB”: (VIIIB”) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl,
  • the compound is of Formula XIC: (XIC) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C1-6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cyclo
  • the compound is of Formula XIIC’: (XIC’) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted spirocyclic group, optionally substituted heterospirocyclic group, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted cycloalky
  • the compound is of Formula XIIIC: (XIIIC) or a pharmaceutically acceptable salt thereof.
  • R 15 is selected from halogen, cyano, hydroxyl
  • R 15 is selected from fluoro, methyl, trifluoromethyl, and difluoromethyl. [00315] In some embodiments of any one of Formulae VIIIA, VIIIA’, VIIIA”, VIIIB, VIIIB”, VIIC, XIIC”, VIIB’, or XIIIC, R 43 is an optionally substituted carboxyl.
  • R 43 is or wherein: L 2 and L 4 are independently an optional linker selected from a bond, -CONR 45 -, -CO-, - COCH2-, -C(O)O(CR45 2)i-, -SO2-, -SO2NR 45 -, -SO2CH2-, optionally substituted methylene, and optionally substituted ethylene; Ring B and Ring D are independently an optionally substituted cyclic group (e.g., a saturated, partially saturated, or unsaturated monocyclic, bicyclic or spirocyclic group that is a carbocycle, heterocycle, heteroaryl, and/or aryl); each R 45 is independently H, optionally substituted (C1-6)alkyl, optionally substituted carbocycle (e.g.
  • each R 51 and each R 52 is independently selected from H, optionally substituted (C1- 6)alkyl, (C1-6)haloalkyl, optionally substituted (C1-6)alkoxyl, halogen, hydroxyl, carboxy, CF 3 , CHF 2 , CN, NO 2 , B(OH) 2 , optionally substituted cycloalkyl, optionally substituted amino, optionally substituted (C 1-6 )alkylamino, optionally substituted (C 1-6 )dialkylamino, optionally substituted sulfonamide, optionally substituted sulfonyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; j is an integer from 0 to 6; h is an integer from 0 to 6; and i is an integer from 0 to 6.
  • Ring B and Ring D are connected via a sigma bond. In some embodiments, Ring B and Ring D are connected via a spirocyclic ring junction (e.g., a quaternary carbon atom). [00318] In some embodiments of Formula VIIIA, the compound is of Formula C:
  • R 11 is CH3 or CF 3 .
  • Ring B is an optionally substituted 4- to 7-membered carbocycle
  • Ring D is selected from optionally substituted 3- to 7-membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, optionally substituted aryl, and optionally substituted 5- to 6-membered heteroaryl.
  • R 25 or R 43 is selected from:
  • R43 is selected from , , and . [00323] In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is .In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is
  • R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . In some embodiments, R 43 is . [00324] In some embodiments of R 42 and R 43 , cyclic group B is selected from optionally substituted (C 3 - 8 )cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl. In some embodiments, B is an optionally substituted (C3- 8)cycloalkyl.
  • the (C3-8)cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, the (C3-8)cycloalkyl comprises bicyclo[1.1.1]pentyl, spiro[2,3]hexane, or bicyclo[3.1.0]hexyl. [00325] In some embodiments of R 42 and R 43 , cyclic group B is an optionally substituted heterocycle.
  • the optionally substituted heterocycle comprises tetrahydropyran, tetrahydrofuran, triazole, oxetane, azetidine, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-thiopyran 1,1-dioxide, or morpholinyl.
  • the heterocycle comprises 4,5,6,7-tetrahydropyrazolo[1.5- ⁇ ]pyrizinyl, hexahydro-pyrrolo[3,4- C]pyrrole, 2-Oxabicyclo[2.2.2]octane, oxaspiro[3,5]nonane, hexahydropyrazino[2,1- c][1,4]oxazine, 8-azabicyclo[3.2.1]octane, 2-azabicyclo[3.1.0]hexane, 1,1-dioxidothietane, indole, imidazol[1,2-a]pyridine, 1,4,5,6-tetrahydrocyclopenta[c]pyrazole, 6,8- dioxabicyclo[3.2.1]octane, 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]thiazine, oxobicyclo[3.1.0]hex
  • the heterocycle comprises 4-azaspiro[2.3]hexane, 6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 3- azaspiro[5.5]undecane, or 2-thiaspiro[3.3]heptane 2,2-dioxide.
  • B is an optionally substituted heteroaryl.
  • the heteroaryl comprises pyridinyl, pyrazolyl, pyrrole, thiazolyl, isothiazolyl, imidazolyl, furanyl, or thiophenyl.
  • the heteroaryl comprises benzodioxan, furo[2,3-c]pyridinyl, quinolinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5- a]pyridinyl, or indazolyl.
  • B is an optionally substituted aryl.
  • the aryl group is optionally substituted phenyl.
  • cyclic group D is selected from optionally substituted (C3-8)cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl.
  • D is an optionally substituted heterocycle.
  • the heterocycle comprises pyrrolidine, morpholine, piperidinyl, or piperazinyl.
  • cyclic group B is an optionally substituted aryl; and D is an optionally substituted heterocycle.
  • cyclic group B is optionally substituted phenyl; and D is optionally substituted pyrrolidine, optionally substituted morpholine, optionally substituted piperidinyl, or optionally substituted piperazinyl.
  • cyclic group B is an optionally substituted heteroaryl; and D is an optionally substituted heterocycle.
  • cyclic group B is an optionally substituted (C 3 - 8 )cycloalkyl; and D is an optionally substituted aryl.
  • cyclic group B is a an optionally substituted heterocycle, wherein the heterocycle is a spirocyclic group, and linker L 2 is absent.
  • L 1 is -CH 2 -.
  • L 1 is -CONH-.
  • L 1 is -NHCO-. [00334] In some embodiments of R 42 , L 1 is -NHCOCH2-. [00335] In some embodiments of R 42 , L 1 is -S(O)(NR 45 )-. [00336] In some embodiments of R 42 , L 1 is -S(O)(NR 45 )NR 45 -. [00337] In some embodiments of R 42 , L 1 is -NR 45 S(O)(NR 45 )-. [00338] In some embodiments of R 42 , L 1 is -SO 2 -. [00339] In some embodiments of R 42 , L 1 is -SO2NR 45 -.
  • L 1 is -NR 45 SO2-.
  • L 2 is -CO-.
  • L 2 is -CH2-.
  • L 2 is -C(O)O(CR 45 2 ) i -, wherein R 45 is H or CH 3 , and i is 1 or 2.
  • R 45 is H or CH 3 , and i is 1 or 2.
  • L 2 is -C(O)O -.
  • each R 51 and each R 52 is independently selected from (C1-3)alkyl, (C1-6)alkyl, halogen, NO2, OH, CN, CH2CN, halo(C1-3)alkyl, substituted (C1-3)alkyl, substituted (C1-3)alkoxyl, substituted amino, di(C1-3)alkyl substituted amino, C(O)O(C1-3)alkyl, C(O)NH(C1-3)alkyl, C(O)NH2, CH2OH, O(C1-3)alkylene-OH, (C1- 3)alkylene-O(C1-3)alkyl, SO2-(C1-3)alkyl, SO2-aryl, O(C1-3)alkylene-aryl.
  • each R 51 and each R 52 is independently selected from CH 3 , OCH 3 , CH 2 CH 3 , F, Cl, Br, OH, CN, CH 2 CN, CF 3 , CHF 2 , CH 2 F, OCHF 2 , OCF 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , NHBoc, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, C(O)CH 3 , OC(O)CH 3 , C(O)OCH 3 , C(O)OH, C(O)OCH 2 CH 3 , C(O)NHCH 3 , C(O)NH 2 , OCH 2 CH 3 , NO 2 , CH2CH2OCH3, C(CH3)3, CH2OH, OCH2CH2OH, CH(CH3)OH, CH(CH3)CN, C(CH3) 2 OH, C(CH3) 2 CN, OCH2
  • R 43 , R 51 and group D are attached to the same carbon atom of group A.
  • X 11 is NH.
  • R 11 is R 8 .
  • R 8 is (C1-6)alkyl (e.g., methyl or ethyl). In some embodiments, R 8 is methyl or ethyl.
