WO2024064316A1 - Compounds and compositions as smarca2/4 inhibitors and uses thereof - Google Patents

Compounds and compositions as smarca2/4 inhibitors and uses thereof Download PDF

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Publication number
WO2024064316A1
WO2024064316A1 PCT/US2023/033441 US2023033441W WO2024064316A1 WO 2024064316 A1 WO2024064316 A1 WO 2024064316A1 US 2023033441 W US2023033441 W US 2023033441W WO 2024064316 A1 WO2024064316 A1 WO 2024064316A1
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Prior art keywords
carbocyclyl
alkyl
alkynyl
alkenyl
aryl
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PCT/US2023/033441
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French (fr)
Inventor
Shaomeng Wang
Lingying LENG
Wenbin TU
Lin Yang
Mi Wang
Paul Kirchhoff
Guozhang Xu
Zhenwu Li
Jelena TOSOVIC
Jeanne STUCKEY
Original Assignee
Regents Of The University Of Michigan
Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc.
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Application filed by Regents Of The University Of Michigan, Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc. filed Critical Regents Of The University Of Michigan
Publication of WO2024064316A1 publication Critical patent/WO2024064316A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/16—Peri-condensed systems
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • Chromatin functions to package, strengthen, and control expression and DNA replication.
  • the chromatin structure is controlled by a series of post-translational modifications, most commonly within the "histone tails" which extend beyond the core nucleosome structure.
  • These epigenetic modifications including acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation, are then interpreted by the cell to allow gene-specific regulation of chromatin structure and thereby transcription.
  • Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • acetylate or de-acetylate specific histone lysine residues are Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A members 2 and 4 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A members 2 and 4
  • PB1 polybromo-1
  • the present disclosure provides compounds or conjguates of Formula II: , and pharmaceutically acceptable thereof, wherein each of the variables in Formulae II is described, embodied, and exemplified herein.
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods of inhibiting a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein. 2 282341894 v2 PRSC-068/001WO (343170-2269) [0009] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a SMARCA2 or SMARCA4 protein in a subject. [0010] In certain aspects, the present discloure provides compounds disclosed herein for use in inhibiting a SMARCA2 or SMARCA4 protein in a subject.
  • the present disclosure provides methods of degrading a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a conjugate disclosed herein.
  • the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a subject.
  • the present discloure provides conjugates disclosed herein for use in degrading a SMARCA2 or SMARCA4 protein in a subject.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).
  • the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a conjugate disclosed herein (e.g., in a therapeutically effective amount).
  • the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • DETAILED DESCRIPTION [0020] The present disclosure relates to compounds and compositions that are useful as SMARCA2 or SMARCA4 protein inhibitors.
  • the present disclosure also relates to methods of 3 282341894 v2 PRSC-068/001WO (343170-2269) inhibiting a SMARCA2 or SMARCA4 protein comprising contacting the SMARCA2 or SMARCA4 protein with a SMARCA2 or SMARCA4 protein inhibitor disclosed herein.
  • the invention also relates to methods of treating a SMARCA2 or SMARCA4 protein-mediated disease or condition in a subject in need thereof by administering (e.g., in a therapeutically effective amount) a SMARCA2 or SMARCA4 protein inhibitor disclosed herein.
  • the invention further relates to methods of treating a SMARCA2 or SMARCA4 protein-mediated disease or condition in a subject in need thereof, comprising administering (e.g., in a therapeutically effective amount) a pharmaceutical composition comprising an amount of a SMARCA2 or SMARCA4 protein inhibitor disclosed herein.
  • the compound is not 2) when i) R A1 is hydrogen; and ii) E 1 is CR E1 , E 2 is CR E2 , E 3 is CR E3 , and E 4 is CR E4 ; wherein R E1 , R E2 , R E3 , and R E4 are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy, then i) R C are not both optionally substituted phenyl; and ii) when one R C is optionally substituted thiophenyl, then the other R C is not optionally substituted phenyl.
  • the compound is a compound of Formula II-1 or II-2 13 282341894 v2 PRSC-068/001WO (343170-2269) 2), or a each R C is - - - - 6 C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1 0 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u ; and R A1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl,
  • the compound is a compound of Formula II-1-i, II-1-ii, II-1-iii, II-2-i, II-2-ii, or II-2-iii 21 282341894 v2 PRSC-068/001WO (343170-2269) i), , or a each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • the compound is a compound of Formula II-1-iv, II-1-v, II-1-vi, II-2-iv, II-2-v, or II-2-vi 22 282341894 v2 PRSC-068/001WO (343170-2269) , , or each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u ; and R A1 is halogen.
  • a 1 is CR A1 or N. In certain embodiments, A 1 is N. In certain embodiments, A 1 is CR A1 .
  • a 2 is CR A2 or N. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CR A2 .
  • a 3 is CR A3 or N. In certain embodiments, A 3 is N. In certain embodiments, A 3 is CR A3 . 23 282341894 v2 PRSC-068/001WO (343170-2269) [0035] In certain embodiments, A 4 is CR A4 or N. In certain embodiments, A 4 is N.
  • a 4 is CR A4 .
  • none of A 1 , A 2 , A 3 , and A 4 is N.
  • one of A 1 , A 2 , A 3 , and A 4 is N.
  • two of A 1 , A 2 , A 3 , and A 4 are N.
  • three of A 1 , A 2 , A 3 , and A 4 are N.
  • each of A 1 , A 2 , A 3 , and A 4 is N.
  • a 1 is CR A1 , and none of A 2 , A 3 , and A 4 is N (i.e., A 1 is CR A1 , A 2 is CR A2 ; A 3 is CR A3 ; and A 4 is CR A4 ).
  • a 1 is CR A1 , and one of A 2 , A 3 , and A 4 is N.
  • a 1 is CR A1 , and two of A 2 , A 3 , and A 4 are N.
  • a 1 is CR A1 , and each of A 2 , A 3 , and A 4 is N.
  • a 1 is CR A1
  • a 3 is CR A3
  • one of A 2 and A 4 is N.
  • a 1 is CR A1
  • a 3 is CR A3
  • each of A 2 and A 4 is N.
  • R A1 , R A2 , R A3 , and R A4 when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C 4 ), i-butoxy (C 4 ),
  • R A1 , R A2 , R A3 , and R A4 when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R A1 , R A2 , R A3 , and R A4 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R A1 , R A2 , R A3 , and R A4 when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R A1 , R A2 , R A3 , and R A4 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 25 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R A1 is halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C 5 ).
  • R A1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R A1 is halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R A1 is halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R A1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R A1 is halogen.
  • R A1 is not hydrogen.
  • R A1 is hydrogen.
  • R A1 is halogen, -CN, - OH, -NH 2 , or C 1-6 alkyl.