  • R 8 is optionally substituted (C3-7)cycloalkyl or optionally substituted (C2-6)heterocyclyl.
  • R 11 is - NR 9 R 10 .
  • R 9 is H
  • R 10 is H, or (C 1-6 )alkyl.
  • Exemplary CDK4 inhibitor compounds of this disclosure include compounds shown in Table 1, and pharmaceutically acceptable salts thereof.
  • any of the compounds of this disclosure may be present in a salt form. In some cases, the salt form of the compound is a pharmaceutically acceptable salt.
  • “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.
  • Salts, solvates, hydrates, and prodrug forms of a compound are of interest. All such forms are embraced by the present disclosure.
  • the compounds described herein include salts, solvates, hydrates, prodrug and isomer forms thereof, including the pharmaceutically acceptable salts, solvates, hydrates, prodrugs and isomers thereof.
  • a compound may be a metabolized into a pharmaceutically active derivative.
  • 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.
  • solvate refers to a molecular complex of a compound (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
  • a solvate can be in a liquid or solid form.
  • 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 described herein may be present in a prodrug form.
  • a prodrug derivative of a compound generally includes a labile promoiety substituent at a suitable site of the parent compound. The promoiety refers to the group that is removed by enzymatic or chemical reactions, when a prodrug is converted to the drug in vivo.
  • the promoiety is a group, such as an optionally substituted alkanoyl, attached via an ester linkage to a hydroxyl group of the parent compound.
  • an ester promoiety can be incorporated at a hydroxyl group of the compound (e.g., as described in Formulae A, A’, I, or II).
  • the promoiety is the part of an ester group attached to a hydroxyl, such as -COCH 3 , -COCH(CH 3 ) 2 or -COC(CH 3 ) 3 .
  • the promoiety is -CH2OCOC(CH3)3.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F 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.
  • 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. [00362] In some embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of Formulas described herein. 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 R 1 -R 52 , etc.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3 , CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 etc.).
  • a biopharmaceutical agent such as an antibody or a fragment thereof.
  • the conjugate is a antibody-drug conjugate (ADC) of a compound of the present disclosure.
  • ADC antibody-drug conjugate
  • a pharmaceutical composition comprising the subject CDK4 inhibitor compounds and a pharmaceutically acceptable carrier or excipient.
  • a “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human.
  • 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).
  • 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.
  • routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like.
  • 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.
  • compositions comprising compounds of the present disclosure can further comprise at least one additional active agent.
  • effective amount means a sufficient amount of the composition to provide the desired utility when administered to a subject having a particular condition.
  • 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.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable carrier or excipient” can encompass substances referred to as pharmaceutically acceptable diluents, pharmaceutically acceptable additives, and pharmaceutically acceptable carriers.
  • a pharmaceutically acceptable carrier, diluent or excipient for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990), and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, 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.
  • 3.3.1 Methods of Inhibiting CDK4 [00372] As illustrated in the working examples the subject compounds can inhibit cyclin- dependent kinase 4 (CDK4).
  • inhibiting a CDK4 it is meant that the activity of the enzyme 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).
  • inhibiting a CDK4 means decreasing the activity of the enzyme by a factor of 2 or more, such as 3 or more, 5 or more, 10 or more, 100 or more, or 1000 or more, relative to its normal activity (e.g., relative to a control as measured by any convenient assay).
  • the method is a method of inhibiting CDK4 in a sample.
  • 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.
  • a method of inhibiting cyclin-dependent kinase 4 (CDK4) comprising contacting a biological sample containing CDK4 with an effective amount of a subject compound or a pharmaceutical composition, as described herein, to inhibit CDK4.
  • a method of inhibiting CDK4 comprising contacting a sample with a CDK4 inhibitor to inhibit activity of CDK4.
  • the sample is a cellular sample.
  • the CDK4 inhibitor is an inhibitor as defined herein. In some embodiments, the CDK4 inhibitor is an inhibitor according to any one of formulas I-VIIIB. In some cases, the CDK4 inhibitor is any compound illustrated in Table 1. [00377] In some embodiments the CDK4 inhibitor is a classic or non-covalent inhibitor. In some embodiments, there is provided a method of inhibiting CDK4, the method comprising contacting a sample with a CDK4 inhibitor that associates with CDK4 to inhibit CDK4. [00378] In some embodiments, the subject compounds have a CDK4 inhibition profile that reflects activity against additional enzymes. In some embodiments, the subject compounds specifically inhibit CDK4 without undesired inhibition of one or more other enzymes.
  • the subject compounds selectively inhibit CDK4 over CDK1. In some embodiments, the subject compounds selectively inhibit CDK4 over CDK2. In some embodiments, the subject compounds selectively inhibit CDK4 over CDK6. [00379] In some embodiments, the subject compounds inhibit CDK4, as determined by an inhibition assay, e.g., by an assay that determines the level of activity of the enzyme either in a cell-free system or in a cell after treatment with a subject compound, relative to a control, by measuring the IC50 or EC50 value, respectively.
  • 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.
  • the subject compounds have an IC50 value (or EC50 value) of 10 ⁇ or less, such as 3 ⁇ or less, 1 ⁇ 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.
  • IC50 value or EC50 value of 10 ⁇ or less, such as 3 ⁇ or less, 1 ⁇ 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.
  • aspects of the disclosure include methods of inhibiting CDK4.
  • a subject compound may inhibit at activity of CDK4 in the range of 10% to 100%, e.g., by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more.
  • a subject compound may inhibit its target with an IC50 of 1 x 10 "6 M or less (e.g., 1 x 10 "6 M or less, 1 x 10 "7 M or less, 1 x 10 "8 M or less, 1 x 10 -9 M or less, 1 x 10 10 M or less, or 1 x 10 11 M or less).
  • the protocols that may be employed in determining CDK (e.g., CDK1, 2, 4 and/or 6) 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).
  • the subject method is an in vitro method that includes contacting a sample with a subject compound that specifically inhibits CDK4.
  • the sample is suspected of containing CDK4 and the subject method further comprises evaluating whether the compound inhibits CDK4.
  • 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.
  • 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 CDK4, 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.
  • the sample is known to contain CDK4.
  • the method is a method of reducing cancer cell proliferation, where the method includes contacting the cell with an effective amount of a subject CDK4 inhibitor compound (e.g., as described herein) to reduce cancer cell proliferation.
  • the method can be performed in combination with a chemotherapeutic agent (e.g., as described herein).
  • the cancer cells can be in vitro or in vivo.
  • the method includes contacting the cell with a CDK4 inhibitor compound (e.g., as described herein) and contacting the cell with a chemotherapeutic agent. Any convenient cancer cells can be targeted.
  • a method of inhibiting CDK4 in a subject comprising administering to the subject a compound or a pharmaceutical composition, as described herein, to inhibit CDK4 in the subject. 3.3.2 Methods of Treatment [00388] Compounds of the present disclosure can inhibit CDK4 and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by CDK4.
  • a method of treating a disease or disorder associated with CDK4 in a subject comprising administering to the subject suffering from a disease or disorder associated with CDK4 a therapeutically effective amount of a compound, or a pharmaceutical composition as described herein.
  • diseases or disorders associated with CDK4 include cancer and other diseases of proliferation disorders.
  • 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 CDK4 inhibitor compound can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK4 kinase activity.
  • Such diseases or disorders associated with CDK4 include cancer and other diseases of proliferation disorders.
  • the present disclosure provides treatment of an individual or a patient in vivo using a subject compound (e.g., a compound of Formula (A) or a salt or stereoisomer thereof) such that growth of cancerous tumors is inhibited.
  • a subject CDK4 inhibitor compound can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK4 kinase activity.
  • the CDK4 inhibitor is an inhibitor as defined herein.
  • the CDK4 inhibitor is an inhibitor according to any one of formulas A-A’, or I-XVB.
  • the CDK4 inhibitor is a compound illustrated in Table 1.
  • a subject CDK4 inhibitor compound can be used in conjunction with other agents or standard cancer treatments.
  • 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.
  • a method of inhibiting CDK4 comprising contacting the CDK4 with a subject CDK4 inhibitor compound.
  • provided herein is a method of inhibiting CDK4 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.