  • R A1 is halogen.
  • R A1 is - CN.
  • R A1 is -OH.
  • R A1 is -NH2.
  • R A1 is C1-6 alkyl.
  • R A2 is hydrogen.
  • R A3 is hydrogen.
  • R A4 is hydrogen. 27 282341894 v2 PRSC-068/001WO (343170-2269) [0054]
  • each R C is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C 1 ),
  • each R C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C 6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • each R C is independently C 1-6 alkyl optionally substituted with one or more R u .
  • at least one R C is C1-6 alkyl optionally substituted with one or more R u .
  • Ring D is C 3-12 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cycl
  • each R D is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), s-butoxy (C
  • each R D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R D is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • each R D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • each R D is independently oxo, halogen, or -OH. In certain embodiments, at least one R D is oxo. In certain embodiments, at least one R D is halogen. In certain embodiments, at least one R D is -OH. 31 282341894 v2 PRSC-068/001WO (343170-2269) [0069] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, d is 6. In certain embodiments, d is 7. In certain embodiments, d is 8. In certain embodiments, d is 9.
  • E 1 is CR E1 or N. In certain embodiments, E 1 is N. In certain embodiments, E 1 is CR E1 .
  • E 2 is CR E2 or N. In certain embodiments, E 2 is N. In certain embodiments, E 2 is CR E2 .
  • E 3 is CR E3 or N. In certain embodiments, E 3 is N. In certain embodiments, E 3 is CR E3 .
  • E 4 is CR E4 or N. In certain embodiments, E 4 is N. In certain embodiments, E 4 is CR E4 .
  • none of E 1 , E 2 , E 3 , and E 4 is N. In certain embodiments, one of E 1 , E 2 , E 3 , and E 4 is N. In certain embodiments, two of E 1 , E 2 , E 3 , and E 4 are N. In certain embodiments, three of E 1 , E 2 , E 3 , and E 4 are N. In certain embodiments, each of E 1 , E 2 , E 3 , and E 4 is N. [0075] In certain embodiments, one or two of E 1 , E 2 , E 3 , and E 4 is N.
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), n-propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C4), i
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, 33 282341894 v2 PRSC-068/001WO (343170-2269) alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R E1 , R E2 , R E3 , and R E4 when applicable, are independently hydrogen or halogen.
  • R E1 is hydrogen. In certain embodiments, R E2 is hydrogen. In certain embodiments, R E3 is hydrogen. In certain embodiments, R E4 is hydrogen. [0083] In certain embodiments, R E2 , R E3 , or R E4 is . [0084] In certain embodiments, none none of E 1 , E 2 , and E 4 , or none of E 1 , E 2 , and E 3 is N. [0085] In certain embodiments, one of E 1 , E 3 , and E 4 , one of E 1 , E 2 , and E 4 , or one of E 1 , E 2 , and E 3 is N.
  • two of E 1 , E 3 , and E 4 , two of E 1 , E 2 , and E 4 , or two of E 1 , E 2 , and E 3 are N.
  • each of E 1 , E 3 , and E 4 , each of E 1 , E 2 , and E 4 , or each of E 1 , E 2 , and E 3 is N.
  • R E3 is one or two of E 1 , E 2 , and E 4 are N.
  • R E2 is 282341894 v2 PRSC-068/001WO (343170-2269) one or two of E 1 , E 3 , and E 4 are N.
  • Ring F is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C3)
  • Ring F is C5-10 carbocyclyl or 5- to 10-membered heterocyclyl. [0092] In certain embodiments, Ring F is cyclohexyl, piperidinyl, 2,7-diazaspiro[3.5]nonanyl, 3,9- diazaspiro[5.5]undecanyl, or 2-azaspiro[3.5]nonanyl.
  • each R F is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), t- butoxy (C
  • each R F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R F is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • each R F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, 36 282341894 v2 PRSC-068/001WO (343170-2269) wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • R b is hydrogen or 3- to 12-membered heterocyclyl.
  • f is 0. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5.
  • f is 6. In certain embodiments, f is 7. In certain embodiments, f is 8. In certain embodiments, f is 9. In certain embodiments, f is 10. [0100] In certain aspects, the present disclosure provides compounds of Formula I: , and pharmaceutically acceptable thereof, wherein: X 1 is CR X1 or N; X 2 is CR X2 or N; X 3 is CR X3 or N; X 4 is CR X4 or N; R X1 , R X2 , R X3 , and R X4 are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SR b ,
  • the compound is not 2) when i) R X1 is hydrogen; and ii) Y 1 is CR Y1 , Y 2 is CR Y2 , Y 3 is CR Y3 , and Y 4 is CR Y4 ; R Y1 , R Y2 , R Y3 , and R Y4 are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy, then i) R C are not both optionally substituted phenyl; and ii) when one R C is optionally substituted thiophenyl, then other R C is not optionally substituted phenyl.
  • the compound is a compound of Formula I-1 or I-2 2), or a each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • the compound is a compound of Formula I-1’ or I-2’ 40 282341894 v2 PRSC-068/001WO (343170-2269) , or a C each R is - - - - - 6 6 alkoxy, C 1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u ; and R X1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alky
  • R X1 is halogen.
  • R Y1 , R Y2 , R Y3 , and R Y4 are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • two of Y 1 , Y 2 , Y 3 , and Y 4 is N. In certain embodiments, one of Y 1 , Y 2 , Y 3 , and Y 4 are N.
  • two or three of R Y1 , R Y2 , R Y3 , and R Y4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R
  • R Y1 , R Y2 , R Y3 , and R Y4 are hydrogen.
  • the compound is a compound of Formula I-1-i, I-1-ii, I-2-i, or I- 2-ii , ii), or a each R C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u ; Ring F is C 3-12 carbocyclyl or 3- to 12-membered heterocycle
  • R X1 is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R X1 is halogen.
  • the compound is a compound of Formula I-1-iii, I-1-iv, I-2-iii, or I-2-iv , , or each R C is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u ; and R X1 is halogen.
  • Ring F is 3-membered heterocyclyl. In certain embodiments, Ring F is 4-membered heterocyclyl. In certain embodiments, Ring F is 5-membered heterocyclyl. In certain embodiments, Ring F is 6-membered heterocyclyl. In certain embodiments, Ring F is 7- membered heterocyclyl. In certain embodiments, Ring F is 8-membered heterocyclyl. In certain 43 282341894 v2 PRSC-068/001WO (343170-2269) embodiments, Ring F is 9-membered heterocyclyl. In certain embodiments, Ring F is 10- membered heterocyclyl. In certain embodiments, Ring F is 11-membered heterocyclyl.