  • a method of inhibiting CDK4 comprising contacting the CDK4 with a subject CDK4 inhibitor compound.
  • a method of inhibiting CDK4 in a patient comprising administering to the patient a compound of Formula (A) or any of the Formulae as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • 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 CDK4 inhibitor compound.
  • the cancer is characterized by activation of cyclin D.
  • a method of treating a disease or disorder associated with CDK4 in a patient comprising administering to the patient a therapeutically effective amount of a subject CDK4 inhibitor compound.
  • provided herein is a method of treating a disease or disorder associated with CDK2 and/or CDK4 in a patient or subject, the method comprising co- administering to the patient a therapeutically effective amount of a compound of Formula (A) or (I) with a compound of PCT/US2024/029323.
  • a method of treating a disease or disorder associated with CDK4 in a patient or subject the method comprising co-administering to the patient a therapeutically effective amount of a compound of Formula (A) or (I) with another therapeutically active agent.
  • the present disclosure provides for treatment of cancer by administration to a subject, a compound of Formulae A, A’, I, or II or composition comprising a compound of Formulae A, A’, I, or II.
  • the cancer is selected from breast cancer, endometrial cancer, gastric cancer, lung cancer, melanoma, ovarian cancer, prostate cancer, uterine cancer, and thyroid cancer.
  • the cancer is breast cancer.
  • the cancer is gastric cancer.
  • the cancer is endometrial cancer.
  • the cancer is lung cancer.
  • the cancer is melanoma.
  • the cancer is ovarian cancer.
  • the cancer is prostate cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is thyroid cancer.
  • breast cancer is selected from estrogen-receptor positive human epidermal growth factor receptor 2 negative (ER + HER2-) cancer, human epidermal growth factor receptor 2 positive (HER2 + ) cancer, KAT6A-dependent breast cancer, and triple negative breast cancer (TNBC).
  • gastric (stomach) cancer is adenocarcinoma, gastrointestinal stromal tumors, neuroendocrine tumors, or lymphatic stomach cancer.
  • the present disclosure provides for treatment of gynecological cancers that overexpress CCNE1 and/or CCNE2 and/or CCNE3. In some embodiments, this disclosure provides for treatment of tumors overexpressing CCNE1 and/or CCNE2 and/or CCNE3. [00404] In some embodiments, the present disclosure provides for treatment of BRAF- mutant melanoma, BRAF-mutant non-small cell lung cancer (NSCLC), and BRAF-mutant thyroid cancer. In some embodiments, the cancer is BRAF-mutant melanoma. In some embodiments, the cancer is BRAF-mutant non-small cell lung cancer (NSCLC). In some embodiments, the cancer is BRAF-mutant thyroid cancer.
  • NSCLC BRAF-mutant non-small cell lung cancer
  • the cancer is EGFR-mutant non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the cancer is Mat- altered solid tumors, such as lung or pancreatic cancers, etc.
  • 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.
  • the application of interest is a therapeutic application, for example, in the treatment of a disease.
  • compositions and methods of the present application may be used to deliver a subject CDK4 inhibitor to a cell to treat a disease or condition where the underlying pathology is, wholly or partially, mediated by CDK4.
  • compositions of the present application may be used in the treatment of diseases or disorders associated with CDK4 such as cancer and other diseases with proliferation disorder.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • 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.
  • a range includes each individual member.
  • a group having 1-3 articles refers to groups having 1, 2, or 3 articles.
  • a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.
  • the compounds in any of the formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.
  • 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.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • —(C ⁇ O)NH 2 is attached through carbon of the carbonyl (C ⁇ O) group.
  • reference to an atom is meant to include isotopes of that atom.
  • reference to H is meant to include 1 H, 2 H (i.e., D) and 3 H (i.e., T), and reference to C is meant to include 12 C and all isotopes of carbon (such as 13 C).
  • 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, ⁇ , ⁇ , ⁇ - trideuterotoluene and toluene are isotopologues of each other. It is understood to a person having ordinary skill in the art, a compounds disclosed herein also provide for isotopologues of each other.
  • 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F 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.
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 90, 95 or 99% enriched at a desired location.
  • substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the formulae described herein.
  • the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R, R’, and R’’ etc.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3 , CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 etc.).
  • the unsubstituted carbons may be deuterated.
  • “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon.
  • “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions.
  • “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms.
  • the aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri- unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration.
  • the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2, C 1 -C 3 , C1-C4, C1-C5 or C1-C6.
  • the specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species.
  • C 1 -C 6 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C1-C4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group.
  • the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the alkyl contains from 1 to about 8 carbon atoms.
  • the alkyl is C1-C2, C 1 -C 3 , C1-C4, C1-C5, or C1-C6.
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C1-C6 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed.
  • C 1 -C 4 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted.
  • alkyl also encompasses cycloalkyl or carbocyclic groups.
  • alkyl is a linear or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds that may occur at a stable point along the chain.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted.
  • Alkenyl also encompasses cycloalkyl or carbocyclic groups possessing at least one point of unsaturation.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain.
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5- hexynyl.
  • the alkynyl group is optionally substituted.
  • Alkynyl also encompasses cycloalkyl or carbocyclic groups possessing at least one triple bond.
  • Alkylene is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 1 -C 2 alkylene, C 1 -C 3 alkylene, C 1 -C 4 alkylene, C 1 -C 6 alkylene, or C 1 - C 6 alkylene.
  • Alkenylene is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene.
  • Alkynylene is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkynylene.
  • amino refers to the group -NRR’ wherein R and R’ are independently hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and/or heteroatom-containing variants thereof.
  • “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant or concatenated. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule.
  • “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • Halo and halogen refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl is a branched or straight-chain alkyl groupssubstituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perhaloalkyl means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.
  • heteroalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • heteroaliphatic refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety.
  • heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, —O-alkyl-O- alkyl, alkyl-O-haloalkyl, etc.
  • Heterocycloalkyl is an alkyl group as defined herein substituted with a heterocyclo group as defined herein.
  • Arylalkyl is an alkyl group as defined herein substituted with an aryl group as defined herein.
  • Heteroarylalkyl is an alkyl group as defined herein substituted with a heteroaryl group as defined herein.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms.
  • the term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
  • alkynyl and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.
  • the term “heterocyclyl” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems).
  • heterocyclyl group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
  • saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.
  • pyrrolidinyl imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • Examples of partially saturated and saturated heterocyclo groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a- hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoly
  • Heterocyclo groups also include radicals where heterocyclic radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indoline, isoindoline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially uns
  • heteroaryl denotes aryl ring systems that contain one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.
  • Examples include but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and
  • the terms “may”, “optional”, “optionally”, or “may optionally” mean that the subsequently described circumstance may or may not occur (i.e., can occur), so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase "optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 - C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 1 -C 12 heterocycloalkyl, C 3 -C 12 heterocycloalkenyl, C 1 - C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, C 1 - C10 dialkylamino, arylamino, diarylamino, sulfoximino, arylsulfoximino, C1- C10 alkylsulfoximino, sulfonimidamido, arylsulfonimidamido, C1-C10 alkylsululfonimi
  • any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or
  • “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, alkyl including C1-C6alkyl, alkenyl including C2-C6alkenyl, alkynyl including C2-C6alkynyl, —C1-C6alkoxy, alkanoyl including C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 2 alkyl, haloalkyl including C 1 -C 6 haloalkyl, hydoxyC 1 -C 6 alkyl, ester, carbamate, urea, sulfonamide, — C 1 -C 6 alkyl(heterocyclo), C 1 -C
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined herein.
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “hydroxyalkyl” refers to the group HO-(alkyl)-.
  • any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • a substituent may contribute to optical isomerism and/or stereo isomerism of a compound.
  • 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.
  • solvate refers to a molecular complex of a compound (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • 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. D 2 O, d 6 -acetone, d 6 -DMSO.
  • a solvate can be in a liquid or solid form.
  • a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison.
  • information about a reference compound is obtained simultaneously with information about a particular compound.
  • 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.
  • the terms "individual,” “subject”, “patient” and “host” are used interchangeably herein and refer to any subject for whom diagnosis, treatment or therapy is desired.
  • the subject is a mammal.
  • the subject is a human being.
  • the subject is a patient.
  • the subject is a human patient.
  • the subject can have or is suspected of having a disorder or health condition associated with a gene- of-interest (GOI).
  • GOI gene- of-interest
  • the subject is a human who is diagnosed with a risk of disorder or health condition associated with a GOI at the time of diagnosis or later.
  • the diagnosis with a risk of disorder or health condition associated with a GOI can be determined based on the presence of one or more mutations in the endogenous GOI or genomic sequence near the GOI in the genome that may affect the expression of GOI.
  • treatment used to refer to a disease or condition means that at least an amelioration of the symptoms associated with the condition afflicting an individual is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., a symptom, associated with the condition (e.g., hemophilia A) being treated.
  • treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or eliminated entirely such that the host no longer suffers from the condition, or at least the symptoms that characterize the condition.
  • treatment includes: (i) prevention, that is, reducing the risk of development of clinical symptoms, including causing the clinical symptoms not to develop, e.g., preventing disease progression; (ii) inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease.
  • Embodiment 2 The compound of embodiment 1, wherein the compound is of Formula (II) (II) or a pharmaceutically acceptable salt thereof.
  • Embodiment 3. The compound of embodiment 1 or 2, wherein Y 11 is NR 9 , and R 9 is Z.
  • Embodiment 4. The compound of embodiment 1 or 2, wherein Y 11 is O, S, SO or SO2.
  • Embodiment 5. The compound of embodiment 1 or 2, wherein Y 11 is CH2, CHR 16 or C(R 16 ) 2 .
  • Embodiment 6. The compound of any one of embodiments 1 to 5, wherein R 31 is H.
  • Embodiment 7. The compound of any one of embodiments 1 to 6, wherein n is 0.
  • R 4 is selected from substituted amine, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl and optionally substituted aryl.
  • Embodiment 9. The compound of embodiment 8, wherein R 4 is optionally substituted alkynyl.
  • Embodiment 10. The compound of embodiment 8, wherein R 4 is optionally substituted cycloalkyl.
  • Embodiment 11 The compound of embodiment 8, wherein R 4 is optionally substituted cycloalkene.
  • Embodiment 12 The compound of embodiment 8, wherein R 4 is optionally substituted heterocycle.
  • Embodiment 13 is selected from substituted amine, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl and optionally substituted
  • R 4 comprises an amine, (C 2-6 )alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, octahydrocyclopenta[c]pyrrole, pyrazole, azetidine, azepane, 1,4-diazepine, 3-azabicyclo[3.1.0]hexane, 2,7-diazaspiro[4.4]nonan-1-one, 2,7-diazaspiro[4.4]nonane, pyridyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, azaindole, indoline, oxindole, triazole, oxadiazole, cyclohexanone, or substituted versions
  • Embodiment 21 The compound of embodiment 20, wherein R 4 is of Formula 4A.
  • Embodiment 22 The compound of embodiment 21, wherein R 4 is of formula: (4A1), or (4A2).
  • Embodiment 23 The compound of embodiment 22, wherein R 4 is of formula: (4A1a).
  • Embodiment 24 The compound of embodiment 22, wherein R 4 is of the formula: (4A2a) (4A2b), or (4A2c).
  • Embodiment 25 The compound of embodiment 24, wherein R 4 is of the formula: (4A2a”).
  • Embodiment 26 The compound of any one of embodiments 22 to 25, wherein r is 1.
  • Embodiment 27 The compound of any one of embodiments 22 to 25, wherein r is 2.
  • Embodiment 28 The compound of any one of embodiments 22 to 25, wherein r is 1.
  • Embodiment 37 The compound of any one of embodiments 33 to 35, wherein r is 1.
  • Embodiment 38 The compound of embodiment 20, wherein R 4 is of Formula 4E: (4E).
  • Embodiment 39 The compound of embodiment 38, wherein R 4 is selected from one of the following structures: , , , , , and .
  • Embodiment 40 The compound of embodiment 39, wherein R 4 is selected from one of the following structures: , , , , , and .
  • Embodiment 41 Embodiment 41.
  • R 25 is of structure: wherein R 33 – R 37 are independently selected from H, CF 3 , CHF2, CH2F, CH3, OH, OCH3, and halogen (e.g., F), and/or any two of R 33 – R 37 are cyclically linked and together with the carbon atom(s) to which they are attached provide an optionally substituted cycloalkyl (e.g., cyclopropyl or cyclobutyl).
  • Embodiment 42 The compound of embodiment 41, wherein R 35 is OH.
  • Embodiment 43. The compound of embodiment 42, wherein R 25 is: or .
  • Embodiment 44 The compound of embodiment 42, wherein R 25 is: or .
  • Embodiment 45 The compound of embodiment 44, wherein X 5 is CR 26 .
  • Embodiment 46 The compound of embodiment 44, wherein X 5 is N.
  • Embodiment 47 The compound of embodiment 20, wherein R 4 is of Formula 4M: (4M).
  • Embodiment 48 The compound of embodiment 47, wherein R 4 is: , or .
  • Embodiment 49 The compound of embodiment 20, wherein R 4 is of Formula 4G: (4G).
  • Embodiment 50 The compound of embodiment 49, wherein X 8 is N Embodiment 51.
  • the compound of embodiment 49, wherein X 8 is CH.
  • Embodiment 52 The compound of embodiment 49, wherein X 8 is N Embodiment 51.
  • the compound of embodiment 49, wherein X 8 is CH.
  • the compound of embodiment 49, wherein X 8 is CH.
  • Embodiment 52 The compound of
  • Embodiment 55 The compound of embodiment 54, wherein R 23 is of Formula 4F (4F).
  • Embodiment 56 The compound of embodiment 55, wherein R 23 is selected from one of the following structures: , , , and .
  • Embodiment 57 The compound of embodiment 20, wherein R 4 is of Formula 4F: (4F).
  • Embodiment 58 The compound of embodiment 57, wherein R 4 is selected from one of the following structures: , , , and .
  • Embodiment 59 The compound of embodiment 20, wherein R 4 is of Formula 4H: (4H).
  • Embodiment 60 The compound of embodiment 54, wherein R 23 is of Formula 4F (4F).
  • Embodiment 61 The compound of embodiment 20, wherein R 4 is of formula 4N.
  • Embodiment 62 The compound of 61, wherein X 12 is NR 25 .
  • Embodiment 63 The compound of embodiment 20, wherein R 4 is of formula 4O.
  • Embodiment 64 The compound of embodiment 63, wherein X 12 is NR 25 .
  • Embodiment 65 The compound of embodiment 20, wherein R 4 is of formula 4P.
  • Embodiment 66 The compound of embodiment 65. wherein X 12 is NR 25 .
  • Embodiment 70 The compound of embodiment 20, wherein R 4 is of formula 4Q or 4R.
  • Embodiment 68 The compound of embodiment 67, wherein X 12 is NR 25 .
  • Embodiment 69 The compound of any one of embodiments 1 to 68, wherein Z comprises a hydrophilic moiety and is substantially biologically inert.
  • Embodiment 70 The compound of any one of embodiments 1 to 68, wherein Z comprises a hydrophilic moiety and is substantially biologically inert.
  • Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.
  • Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.
  • Z is of one of Z1-Z6: (Z1), ( Z2), (Z3), (Z4), (Z5), or (Z6), wherein: Y 9 is absent, -O-, -NR 9 -, -(C 1-6 )alkylene-O-, -(C 1-6 )alkylene-NR 9 -; X 11 is absent, O, or NH; R 11 is selected from halogen, R 8 , -NR 9 R 10 , (C1-6)alkyl, cycloalkyl, heterocyclyl, and substituted versions thereof; R 8 is (C1-6)alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof; each R 9 is independently H or optionally substituted (C1-6)alkyl; each R 10 is independently H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 3- 8 )cycloalkyl, optionally substituted heterocycl
  • Embodiment 74 The compound of embodiment 73, wherein Z is of formula Z1 and is of one of the following structures: , , , or , wherein: R 11 is R 8 , -NR 9 R 10 , (C1-6)alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 8 is (C1-6)alkyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C1-6)alkyl; and R 10 is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl.