  • Ring F is 12-membered heterocyclyl. [0116] In certain embodiments, Ring F is 3- to 12-membered heterocyclyl. In certain embodiments, Ring F is 3- to 11-membered heterocyclyl. In certain embodiments, Ring F is 3- to 10-membered heterocyclyl. In certain embodiments, Ring F is 3- to 9-membered heterocyclyl. In certain embodiments, Ring F is 3- to 8-membered heterocyclyl. In certain embodiments, Ring F is 3- to 7-membered heterocyclyl. In certain embodiments, Ring F is 3- to 6-membered heterocyclyl. In certain embodiments, Ring F is 3- to 5-membered heterocyclyl.
  • Ring F is 3- to 4-membered heterocyclyl. In certain embodiments, Ring F is 4- to 12-membered heterocyclyl. In certain embodiments, Ring F is 4- to 11-membered heterocyclyl. In certain embodiments, Ring F is 4- to 10-membered heterocyclyl. In certain embodiments, Ring F is 4- to 9-membered heterocyclyl. In certain embodiments, Ring F is 4- to 8-membered heterocyclyl. In certain embodiments, Ring F is 4- to 7-membered heterocyclyl. In certain embodiments, Ring F is 4- to 6-membered heterocyclyl. In certain embodiments, Ring F is 4- to 5-membered heterocyclyl.
  • Ring F is 5- to 12-membered heterocyclyl. In certain embodiments, Ring F is 5- to 11-membered heterocyclyl. In certain embodiments, Ring F is 5- to 10-membered heterocyclyl. In certain embodiments, Ring F is 5- to 9-membered heterocyclyl. In certain embodiments, Ring F is 5- to 8-membered heterocyclyl. In certain embodiments, Ring F is 5- to 7-membered heterocyclyl. In certain embodiments, Ring F is 5- to 6-membered heterocyclyl. In certain embodiments, Ring F is 6- to 12-membered heterocyclyl. In certain embodiments, Ring F is 6- to 11-membered heterocyclyl.
  • Ring F is 6- to 10-membered heterocyclyl. In certain embodiments, Ring F is 6- to 9-membered heterocyclyl. In certain embodiments, Ring F is 6- to 8-membered heterocyclyl. In certain embodiments, Ring F is 6- to 7-membered heterocyclyl. In certain embodiments, Ring F is 8- to 12-membered heterocyclyl. In certain embodiments, Ring F is 8- to 11-membered heterocyclyl. In certain embodiments, Ring F is 8- to 10-membered heterocyclyl. In certain embodiments, Ring F is 8- to 9-membered heterocyclyl. In certain embodiments, Ring F is 9- to 12-membered heterocyclyl.
  • Ring F is 9- to 11-membered heterocyclyl. In certain embodiments, Ring F is 9- to 10-membered heterocyclyl. In certain embodiments, Ring F is 10- to 12-membered heterocyclyl. 44 282341894 v2 PRSC-068/001WO (343170-2269) In certain embodiments, Ring F is 10- to 11-membered heterocyclyl. In certain embodiments, Ring F is 11- to 12-membered heterocyclyl. [0117] In certain embodiments, Ring F is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring F is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0118] In certain embodiments, Ring F is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring F is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • each R F is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9. In certain embodiments, p is 10.
  • R Y1 , R Y2 , and R Y4 or R Y1 , R Y3 , and R Y4 are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each of R Y1 , R Y2 , and R Y4 or each of R Y1 , R Y3 , and R Y4 is hydrogen.
  • one or two of Y 1 , Y 2 , and Y 4 or one or two of Y 1 , Y 3 , and Y 4 is N.
  • one or two of R Y1 , R Y2 , and R Y4 or one or two of R Y1 , R Y3 , and R Y4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R Y1 , R Y2 , and R Y4 or one or two of R Y1 , R Y3 , and R Y4 are hydrogen.
  • each of R X2 , R X3 , and R X4 is independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each of R X2 , R X3 , and R X4 is hydrogen.
  • Ring D is 3-membered heterocyclyl. In certain embodiments, Ring D is 4-membered heterocyclyl. In certain embodiments, Ring D is 5-membered heterocyclyl. In certain embodiments, Ring D is 6-membered heterocyclyl. In certain embodiments, Ring D is 7- membered heterocyclyl. In certain embodiments, Ring D is 8-membered heterocyclyl. In certain embodiments, Ring D is 9-membered heterocyclyl. In certain embodiments, Ring D is 10- membered heterocyclyl. In certain embodiments, Ring D is 11-membered heterocyclyl.
  • Ring D is 12-membered heterocyclyl. [0129] In certain embodiments, Ring D is 3- to 12-membered heterocyclyl. In certain embodiments, Ring D is 3- to 11-membered heterocyclyl. In certain embodiments, Ring D is 3- to 10-membered heterocyclyl. In certain embodiments, Ring D is 3- to 9-membered heterocyclyl. In certain embodiments, Ring D is 3- to 8-membered heterocyclyl. In certain embodiments, Ring D is 3- to 7-membered heterocyclyl. In certain embodiments, Ring D is 3- to 6-membered heterocyclyl. In certain embodiments, Ring D is 3- to 5-membered heterocyclyl.
  • Ring D is 3- to 4-membered heterocyclyl. In certain embodiments, Ring D is 4- to 12-membered heterocyclyl. In certain embodiments, Ring D is 4- to 11-membered heterocyclyl. 46 282341894 v2 PRSC-068/001WO (343170-2269) In certain embodiments, Ring D is 4- to 10-membered heterocyclyl. In certain embodiments, Ring D is 4- to 9-membered heterocyclyl. In certain embodiments, Ring D is 4- to 8-membered heterocyclyl. In certain embodiments, Ring D is 4- to 7-membered heterocyclyl. In certain embodiments, Ring D is 4- to 6-membered heterocyclyl.
  • Ring D is 4- to 5-membered heterocyclyl. In certain embodiments, Ring D is 5- to 12-membered heterocyclyl. In certain embodiments, Ring D is 5- to 11-membered heterocyclyl. In certain embodiments, Ring D is 5- to 10-membered heterocyclyl. In certain embodiments, Ring D is 5- to 9-membered heterocyclyl. In certain embodiments, Ring D is 5- to 8-membered heterocyclyl. In certain embodiments, Ring D is 5- to 7-membered heterocyclyl. In certain embodiments, Ring D is 5- to 6-membered heterocyclyl. In certain embodiments, Ring D is 6- to 12-membered heterocyclyl.
  • Ring D is 6- to 11-membered heterocyclyl. In certain embodiments, Ring D is 6- to 10-membered heterocyclyl. In certain embodiments, Ring D is 6- to 9-membered heterocyclyl. In certain embodiments, Ring D is 6- to 8-membered heterocyclyl. In certain embodiments, Ring D is 6- to 7-membered heterocyclyl. In certain embodiments, Ring D is 8- to 12-membered heterocyclyl. In certain embodiments, Ring D is 8- to 11-membered heterocyclyl. In certain embodiments, Ring D is 8- to 10-membered heterocyclyl. In certain embodiments, Ring D is 8- to 9-membered heterocyclyl.
  • Ring D is 9- to 12-membered heterocyclyl. In certain embodiments, Ring D is 9- to 11-membered heterocyclyl. In certain embodiments, Ring D is 9- to 10-membered heterocyclyl. In certain embodiments, Ring D is 10- to 12-membered heterocyclyl. In certain embodiments, Ring D is 10- to 11-membered heterocyclyl. In certain embodiments, Ring D is 11- to 12-membered heterocyclyl. [0130] In certain embodiments, Ring D is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring D is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0131] In certain embodiments, Ring D is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring D is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0132] In certain embodiments, Ring D is C3 carbocyclyl. In certain embodiments, Ring D is C4 carbocyclyl. In certain embodiments, Ring D is C5 carbocyclyl. In certain embodiments, Ring D is C 6 carbocyclyl.
  • Ring D is C 7 carbocyclyl. In certain embodiments, Ring D is C8 carbocyclyl. In certain embodiments, Ring D is C9 carbocyclyl. In certain embodiments, Ring D is C10 carbocyclyl. In certain embodiments, Ring D is C11 carbocyclyl. In certain embodiments, Ring D is C 12 carbocyclyl. [0133] In certain embodiments, Ring D is C 3-12 carbocyclyl. In certain embodiments, Ring D is C 3- 11 carbocyclyl. In certain embodiments, Ring D is C3-10 carbocyclyl. In certain embodiments, Ring D is C3-9 carbocyclyl. In certain embodiments, Ring D is C3-8 carbocyclyl.
  • Ring D is C 3-7 carbocyclyl. In certain embodiments, Ring D is C 3-6 carbocyclyl. In certain embodiments, Ring D is C3-5 carbocyclyl. In certain embodiments, Ring D is C3-4 carbocyclyl. In certain embodiments, Ring D is C4-12 carbocyclyl. In certain embodiments, Ring D is C4-11 carbocyclyl. In certain embodiments, Ring D is C 4-10 carbocyclyl. In certain embodiments, Ring D is C4-9 carbocyclyl. In certain embodiments, Ring D is C4-8 carbocyclyl. In certain embodiments, Ring D is C4-7 carbocyclyl. In certain embodiments, Ring D is C4-6 carbocyclyl.
  • Ring D is C 4-5 carbocyclyl. In certain embodiments, Ring D is C 5-12 carbocyclyl. In certain embodiments, Ring D is C 5-11 carbocyclyl. In certain embodiments, Ring D is C 5-10 carbocyclyl. In certain embodiments, Ring D is C5-9 carbocyclyl. In certain embodiments, Ring D is C5-8 carbocyclyl. In certain embodiments, Ring D is C5-7 carbocyclyl. In certain embodiments, Ring D is C 5-6 carbocyclyl. In certain embodiments, Ring D is C 6-12 carbocyclyl. In certain embodiments, Ring D is C6-11 carbocyclyl. In certain embodiments, Ring D is C6-10 carbocyclyl.
  • Ring D is C6-9 carbocyclyl. In certain embodiments, Ring D is C6-8 carbocyclyl. In certain embodiments, Ring D is C 6-7 carbocyclyl. In certain embodiments, Ring D is C7-12 carbocyclyl. In certain embodiments, Ring D is C7-11 carbocyclyl. In certain embodiments, Ring D is C7-10 carbocyclyl. In certain embodiments, Ring D is C7-9 carbocyclyl. In certain embodiments, Ring D is C 7-8 carbocyclyl. In certain embodiments, Ring D is C 8-12 carbocyclyl. In certain embodiments, Ring D is C 8-11 carbocyclyl.
  • Ring D is C 8-10 48 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl. In certain embodiments, Ring D is C 8-9 carbocyclyl. In certain embodiments, Ring D is C9-12 carbocyclyl. In certain embodiments, Ring D is C9-11 carbocyclyl. In certain embodiments, Ring D is C9-10 carbocyclyl. In certain embodiments, Ring D is C10-12 carbocyclyl. In certain embodiments, Ring D is C 10-11 carbocyclyl. In certain embodiments, Ring D is C 11-12 carbocyclyl. [0134] In certain embodiments, Ring D is C4-12 carbocycle and 3- to 12-membered heterocycle.
  • Ring D is C4-12 carbocycle.
  • Ring D is C 5-7 carbocycle.
  • Ring D is 3- to 12-membered heterocycle.
  • Ring D is 5- to 7-membered heterocycle.
  • each R D is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R D is independently oxo, halogen, or -OH.
  • at least one R D is oxo. In certain embodiments, at least one R D is halogen. In certain embodiments, at least one R D is -OH.
  • at least one R D is oxo. In certain embodiments, at least one R D is halogen. In certain embodiments, at least one R D is -OH.
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.
  • m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [0144] In certain embodiments, m is 0 or 1. [0145] In certain embodiments, two R C form an oxo.
  • each R C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • At least one R C is C 1-6 alkyl. 49 282341894 v2 PRSC-068/001WO (343170-2269) [0148] In certain embodiments, each of R C is C 1-6 alkyl. [0149] In certain embodiments, at least one R C is methyl. [0150] In certain embodiments, each of R C is methyl.
  • each R a is independently C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2- butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 ), C 2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), n
  • each R a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl.
  • each R a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R a is independently C 1-6 alkyl, C 3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R b is independently hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 ), C 2-6 alkynyl (e.g., ethynyl (C 2 ), 1-
  • each R b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R b is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C 2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R c and each R d is independently hydrogen, C1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., e
  • each R c and each R d is independently hydrogen, C 1-6 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more R u .
  • R c and R d together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R u .
  • R a , R b , R c , and R d is independently and optionally substituted with one or more R z .
  • R z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C 5 ), or hexoxy (C 6 )), C 1-6 alkylamino
  • each R u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocycl
  • each R u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, and 3- to 6-membered heterocycl
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • two R u together with the carbon atom(s) to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6- membered ring and 1-3 heteroatoms selected from N, O, and S), C 6 aryl (i.e., phenyl), or 5- to 6- membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S),
  • C 6 aryl i.
  • two R u together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R z .
  • C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (
  • two geminal R u together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 54 282341894 v2 PRSC-068/001WO (343170-2269) 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R z .
  • C3-6 carbocyclyl e.g., cyclopropy
  • the compound is selected from the compounds in Tables 1’ and 2, or a pharmaceutically acceptable salt thereof.