  • Embodiment 75 Embodiment 75.
  • the compound of embodiment 74, wherein Z is and R 8 is (C 1 - C6)alkyl.
  • Embodiment 76 The compound of embodiment 75, wherein R 8 is methyl.
  • Embodiment 77 The compound of embodiment 74, wherein Z is and R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.
  • Embodiment 78 The compound of embodiment 77, wherein R 8 is (C3-4)cycloalkyl or (C2- 4)heterocyclyl.
  • Embodiment 79 The compound of embodiment 74, wherein Z is , R 9 is H, and R 10 is H, or optionally substituted (C1-6)alkyl.
  • Embodiment 80 The compound of any one of embodiments 74-79, wherein X 11 is O.
  • Embodiment 81. The compound of any one of embodiments 74-79, wherein X 11 is NH.
  • Embodiment 82. The compound of any one of embodiment 74, wherein Z is and R 8 is (C 1 -C 6 )alkyl.
  • Embodiment 83. The compound of embodiment 73, wherein Z is of Formula Z4 wherein s is 0: wherein; R 9 is H; and R 10 is -SO 2 R 18 ; and R 18 is optionally substituted (C 1-6 )alkyl, or amino.
  • Embodiment 88 The compound of embodiment 87, wherein q is 0, and R 13 is H or (C 1- 3 )alkyl (e.g., methyl).
  • Embodiment 89 The compound of embodiment 75, wherein Z is of Formula Z6, (Z6) wherein: u is 0, 1, or 2; and R 14 is H, optionally substituted (C 1-6 )alkyl.
  • Embodiment 90 The compound of any one of embodiments 1 to 89, wherein R 5 is selected from H, CH3, CF 3 , and halogen.
  • Embodiment 91 The compound of embodiment 90, wherein R 5 is H.
  • Embodiment 97 The compound of embodiment 96, wherein R 2 is H.
  • Embodiment 98. The compound of any one of embodiments 1 to 97, wherein m and p are both 1, and the compound is of Formula III: (III).
  • Embodiment 99. The compound of any one of embodiments 1 to 97, wherein m and p are both 0. Embodiment 100.
  • Embodiment 101 The compound of any one of embodiments 1 to 97, wherein m is 1 and p is 0. Embodiment 101.
  • Embodiment 102 The compound of any one of embodiments 1 to 97, wherein m is 2 and p is 0.
  • Embodiment 103 The compound of any one of embodiments 1 to 97, wherein m is 0 and p is 2.
  • Embodiment 104 The compound of any one of embodiments 1 to 97, wherein m is 2 and p is 1.
  • Embodiment 105 The compound of any one of embodiments 1 to 97, wherein m is 1 and p is 2.
  • Embodiment 106 The compound of any one of embodiments 1 to 97, wherein m is 1 and p is 2.
  • Embodiment 107 The compound of any one of embodiments 1 to 97, wherein m is 2 and p is 2.
  • Embodiment 107 The compound of any one of embodiments 1 to 98, wherein the compound is of any one of Formulae IA-IM: (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), and (IM), or a pharmaceutically acceptable salt thereof.
  • Embodiment 108. The compound of embodiment 107, wherein R 3 is CN.
  • Embodiment 109. The compound of embodiment 107, wherein R 3 is H.
  • Embodiment 110 The compound of embodiment 107, wherein R 3 is H.
  • Embodiment 115 The compound of embodiment 2 or 107, wherein the compound is of Formula (IVB): (IVB) or a pharmaceutically acceptable salt thereof, wherein: each R 16 is independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; and R 1 -R 2 , R 5 and R 7 are independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, halo(C 1-6 )alkyl, -COR 30 , -OR 30 , halogen, and
  • Embodiment 116 The compound of embodiment 2 or 107, wherein the compound is of Formula IVC: (IVC) or a pharmaceutically acceptable salt thereof, wherein: each R 16 is independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C1-6)alkoxyl, hydroxyl, halogen, and CN; n is an integer from 0 to 6; R 4 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; and R 1 -R 2 , R 5 and R 7 are independently selected from H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxyl, halo(C 1-6 )alkyl, -COR 30 , -OR 30 , halogen, and CN.
  • Embodiment 119 The compound of embodiment 118, wherein the compound is of Formula VI: (VIA) or a pharmaceutically acceptable salt thereof, wherein: R 42 is H, optionally substituted (C 1 - 6 )alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted carbocycle (e.g. cycloalkyl), optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl.
  • Embodiment 120 The compound of embodiment 119, wherein the compound is of Formula VIIA:
  • Embodiment 121 The compound of embodiment 115, wherein the compound is of Formula VB: (VB) or a pharmaceutically acceptable salt thereof.
  • Embodiment 122. The compound of embodiment 121, wherein the compound is of Formula VIB: (VIB) or a pharmaceutically acceptable salt thereof, wherein: R 42 is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted carbocycle (e.g.
  • Embodiment 123 The compound of embodiment 122, wherein the compound is of Formula VIIB: (VIIB) or a pharmaceutically acceptable salt thereof.
  • Embodiment 124. The compound of embodiment 116, wherein the compound is of Formula VC: (VC) or a pharmaceutically acceptable salt thereof.
  • Embodiment 125. The compound of embodiment 124, wherein the compound is of Formula VIC:
  • R 42 is H, optionally substituted (C 1 - 6 )alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonamide, optionally substituted sulfonimidamide, optionally substituted carboxamide, optionally substituted carbocycle (e.g. cycloalkyl), optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl.
  • Embodiment 127 The compound of embodiment 119, 120, 122, 123, or 125, 126, wherein R 42 is or wherein: L 1 is selected from -CONR 45 -, -NR 46 CO-, -CO-, -SO2NR 45 -, -NR 46 SO2-, -SO2-, - CONR 45 CR 45 2-, -NR 46 (CR 45 2)i-, optionally substituted methylene, and optionally substituted ethylene; B and D are independently an optionally substituted cyclic group (e.g., a saturated, partially saturated, or unsaturated monocyclic, bicyclic or spirocyclic group that is a carbocycle, heterocycle, heteroaryl, and/or aryl); R 45 is H or optionally substituted (C1-6)alkyl, optionally substituted carbocycle (e.g.
  • R 46 is H, optionally substituted (C1-6)alkyl, or optionally substituted carbocycle; each R 51 and each R 52 is independently selected from H, optionally substituted (C 1 - 6 )alkyl, optionally substituted (C 1 - 6 )alkoxyl, halogen, hydroxyl, carboxy, carboxamide, CN, NO 2 , optionally substituted cycloalkyl, optionally substituted amino, optionally substituted sulfonamide, optionally substituted sulfonyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; j is an integer from 0 to 6; h is an integer from 0 to 6; and i is an integer from 0 to 6.
  • Embodiment 128 The compound of embodiment 114, wherein the compound is of Formula VIIIA: (VIIIA) or a pharmaceutically acceptable salt thereof, wherein: R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl.
  • R 43 is H, optionally substituted C 1 - 6 alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfoximine, optionally substituted sulfonimidamide, optionally substituted cycloalkyl, optionally substituted cycloalkene, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted ary
  • R 43 is or wherein: L 2 is an optional linker selected from -CONR 45 -, -CO-, -COCH 2 -, -SO 2 -, -SO 2 NR 45 -, - SO 2 CH 2 -, optionally substituted methylene, and optionally substituted ethylene; B and D are independently an optionally substituted cyclic group (e.g., a saturated, partially saturated, or unsaturated monocyclic, bicyclic or spirocyclic group that is a carbocycle, heterocycle, heteroaryl, and/or aryl); R 45 is H or optionally substituted (C1-6)alkyl, optionally substituted carbocycle (e.g.
  • each R 51 and each R 52 is independently selected from H, optionally substituted (C 1 - 6 )alkyl, optionally substituted (C 1 - 6 )alkoxyl, halogen, hydroxyl, carboxy, carboxamide, CN, NO 2 , optionally substituted cycloalkyl, optionally substituted amino, optionally substituted sulfonamide, optionally substituted sulfonyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl; j is an integer from 0 to 6; and h is an integer from 0 to 6.
  • Embodiment 132 The compound of embodiment 127 or 131, wherein B is selected from optionally substituted (C 3 - 8 )cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl.
  • Embodiment 133 The compound of embodiment 132, wherein B is an optionally substituted (C3-8)cycloalkyl.
  • Embodiment 134 The compound of embodiment 133, the (C 3 - 8 )cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the compound of embodiment 133, wherein the (C3-8)cycloalkyl comprises bicyclo[1.1.1]pentyl, spiro[2,3]hexane, or bicyclo[3.1.0]hexyl.
  • Embodiment 136. The compound of embodiment 132, wherein B is an optionally substituted heterocycle.
  • the compound of embodiment 136, wherein the heterocycle comprises tetrahydropyran, tetrahydrofuran, triazole, oxetane, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-thiopyran 1,1-dioxide, or morpholinyl.
  • heterocycle comprises 4,5,6,7-tetrahydropyrazolo[1.5- ⁇ ]pyrizinyl, hexahydro-pyrrolo[3,4-C]pyrrole, 2- Oxabicyclo[2.2.2]octane, hexahydropyrazino[2,1-c][1,4]oxazine, 8-azabicyclo[3.2.1]octane, 2- azabicyclo[3.1.0]hexane, 1,1-dioxidothietane, indole, imidazol[1,2-a]pyridine, 1,4,5,6- tetrahydrocyclopenta[c]pyrazole, 6,8-dioxabicyclo[3.2.1]octane, 6,7-Dihydro-4H-pyrazolo[5,1- c][1,4]thiazine, oxobicyclo[3.1.0]hexane, or 2,2-dimethyl-1
  • Embodiment 139 The compound of embodiment 136, wherein the heterocycle comprises 4- azaspiro[2.3]hexane, 6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, or 2-thiaspiro[3.3]heptane 2,2-dioxide.
  • Embodiment 140 The compound of embodiment 132, wherein B is an optionally substituted heteroaryl.
  • Embodiment 141 The compound of embodiment 132, wherein B is an optionally substituted heteroaryl.
  • the compound of embodiment 140, wherein the heteroaryl comprises pyridinyl, pyrazolyl, pyrrole, thiazolyl, isothiazolyl, imidazolyl, furanyl, or thiophenyl.
  • Embodiment 142. The compound of embodiment 140, wherein the heteroaryl comprises benzodioxan, furo[2,3-c]pyridinyl, quinolinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, or indazolyl.
  • Embodiment 143 The compound of embodiment 132, wherein B is an optionally substituted aryl.
  • Embodiment 145 The compound of any one of embodiments 132 to 144, wherein D is selected from optionally substituted (C3-8)cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl.
  • Embodiment 146 The compound of embodiment 145, wherein D is an optionally substituted heterocycle.
  • Embodiment 147 The compound of embodiment 146, wherein the heterocycle comprises pyrrolidine, morpholine, piperidinyl, or piperazinyl.
  • Embodiment 148 The compound of embodiment 146, wherein the heterocycle comprises pyrrolidine, morpholine, piperidinyl, or piperazinyl.
  • Embodiment 149 The compound of embodiment 148, wherein: B is optionally substituted aryl; and D is an optionally substituted heterocycle.
  • Embodiment 149 The compound of embodiment 148, wherein: B is optionally substituted phenyl; and D is optionally substituted pyrrolidine, optionally substituted morpholine, optionally substituted piperidinyl, or optionally substituted piperazinyl.
  • Embodiment 150 The compound of embodiment 145, wherein: B is an optionally substituted heteroaryl; and D is an optionally substituted heterocycle.
  • Embodiment 151 The compound of any one of embodiments 127 and 131 to 150, wherein L 1 or L 2 is -CH 2 -.
  • Embodiment 152 The compound of any one of embodiments 127 and 131 to 150, wherein L 1 or L 2 is -CH 2 -.
  • each R 51 and each R 52 is independently selected from (C 1 - 3 )alkyl, (C 1 - 6 )alkoyl, halogen, NO 2 , OH, CN, CH 2 CN, halo(C 1 - 3 )alkyl, substituted (C 1 - 3 )alkyl, substituted (C 1 - 3 )alkoxyl, di(C 1 - 3 )alkyl substituted amino, C(O)O(C1-3)alkyl, C(O)NH(C1-3)alkyl, C(O)NH2, CH2OH, O(C1-3)alkylene- OH, (C1-3)alkylene-O(C1-3)alkyl, SO2-(C1-3)alkyl.
  • Embodiment 157 The compound of any one of embodiments 127 and 131 to 150, wherein each R 51 and each R 52 is independently selected from CH 3 , OCH 3 , CH 2 CH 3 , F, Cl, Br, OH, CN, CH 2 CN, CF 3 , CHF 2 , OCHF 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, OC(O)CH 3 , C(O)OCH 3 , C(O)OCH 2 CH 3 , C(O)NHCH 3 , C(O)NH 2 , OCH 2 CH 3 , NO 2 , CH 2 CH 2 OCH 3 , C(CH 3 ) 3 , CH 2 OH, OCH 2 CH 2 OH, CH(CH 3 )OH, CH(CH 3 )CN, C(CH 3 ) 2 OH, C(CH3) 2 CN, OCH2CN, OCH(CH
  • Embodiment 158 The compound of any one of embodiments 114 to 157, wherein X 11 is O.
  • Embodiment 159. The compound of any one of embodiments 114 to 157, wherein X 11 is NH.
  • Embodiment 160 The compound of any one of embodiments 114 to 157, wherein X 11 is absent.
  • Embodiment 161. The compound of any one of embodiments 114 to 157, wherein R 11 is R 8 .
  • Embodiment 162. The compound of embodiment 161 wherein R 8 is (C1-6)alkyl (e.g., methyl or ethyl).
  • Embodiment 161 The compound of embodiment 161, wherein R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.
  • Embodiment 164 The compound of any one of embodiments 114 to 157, wherein R 11 is - NR 9 R 10 .
  • Embodiment 165 The compound of embodiment 164, wherein R 9 is H, and R 10 is H, or (C 1- 6 )alkyl.
  • Embodiment 166 The compound of embodiment 161, wherein R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.
  • Embodiment 164 The compound of any one of embodiments 114 to 157, wherein R 11 is - NR 9 R 10 .
  • Embodiment 165 The compound of embodiment 164, wherein R 9 is H, and R 10 is H, or (C 1- 6 )alkyl.
  • Embodiment 167 The compound of embodiment 166, wherein the compound is of Formula A’: (A’) or a pharmaceutically acceptable salt thereof.
  • Embodiment 168. The compound of embodiment 166 or 167, wherein X” is fluoro.
  • Embodiment 169 The compound of any one of embodiments 1 to 168, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 170. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 169 and a pharmaceutically acceptable excipient.
  • Embodiment 172. A method of inhibiting CDK4 in a subject, comprising administering to a subject a compound of any one of embodiments 1 to 169, or a pharmaceutical composition according to embodiment 170, to inhibit CDK4 in the subject.
  • a method of treating a disease or disorder associated with CDK4 in a subject comprising administering to a subject in need thereof a dose of a compound of any one of embodiments 1 to 169, or a pharmaceutical composition of embodiment 170.
  • Embodiment 174. The method of embodiment 173 wherein the disease or disorder associated with CDK4 is cancer.
  • Method A Mobile Phase: A- 0.1 % formic acid in water, B: ACN; flow rate: 2.0 mL/min; Column: X-Select CSH C18 (4.6 x 150 mm, 5 ⁇ m).
  • Method B Mobile Phase: A- 10 mM ammonium bicarbonate in water, B: ACN; flow rate: 2.0 mL/min; Column: X-Bridge C8 (4.6 x 150 mm,5 ⁇ m).