  • Table 1 Compound N o. Structure Chemical Name - n e 55 282341894 v2 PRSC-068/001WO (343170-2269) Compound N o. Structure Chemical Name - - 2- - - 2- '- 56 282341894 v2 PRSC-068/001WO (343170-2269) Compound N o. Structure Chemical Name - - 57 282341894 v2 PRSC-068/001WO (343170-2269) Compound N o.
  • conjugates comprising a compound disclosed herein being connected to a E3 ubiquitin ligase ligand (e.g., cereblon E3 ubiquitin ligase ligand or von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand) (e.g., via a linker).
  • E3 ubiquitin ligase ligand e.g., cereblon E3 ubiquitin ligase ligand or von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand
  • the present disclosure provides conjugates of Formula II , wherein: one of R E1 , R E2 , R E3 , and R E4 is -L-E; or one of R E2 , R E3 , or R E4 is ; L is a linker; and E is a ubiquintin ligase ligand, wherein each of the variables in Formula II is described herein.
  • the conjugate is of Formula II-1 or II-2 82 282341894 v2 PRSC-068/001WO (343170-2269) 2), wherein each [0178] In iii’, II-2-i’, II-2- ii’, II-2-iii’, II-3-i’, II-3-ii’, II-3-iii’, , , PRSC-068/001WO (343170-2269) or wherein iii’, II-3- i’, II-3-ii’, II-3-iii’ is described herein.
  • L is a divalent chemical moiety that connects the E3 ubiquitin ligase ligand with ligand of a protein (e.g., an inhibitor) disclosed herein.
  • L configures the ligand of a protein and the E3 ubiquitin ligase ligand such that the construct functions as a bifunctional degrader which binds the E3 ubiquitin ligase and selectively degrades the target protein.
  • each L ’ is independently C1-6 alkylene (e.g., methylene (-CH2-), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (- CH 2 CH 2 CH 2 CH 2 CH 2 -), and hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -)), C 1-6 heteroalkylene (C 1-6 alkylene comprising 1-6 heteroatoms selected from O, N, and S), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C 4 ), pentenylene (C 5 ), pentadienylene (C 5 ), or hexenylene (C 6 )), C 2-6 alkylene (e.g.,
  • each occurrence of R L’ is independently hydrogen, C1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 alkynyl (e.g., ethynyl (C 2 ), n-propyl (
  • l is 0.
  • t is 1.
  • E is E3 ubiquitin ligase ligand.
  • E is cereblon E3 ubiquitin ligase ligand.
  • Cereblon E3 ubiquitin ligase ligand is a ligand that binds Cereblon E3 ubiquitin ligase.
  • E3 ubiquitin ligase ligands are disclosed in WO2018144649, 86 282341894 v2 PRSC-068/001WO (343170-2269) WO2017176958, WO2021041664, WO2022187423, US20180228907, Lu et al Science 343, 305 (2014), and Kronke et al Science 343, 301 (2014).
  • E is von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand.
  • VHL Von Hippel-Lidau
  • VHL ligand is a residue of a ligand that binds the von Hippel-Lidau E3 ubiquitin ligase (VHL ligand).
  • Representative VHL ligands are disclosed in, for example, i) WO 2019/207538, WO 2020/251972, WO 2020/251971, WO 2021/155321, WO2021/086785, WO 2021/133920, and WO 2022/109396; ii) Kofink, C., Trainor, N., Mair, B. et al.
  • VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.
  • the conjugate is selected from the conjugates in Table 3, or a pharmaceutically acceptable salt thereof.
  • Table 3 Compound S compture Chemical Name - - 1- y- l- e- - - - 87 282341894 v2 PRSC-068/001WO (343170-2269)
  • Compound N o Structure Chemical Name 1- - - - 1- - l- e- - y- l- e- 1- y- l- e- 88 282341894 v2 PRSC-068/001WO (343170-2269) Compound N o.
  • the compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known SMARCA2/4 inhibitors.
  • the compounds of the present disclosure may display more potent SMARCA2/4 activity, more 91 282341894 v2 PRSC-068/001WO (343170-2269) favorable pharmacokinetic properties (e.g., as measured by C max , T max , and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction).
  • hepatic cellular transporter such as OATP1B1
  • a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • a compound of the present disclosure is a solvate.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • compositions include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the 92 282341894 v2 PRSC-068/001WO (343170-2269) methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate, hydroxy
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- 93 282341894 v2 PRSC-068/001WO (343170-2269) hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, aryls
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0203] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”.
  • Solvates are within the scope of the invention.
  • crystalline form may vary from solvate to solvate.
  • all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention.
  • the compounds described herein exist as solvates.
  • the present disclosure provides for methods of treating diseases by administering such solvates.
  • the present 94 282341894 v2 PRSC-068/001WO (343170-2269) disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • a solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure 95 282341894 v2 PRSC-068/001WO (343170-2269) enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
  • Tautomers [0211] In some embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [0212] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist.
  • compositions [0213]
  • the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small 96 282341894 v2 PRSC-068/001WO (343170-2269) molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those 97 282341894 v2 PRSC-068/001WO (343170-2269) skilled in the art.
  • the compounds of the present disclosure i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)
  • General Synthetic Method Scheme 1 General Synthetic Scheme for Preparing Compound “A” Scheme 2.
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art.
  • the binding potency may be determined using homogeneous time-resolved 101 282341894 v2 PRSC-068/001WO (343170-2269) fluorescence (HTRF) assay technology.
  • HTRF fluorescence
  • compounds are serially diluted in certain solvent (e.g., DMSO), and incubated with certain concentration of SMARCA4 (e.g., 0/12 ng/ul) or SMARCA2 (e.g., 0.5 ng/ul) for a certain period of time (e.g., 30 min) at a certain temperature (e.g., 25 o C), followed by addition of diluted bromodomain ligand 2 (peptide histone H3; sequence: ARTKQTARKSTGGKAPRKQLA (Ala-Arg-Thr-Lys-Gln-Thr-Ala-Arg-Lys-Ser- Thr-Gly-Gly-Lys-Ala-Pro-Arg-Lys-Gln-Le
  • terbium-labeled donor and dye-labeled acceptor are added subsequently.
  • HTRF signals are read (e.g., on Envision reader) and data is analyzed using, e.g., XLfit using four parameters dose response curve to determine IC 50 s.
  • the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a SMARCA2 or SMARCA4 protein in a subject or a biological sample.
  • the present disclosure provides compounds disclosed herein for use in inhibiting a SMARCA2 or SMARCA4 protein in a subject or a biological sample.
  • the compound selectively binds the SMARCA2 protein over the SMARCA4 protein.
  • the compound has a dissociation constant for the SMARCA2 protein at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold lower than the dissociation constant for the SMARCA4 protein.