  • Method C Mobile Phase: A- 0.1 % TFA in water, B: ACN; flow rate: 25.0 mL/min; Column: Phenomenex Luna C18 (100 x 30 mm, 5 ⁇ m) [00470]
  • Method D Mobile Phase: A- 0.1 % TFA in water, B: ACN; flow rate: 25.0 mL/min; Column: Welch Ultimate C18 (100 x 40 mm, 7 ⁇ m) [00471]
  • Method E Mobile Phase: A- 0.1 % TFA in water, B: ACN; flow rate: 25.0 mL/min; Column: WePure Biotech XPT C18 (100 x 30 mm, 7 ⁇ m) [00472]
  • Method F Mobile Phase: A- 10 mM ammonium bicarbonate in water, B: ACN; flow rate: 25 mL/min; Column: WePure Biotech XPT C18 (100 x 30 mm, 7 ⁇ m) [00473] Method G
  • NMR data was acquired in Bruker Avance Neo nano bay 400 MHz NMR Spectrometer. Chemical shifts are reported in ppm relative to dimethyl sulfoxide ( ⁇ 2.50), methanol ( ⁇ 3.31), chloroform ( ⁇ 7.26) or other solvent as indicated in NMR spectral data. A small amount (1-5 mg) of sample is dissolved in an appropriate deuterated solvent (0.6 mL).
  • Final compound characterization and purity was assessed by and determined using orthogonal HPLC runs, LCMS and NMR.
  • the synthetic schemes for the preparation of intermediates and compounds of the present invention are detailed below.
  • reaction mixture was quenched by saturated aqueous Na2CO3 (100 ml) at 0 °C, and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.1% TFA) – ACN];gradient:5% – 45% B over 8.0 min) to obtain aniline products.
  • General procedure D is also applicable to Buchwald couplings starting with Core 2.
  • reaction mixture was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H 2 O(0.1%TFA)-ACN];gradient:20%-50% B over 8.0 min) to give the desired aromatic compounds.
  • reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H 2 O (0.1% TFA) – ACN];gradient:5% – 45% B over 8.0 min) to obtain the desired aromatic products.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 10%-40% B over 8.0 min) and then separated by SFC (condition: column: DAICEL CHIRALPAK AD(250 mm*30 mm,10um); mobile phase: [CO 2 -EtOH(0.1% NH 3 H 2 O)]; B%:50%, isocratic elution mode) to obtain the desired benzylic amines.
  • Example 1 Preparation of 3-fluoro-5-(((3S,4R)-4-(7-(((3S,4S)-3-hydroxy-3-methyl-1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl)-3-methylpiperidin-1- yl)methyl)benzonitrile (compound 2016) and 3-fluoro-5-(((3S,4R)-4-(7-(((3R,4R)-3- hydroxy-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl)-3- methylpiperidin-1-yl)methyl)benzonitrile (compound 2030) Preparation of compound 5-3.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to give 3-fluoro-5-[[(3S,4R)-4-[7-[[(3R,4R)-4- hydroxytetrahydrofuran-3-yl]amino]-2,6-naphthyridin-1-yl]-3-methyl-1- piperidyl]methyl]benzonitrile (9.03 mg, 14.23 ⁇ mol, 18.7% yield, 90.7% purity, TFA salt) as a yellow solid.
  • tert-butyl N-(1,1,3-trioxothian-4-yl) carbamate (900 mg, 3.42 mmol, 1 eq) was added to the mixture at 15°C and stirred for 2 h at 40°C under N 2 .
  • the reaction mixture was slowly added MeOH (30 mL) at 0°C and stirred at 25°C for 1 h.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 9 Preparation of 5-((3R,4R)-1-((R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1- yl)-3-fluoropiperidin-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-2,6- naphthyridin-3-amine (compound 2020) and 5-((3R,4R)-1-((S)-5,7-difluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-3-fluoropiperidin-4-yl)-N-((3R,4R)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)-2,6-naphthyridin-3-amine (compound 2020; compound 2021) Preparation of compound 14-2.
  • Racemic 3A was separated by SFC (column: ChiralPak IH, 250*30mm, 10um;mobile phase: [CO2-EtOH(0.1% NH3H2O)];B%:25%, isocratic elution mode) to give tert-butyl 4-(7-chloro- 2,6-naphthyridin-1-yl)-3,3-difluoropiperidine-1-carboxylate enantiomer 1 (140 mg, 364.75 ⁇ mol, 35.0% yield) as a white solid and tert-butyl 4-(7-chloro-2,6-naphthyridin-1-yl)-3,3- difluoropiperidine-1-carboxylate enantiomer 2 (130 mg, 338.70 ⁇ mol, 32.5% yield) as a white solid.
  • reaction mixture was concentrated under reduced pressure to remove solvent and then the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAC (15 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18250*70 mm*10 um; mobile phase: [H 2 O(10 mM NH 4 HCO 3 )-ACN]; gradient: 45%-75% B over 20.0 min) to give tert-butyl 4-(7- chloro-2,6-naphthyridin-1-yl)azepane-1-carboxylate (5 g, 13.82 mmol, 64.6% yield) as a brown solid.
  • reaction mixture was diluted with H2O 50 mL and extracted with EtOAc (50 mL*2). The organic layer was washed with brine (100 mL*3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a crude product.
  • reaction mixture was concentrated under reduced pressure to remove solvent.
  • the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (90 mL*2). The organic layer was washed with brine (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product.
  • Example 14 Preparation of 5-((((1S,3S)-3-(7-(((3R,4R)-3-hydroxy-1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1- yl)cyclopentyl)amino)methyl)nicotinonitrile (compound 2255) [00596] To a solution of (3R,4R)-4-((5-((1S,3S)-3-aminocyclopentyl)-2,6-naphthyridin- 3-yl)amino)-1-(methylsulfonyl)piperidin-3-ol (40 mg, 98.64 ⁇ mol, 1 eq, HCl), 5- formylnicotinonitrile (13.03 mg, 98.64 ⁇ mol, 1 eq) in DCM (2 mL) was added DIEA (12.75 mg, 98.64
  • the reaction mixture was filtered and the filtate was purified by prep- HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [H 2 O (0.1% TFA)- ACN]; gradient: 15%-45% B over 8.0 min) to obtain (3R,4R)-4-[[5-[1-(2,3-dihydro-1,4- benzodioxin-6-yl)-4-fluoro-4-piperidyl]-2,6-naphthyridin-3-yl]amino]-1-methylsulfonyl- piperidin-3-ol (2.33 mg, 2.89 ⁇ mol, 2.66% yield, 83.3% purity, TFA salt) as a yellow solid.
  • Example 21 Preparation of 3-fluoro-5-(((R)-4-(7-(((3R,4R)-3-hydroxy-1- (methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyridin-1-yl)-3-methyl-1,4-diazepan-1- yl)methyl)benzonitrile (compound 2148)
  • Preparation of compound 28-2 [00623] To a solution of 1,7-dichloro-2,6-naphthyridine (200 mg, 1.00 mmol, 1 eq) in DMSO (5 mL) was added DIEA (389.60 mg, 3.01 mmol, 3 eq) and tert-butyl (3R)-3-methyl-1,4- diazepane-1-carboxylate (430.68 mg, 2.01 mmol, 2 eq).
  • reaction mixture was quenched by addition of saturated aqueous Na 2 CO 3 (10 mL) at 0 °C, filtered to obtain filtrate, concentrated, diluted with H2O (10 mL), and extracted with EtOAc (20 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • the compounds of the present disclosure were prepared in a manner similar to the general procedures outlined above.
  • the compounds of Table 1 are exemplary and not particularly limiting.
  • Some compounds of Table 1 are a racemic mixture of enantiomers.
  • Some compounds are a mixture of diastereomers.
  • Some compounds have “&” denoting a single stereoisomeric center configuration (e.g., either R or S), but absolute configuration of that center is unknown despite representation of a particular absolute stereochemistry in a particular structure. In some cases, the relative stereochemistry is known and represented.
  • the plates were incubated at 23 °C for 60.5 ⁇ L per well 4 x EDTA solution were added to each well to stop the reaction.5 ⁇ L 4 x LANCE Ultra Europium- anti-phospho-eIF4E-binding protein 1 (Thr37/46 antibody) were added to each well and the plate was centrifuged for 1 at 800 RPM. The plate was incubated for 60 at 23 °C. Fluorescence was read at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader.
  • the final concentrations of reagents in the activity assay were 1 mM ATP, 50 nM ULightTM-eIF4E- binding protein 1 (Thr37/46) Peptide substrate, 1 % DMSO, 10 mM EDTA, and 0.5 nM LANCE Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37/46), and either 1 nM CDK4/CCND1, 1.5 nM CDK4/CCND3, 0.25 nM CDK6/CCND3, 1 nM CDK6, CCND1, 2 nM CDK2/CCNE1, or 0.5 nM CDK1/CCNB1.