  • the present disclosure provides methods of degrading a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a conjugate disclosed herein.
  • the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a subject.
  • the present discloure provides conjugates disclosed herein for use in degrading a SMARCA2 or SMARCA4 protein in a subject.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).
  • the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a conjugate disclosed herein (e.g., in a therapeutically effective amount).
  • the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the disease or disorder is a SMARCA2 or SMARCA4 protein- mediated disease or disorder.
  • the disease or disorder is selected from a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder.
  • the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer, glioma, breast cancer, pancreatic cancer, colorectal cancer, bladder cancer, endometrial cancer, penile cancer, esophagogastric cancer, hepatobiliary cancer soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non- 103 282341894 v2 PRSC-068/001WO (343170-2269) Hodgkin lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small bowel cancer, non-melanoma skin cancer, melanoma, leukemia, and malignant rhabdoid tumors
  • NSCLC non-small
  • the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).
  • LAD NSCLC adenocarcinoma
  • LUSC NSCL squamous cell carcinoma
  • LIHC liver hepatocellular carcinoma
  • UCEC uterine corpus endometrial carcinoma
  • ESCA esophageal carcinoma
  • STAD stomach adenocarcinoma
  • COAD colon adenocarcinoma
  • BLCA bladder urothelial carcinoma
  • UCS uterine carcinosarcoma
  • the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).
  • the cancer includes, but is not limited to, one or more of the cancers of Table A. Table A.
  • r is a hematological cancer.
  • hematological cancers include, but are not limited to, the cancers listed in Table B.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
  • Table B acute lymphocytic leukemia (ALL) acute eosinophilic leukemia 107 282341894 v2 PRSC-068/001WO (343170-2269) Richter's transformation [0248]
  • the subject is a human.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • the invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • a range of values is listed, it is intended to encompass each value and sub-range within the range.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”).
  • C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3- pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl 109 282341894 v2 PRSC-068/001WO (343170-2269) (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3).
  • the alkyl group is substituted C1-10 alkyl.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • alkelene may be substituted or unsubstituted with one or more substituents as described herein.
  • exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like.
  • Exemplary substituted divalent alkylene groups include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, - C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, - CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH3) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C 2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2- 10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms 110 282341894 v2 PRSC-068/001WO (343170-2269) (“C 2-3 alkenyl”).
  • an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like.
  • alkenyl examples include heptenyl (C7), octenyl (C8), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2-10 alkenyl.
  • the alkenyl group is substituted C 2-10 alkenyl.
  • Alkenylene refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In certain embodiments, 111 282341894 v2 PRSC-068/001WO (343170-2269) an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”).
  • an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C2- 10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.
  • Alkynylene refers to a alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • 1 or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-8 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 112 282341894 v2 PRSC-068/001WO (343170-2269) alkyl”).
  • a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”).
  • a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 alkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC 2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 113 282341894 v2 PRSC-068/001WO (343170-2269) heteroatom (“heteroC 2-3 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”).
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkynyl”).
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2- 3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”).
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.
  • heteroalkylene refers to a divalent 114 282341894 v2 PRSC-068/001WO (343170-2269) radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
  • a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain.
  • Heteroalkylene, “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • 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 (“C6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl).
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6-14 aryl.
  • the aryl group is substituted C6-14 aryl.
  • arylene When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group.
  • An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Heteroaryl refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each 115 282341894 v2 PRSC-068/001WO (343170-2269) heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”).
  • a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”).
  • a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”).
  • a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6- membered heteroaryl”).
  • the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted 116 282341894 v2 PRSC-068/001WO (343170-2269) heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl.
  • the heteroaryl group is substituted 5- to 14-membered heteroaryl.
  • Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroarylene refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group.
  • a “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C 5-12 117 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C 3-10 carbocyclyl include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C 5-12 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C 5-6 carbocyclyl include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 carbocyclyl examples include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl.
  • the carbocyclyl group is substituted C 3-12 carbocyclyl. 118 282341894 v2 PRSC-068/001WO (343170-2269) [0276] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl.
  • the carbocyclyl group is a substituted C 3- 12 carbocyclyl.
  • “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.
  • “Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded.
  • the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded.
  • Bridged carbocyclyl or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded.
  • the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded.
  • Carbocyclylene refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical.
  • the divalent radical may be present on different atoms or 119 282341894 v2 PRSC-068/001WO (343170-2269) the same atom of the carbocyclylene group.
  • a “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Heterocyclyl refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. 120 282341894 v2 PRSC-068/001WO (343170-2269) [0282]
  • a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12- membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 8- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”).
  • the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6- membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.
  • “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings.
  • the number of ring members designates the total number of ring members in the fused ring system.
  • “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • Heterocyclylene refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group.
  • heterocyclylene refers to the number of ring members in the heterocyclylene group.
  • a “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkoxy refers to the group -OR, wherein R is alkyl as defined herein.
  • C1- 6 alkoxy refers to the group -OR, wherein each R is C 1-6 alkyl, as defined herein. Exemplary C 1-6 alkyl is set forth above.
  • Alkylamino refers to the group -NHR or -NR 2 , wherein each R is independently alkyl, as defined herein.
  • C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above.
  • heteroaryl When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.
  • Halo or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
  • Protecting group refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction.
  • a functional group e.g., hydroxyl, amino, thio, and carboxylic acid
  • Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl- protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid- protecting groups, respectively.
  • hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso- propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)).
  • ethers e.g., methoxymethyl (MOM), ⁇ -Methoxyeth
  • amino-protecting groups include but not limited to carbamates (e.g., t- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenyl
  • thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).
  • carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulf
  • Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counterion of an acidic functional group.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural formula indicated herein.
  • metabolically cleavable groups include -COR, -COOR, -CONR2 and -CH2OR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy.
  • Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.
  • “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution- phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, 125 282341894 v2 PRSC-068/001WO (343170-2269) sheep, goats, rodents, cats, and/or dogs.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-
  • an “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • a “therapeutically effective amount” refers to the effective amount for therapeutic treatment.
  • a “prophylatically effective amount” refers to the effective amount for prophylactic treatment.
  • “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).
  • the term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • treating refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treating or “treatment” relates to slowing the progression of the disease.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is termed a “racemic mixture”.
  • “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)- compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound.
  • the weights are based upon total weight of compound.
  • the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)- compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.
  • an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound.
  • the enantiomerically pure (R)- compound in such compositions can, for example, comprise, at least about 95% by weight (R)- compound and at most about 5% by weight (S)-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound.
  • the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0321] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Step 3 To a solution of received acid product (600 mg, 1.47 mmol, 1.0 equiv) in CH3CN (20 mL) was added HATU (725 mg, 1.91 mmol, 1.3 equiv) and DIPEA (570 mg, 4.4 mmol, 3.0 equiv). under stirring, the mixture was bubbled by NH 3 gas for 2 minutes. Then let mixture stirred for 30 min at room temperature.
  • Step 4 [0329] Step 4.
  • the obtained cyclic product 160 mg, 0.26 mmol was dissolved into DCM (5 mL), then TFA (5 mL) was added. The mixture was stirred for 30 minutes. After concentrating, the residue was purified by prepared HPLC C-18 reversal column to get target product (60 mg, 81%).
  • Step 2 To a solution of 1 (600 mg, 1.37 mmol, 1 equiv) in mixture DMSO/H 2 O 2 30% wt (10 mL/2 mL) was added K2CO3 (378 mg, 2.74 mmol, 2.0 equiv). The mixture was stirred for 16 h at 50 °C. After cooling to room temperature, the mixture was purified by C-18 reversal column (elution solvents: CH 3 CN/H 2 O from 10% to 100%, 0.1%TFA) to get target product 4 as a white solid (600 mg, 96%).
  • Step 3 To a solution of 4 (300 mg, 0.65 mmol, 1 equiv) in MeOH (20 mL) was added MeONa (355 mg, 6.58 mmol, 10 equiv). The mixture was refluxed for 16 h. After cooling to 0 ° C, the mixture was neutralized by TFA (0.3 mL). Then the reaction was removed solvent under rotatory evaporator. The reside was dissolved into a mixture of ethyl acetate, the organic phase was washed by brine once.
  • Step 4 To a solution of 5 (50 mg, 1.37 mmol, 1 equiv) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred for 0.5 h. After removing solvent, the mixture was purified by pre- HPLC C-18 reversal column to get target product 6 as a white solid (30 mg, 78%).
  • Step 3 Under nitrogen protection, to a solution of 4 (2.10 g, 6.64 mmol, 1.0 eq) in dry THF (40 mL) was added LHMDS (21.9 mL, 21.9 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 5 (1.61 g, 6.64 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH 4 Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4.
  • Step 4 To a flask was added 6 (600 mg, 1.24 mmol, 1.0 eq), 7 (211 mg, 1.36 mmol, 1.1 eq), Cs2CO3 (805 g, 2.47 mmol, 2.0 eq). Then CH3CN (80 mL and 10 mL) was added to the flask. The suspension was refluxed overnight.
  • Step 3 To a solution of DMSO (4 mL) was added 5 (200 mg, 0.38 mmol, 1 eq), K2CO3 (106 mg, 0.76 mmol, 2 eq) and H 2 O 2 (1 mL).
  • Step 3 To a solution of DMSO (10 mL) was added 5 (200 mg, 0.39 mmol, 1 eq), K 2 CO 3 (109 mg, 0.79 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: 138 282341894 v2 PRSC-068/001WO (343170-2269) CH 3 CN/H 2 O from 10% to 100%, 0.1%TFA) to purify directly to get product (170 mg, 82%).
  • Step 4.6 (100 mg, 0.19 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added.
  • MeONa 103 mg, 1.91 mmol, 10 eq
  • TFA 0.5 mL
  • the solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4.
  • Step 5 To a solution of 7 (30 mg, 0.59 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (16 mg, 66 %).
  • Step 3 To a solution of DMSO (10 mL) was added 5 (200 mg, 0.38 mmol, 1 eq), K 2 CO 3 (106 mg, 0.76 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH 3 CN/H 2 O from 10% to 100%, 0.1%TFA) to purify directly to get product (170 mg, 82%). ESI MS m/z: 538.24 [M+H] + .
  • Step 4.6 (100 mg, 0.19 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added.
  • MeONa 103 mg, 1.91 mmol, 10 eq
  • TFA 0.5 mL
  • the solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na 2 SO 4 .
  • Step 5 To a solution of 7 (30 mg, 0.57 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (18 mg, 74 %).
  • Step 3 To a solution of DMSO (10 mL) was added 5 (200 mg, 0.37 mmol, 1 eq), K 2 CO 3 (104 mg, 0.75 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH 3 CN/H 2 O from 10% to 100%, 0.1%TFA) to purify directly to get product (180 mg, 87%).
  • Step 4.6 (100 mg, 0.18 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added.
  • MeONa 103 mg, 1.91 mmol, 10 eq
  • TFA 0.5 mL
  • the solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na 2 SO 4 .
  • Step 1 To a flask was added 1 (400 mg, 1.04 mmol, 1.0 eq), was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected.
  • Step 2 To a solution of DMSO (10 mL) was added 5 (200 mg, 0.35 mmol, 1 eq), K 2 CO 3 (98mg, 0.71 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h.
  • Step 3 (100 mg, 0.17 mmol, 1.0 eq) was dissolved into dry methanol (20 mL), then MeONa (92 mg, 1.72 mmol, 10 eq) was added. Aftered by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa.
  • Step 2 To a stirred solution of compound 3 (356 mg, 0.74 mmol, 1.0 eq) in methanol (7 mL) was added palladium on carbon (36 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature for 12 h.
  • Step 3 To a stirred solution of compound 4 (70 mg, 0.14 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 5 (25 mg, 0.16 mmol, 1.1 eq) in MeCN (2 mL) was added Cs 2 CO 3 (94 mg, 0.29 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed.
  • Step 4 To a stirred solution of compound 6 (70 mg, 0.11 mmol, 1.0 eq) in DMSO (2 mL) was added H2O2 (30% wt in H2O, 0.3 mL) and K2CO3 (31 mg, 0.22 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 7 (52 mg, 72 %).
  • Step 5 To a stirred solution of compound 7 (52 mg, 0.081 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (1.0 M in MeOH, 0.8 mL, 0.80 mmol, 10 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h.
  • Step 2 To a stirred solution of compound 3 (90 mg, 0.23 mmol, 1.0 eq) in methanol (10 mL) was added palladium on carbon (10 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature for 12 h.
  • Step 3 To a stirred solution of compound 4 (84 mg, 0.22 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 5 (37 mg, 0.24 mmol, 1.1 eq) in MeCN (3 mL) was added Cs2CO3 (142 mg, 0.44 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed.
  • Step 4 To a stirred solution of compound 6 (102 mg, 0.20 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (54 mg, 0.40 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h.
  • Step 5 To a stirred solution of compound 7 (21.4 mg, 0.040 mmol, 1.0 eq) in dry MeOH (3 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.50 mmol, 12 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed.
  • Step 2 To a stirred solution of compound 3 (30 mg, 0.077 mmol, 1.0 eq) in DMF (1 mL) was added NaH (60% wt in mineral oil, 4.6 mg, 0.12 mmol, 1.5 eq).