  • Dose-response titrations were conducted by using an 11-point, half-logarithmic serial dilution scheme typically starting at 10 mM. Signals were reported the ratio of fluorescence units at 665 nm/fluorescence units at 615 nm. Signals are referred to below as “Lance signals”.
  • % inhibition (Lance signal DMSO control – Lance signal value of sample) * 100/ Lance DMSO control - Lance signal value of background), where Lance signal DMSO control represents an average of 2-16 replicates, Lance signal value of sample represents an average of 2 replicates, and Lance signal of background represents an average of 2-16 replicates.
  • CDK Biochemical Assays for assessing potency and selectivity A CDK homogeneous time-resolved fluorescence (HTRF) assay was used to assess the potency and selectively of the compounds described herein with respect to CDK1, CDK2, CDK4 and CDK6.
  • Table 3 illustrates the IC50 for various Example compounds of Formula I with respect to CDK1, CDK2, CDK4 and CDK6.
  • Table 3 IC50 Values for Compounds of Formula I (CDK4/CCND1 IC50, CDK1/CCNB1 IC50, CDK2/CCNE1 IC50, and CDK6/CCND3 IC50) CDK4/CCND1 CDK1/CCNB CDK2/CCNE1 IC50 1 IC50 IC50 CDK6/CCND3 IC50 Ex No.
  • Table 3B illustrates the IC50 for various compounds of the present disclosure with respect to CDK4 and CDK6.
  • REH cells were maintained in RPMI 1640 + 10% FBS. T47D and REH cells were seeded in 40uL in 348 well plates (Grenier Bio, 781946) at a density of 1,000 cells/well and 1,500 cells/well, respectively. Cells were incubated for 6 days at 37 °C and 5% CO2. Cell proliferation was measured using CyQuant (Thermo Fischer Scientific, C35012) as per manufacturer’s instructions. Briefly, plates were equilibrated to room temperature and an equivalent volume of detection reagent was added to each well. Plates were incubated at room temperature for 2 hours. Fluorescence was measured from the bottom of the well using a Pherastar microplate reader (BMG Labtech).
  • IC50 values of some compounds of the present disclosure were determined. Table 5 illustrates the IC50 for various example compounds of the present disclosure. Table 5: IC50 Values for Compounds of Formula I (T47D IC50 / REH IC50) T47D IC50 REH IC50 Cpd.
  • Activity in the REH cell line is a marker of CDK6-dependency.
  • the CYQ selectivity is measure of cellular selectivity that is dependent on specific CDK4 and CDK6 activity. See depmap(dot)org for additional information. Table 6. illustrates the ratio of CDK6/CDK4 activity for REH and T47D cells. Table 6. CyQ Selectivity Data Cpd. # ⁇ 10 10-25 > 25 Cpd. # ⁇ 10 10-25 > 25 2663 x 2913 x 2664 x 2914 x Table 6. CyQ Selectivity Data Cpd. # ⁇ 10 10-25 > 25 Cpd.
  • CyQ Selectivity Data Cpd. # ⁇ 10 10-25 > 25 Cpd. # ⁇ 10 10-25 > 25 2782 ND ND ND 3032 x 2783 x 3033 x 2784 x 3034 x 2785 x 3035 x 2786 ND ND ND 3036 x 2787 ND ND ND 3037 x 2788 ND ND ND 3038 x 2789 ND ND ND 3039 x 2790 ND ND ND 3040 x 2791 ND ND 3041 x 2792 ND ND 3042 x 2793 ND ND 3043 x 2794 ND ND ND 3044 x 2795 ND ND ND 3045 x 2796 x 3046 x 2797 x 3047 x 2798 ND ND 3048 x 2799 ND ND 3049 x 2800 x 3050 x 2801 x 3051 x 2802 x 3052 x 2803 x 3053 x 2804
  • CyQ Selectivity Data Cpd. # ⁇ 10 10-25 > 25 Cpd. # ⁇ 10 10-25 > 25 2821 x 3071 x 2822 x 3072 x 2823 x 3073 x 2824 x 3074 x 2825 x 3075 x 2826 x 3076 x 2827 x 3077 x 2828 x 3078 x 2829 x 3079 x 2830 x 3080 x 2831 x 3081 x 2832 x 3082 x 2833 x 3083 x 2834 x 3084 x 2835 x 3085 x 2836 x 3086 x 2837 ND ND ND 3087 x 2838 ND ND ND 3088 x 2839 ND ND ND 3089 x 2840 ND ND ND 3090 x 2841 x 3091 x 2842 x 3092 x 2843 x 3093 x 2844 x 3094 x 2845 x 3095 x 2846 x 3096 x 28
  • Table 8 IC50 Values for Comparative Compounds (CDK4/CCND3 IC50, CDK1/CCNB1 IC50, CDK2/CCNE1 IC50, and CDK6/CCND1 IC50) CDK4/CCND3 CDK6/CCN C50 CDK2/CCNE1 IC5 D1 I 0 CDK1/CCNB1 IC50 IC50 Cpd # ⁇ 35 - > 30 35 - > ⁇ 35 - ⁇ 35 - > 35 300 0 ⁇ 35 300 300 300 35 300 > 300 35 300 > 300 35 300 > 300 35 300 nM nM nM nM nM nM nM nM 1 29 x x x x x 251 x x x x x 1260 x x x x 1261 x x x x 1262 x x x x 1263 x x x x 1265 x
  • ⁇ Compound 251 exhibits an IC 50 value of less than 35 nM for both CDK2 and CDK4 assays.
  • ⁇ Compound 1260 exhibits an IC 50 value of less than 35 nM in the CDK4 assay, and an IC 50 value of greater than 300 nM in the CDK2 assay.
  • ⁇ Compounds 1261 and 1263 both exhibit IC 50 values of greater than 300 nM for each of the CDK assays.
  • ⁇ Compound 1262 exhibits an IC50 value of from 35-300 nM in the CDK4 assay, and an IC50 value of greater than 300 nM in each of the other assays.
  • Compound 1264 exhibits an IC50 value of from 35-300 nM in the CDK4 assay, and an IC50 value of greater than 300 nM in each of the other assays.
  • the results for comparative compounds 251 and 1260-1263 demonstrate that by including a stereochemically defined hydroxyl group in the piperidine ring exhibited for compound 1260, selectivity is observed with respect to CDK4 over CDK2.
  • Table 9 illustrates the biochemical selectivity of the comparative compounds for CDK6 vs CDK4 (CDK6 IC 50 /CDK4 IC 50 ).
  • Table 9 Biochemical Selectivity Ratio for Comparative Compounds (CDK6/CCND1 IC50 / CDK4/CCND3 IC50) Cpd # ⁇ 2 2-10 > 10 1 29 x 251 x 1260 x 1261 x 1262 x 1 263 x 1264 x 1 265 x [00667] Below are some observations with respect to Table 9: ⁇ Comparative compounds 129, 1260, 1263 and 1265 exhibit a biochemical selectivity ratio of less than 2 with respect to CDK4 and CDK6. ⁇ Compound 251 and 1261-1262 exhibit a biochemical selectively ratio of 2-10 with respect to CDK4 over CDK6.

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Abstract

L'invention concerne des composés inhibiteurs de CDK4 ayant un noyau de naphtyridine. Le noyau de naphtyridine est substitué par un groupe aminé, le groupe aminé étant lui-même substitué par un groupe cyclique ayant un groupe hydrophile ajouté. L'invention concerne également des compositions comprenant les composés inhibiteurs de CDK4. L'invention concerne en outre des méthodes d'utilisation des compositions de l'invention dans la recherche et en tant qu'agents thérapeutiques.
PCT/US2025/029199 2024-05-14 2025-05-13 Composés naphtyridine inhibiteurs de cdk4 Pending WO2025240517A1 (fr)

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WO2014023385A1 (fr) * 2012-08-07 2014-02-13 Merck Patent Gmbh Dérivés de pyridopyrimidine en tant qu'inhibiteurs de protéine kinase
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