  • Step 3 To a stirred solution of compound 5 (28 mg, 0.054 mmol, 1.0 eq) in DMSO (1mL) was added H 2 O 2 (30% wt in H 2 O, 0.2 mL) and K 2 CO 3 (15 mg, 0.11 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 6 (20 mg, 69 %).
  • Step 4 To a stirred solution of compound 7 (20 mg, 0.036 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.50 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h.
  • reaction mixture was stirred at at -78°C for 15 min and 1,4-dibromobutane 2 (137 mg, 0.63 mmol, 1.0 eq) was added dropwise.
  • the reaction mixture was then stirred at room temperature for another 1 h and 60°C overnight. After cooling to room temperature, the mixture was diluted with saturated NH 4 Cl solution (10 mL) and extracted with ethyl acetate (10 mL) 3 times.
  • the combined organic 149 282341894 v2 PRSC-068/001WO (343170-2269) layer was washed with water (20 mL) and saturated brine (20 mL), dried over Na 2 SO 4 and filtered.
  • Step 2 [0383] To a stirred solution of compound 3 (132 mg, 0.36 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 4 (61 mg, 0.39 mmol, 1.1 eq) in MeCN (4 mL) was added Cs2CO3 (231 mg, 0.71 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed.
  • Step 3 [0384] To a stirred solution of compound 5 (146 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H 2 O, 0.1% TFA) to give compound 6 (155 mg, 100 %).
  • Step 4 [0385] To a stirred solution of compound 6 (155 mg, 0.29 mmol, 1.0 eq) in dry MeOH (5 mL) was added sodium methoxide solution (0.5 M in MeOH, 5 mL, 2.50 mmol, 8.5 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (3 mL) and TFA (1 mL) and the rection mixture was stirred at room temperature for 2 h.
  • Step 2 To a flask was added compound 3 (300 mg, 1.02 mmol, 1.0 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2 (347 mg, 1.12 mmol, 1.1 eq), Pd(dppf)Cl 2 (75 mg, 0.10 mmol, 0.1 eq), K 2 CO 3 (282 mg, 2.04 mmol, 2.0 eq).
  • Step 3 To a stirred solution of compound 5 (415 mg, 1.05 mmol, 1.0 eq) in EtOAc (20 mL) was added palladium on carbon (42 mg, 10% wt).
  • Step 4 To a stirred solution of compound 6 (61 mg, 0.15 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 7 (26 mg, 0.17 mmol, 1.1 eq) in MeCN (2 mL) was added Cs 2 CO 3 (100 mg, 0.31 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed.
  • Step 5 To a stirred solution of compound 8 (48 mg, 0.091 mmol, 1.0 eq) in DMSO (2 mL) was added H2O2 (30% wt in H2O, 0.3 mL) and K2CO3 (25 mg, 0.18 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H 2 O, 0.1% TFA) to give compound 9 (29.2 mg, 58 %).
  • Step 6 To a stirred solution of compound 9 (29.2 mg, 0.053 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 1.5 mL, 0.75 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h.
  • Step 2 To a flask was added compound 2 (15 mg, 0.046 mmol, 1.0 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 3 (16 mg, 0.052 mmol, 1.1 eq), Pd(dppf)Cl2 (3.4 mg, 0.0046 mmol, 0.1 eq), K2CO3 (13 mg, 0.094 mmol, 2.0 eq). Dioxane (0.5 mL) and water (0.05 mL) was added and the flask was flushed with nitrogen.
  • Step 3 To a stirred solution of compound 4 (105 mg, 0.25 mmol, 1.0 eq) in MeOH (3 mL) was added palladium on carbon (11 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature overnight. The mixture was filtered by celite and solvent was removed to give crude compound 5 (95 mg, 90 %) which was used in the next step without further purification.
  • Step 4 To a stirred solution of compound 5 (95 mg, 0.23 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 6 (39 mg, 0.25 mmol, 1.1 eq) in MeCN (3 mL) was added Cs2CO3 (148 mg, 0.45 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room 154 282341894 v2 PRSC-068/001WO (343170-2269) temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 7 (79 mg, 62 %).
  • Step 5 To a stirred solution of compound 7 (15 mg, 0.027 mmol, 1.0 eq) in DMSO (2 mL) was added H 2 O 2 (30% wt in H 2 O, 0.2 mL) and K 2 CO 3 (7.5 mg, 0.054 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 8 (7.5 mg, 48 %).
  • Step 6 To a stirred solution of compound 8 (7.5 mg, 0.013 mmol, 1.0 eq) in dry MeOH (0.5 mL) was added sodium methoxide solution (0.5 M in MeOH, 0.5 mL, 0.25 mmol, 20 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h.
  • Step 1 To a solution of tert-butyl 4-(2',4-dioxospiro[cyclohexane-1,3'-indolin]-5'- yl)piperidine-1-carboxylate (60 mg, 0.15 mmol, 1.0 eq) in MeOH (2 mL) was added sodium borohydride (11 mg, 0.30 mmol, 2.0 eq).
  • Step 2 To a stirred solution of compound 2 (23 mg, 0.058 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 3 (10 mg, 0.064 mmol, 1.1 eq) in MeCN (1 mL) was added Cs 2 CO 3 (38 mg, 0.12 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 4 (22 mg, 71 %).
  • Step 3 To a stirred solution of compound 4 (22 mg, 0.040 mmol, 1.0 eq) in DMSO (1.5 mL) was added H2O2 (30% wt in H2O, 0.2 mL) and K2CO3 (11 mg, 0.080 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H 2 O, 0.1% TFA) to give compound 5 (20 mg, 90 %).
  • Step 4 To a stirred solution of compound 5 (20 mg, 0.036 mmol, 1.0 eq) in dry MeOH (1 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.5 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h.
  • reaction mixture was stirred at at - 78°C for 15 min and 1,5-dibromopentane 2 (6.4 mL, 47 mmol, 1.0 eq) was added dropwise.
  • the reaction mixture was then stirred at room temperature for another 1 h and 60°C overnight. After cooling to room temperature, the mixture was diluted with saturated NH 4 Cl solution (50 mL) and extracted with ethyl acetate (100 mL X 3). The combined organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over Na2SO4 and filtered.
  • Step 2 [0424] To a flask was added 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one 3 (2.66 g, 9.40 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate 4 (2.92 g, 9.40 mmol, 1.0 eq), Pd(dppf)Cl2 (692 mg, 0.94 mmol, 0.1 eq), K2CO3 (2.61 g, 18.80 mmol, 2.0 eq).
  • Step 4 [0426] To a stirred solution of compound 6 (268 mg, 0.70 mmol, 1.0 eq), 2,6-difluorobenzonitrile 7 (116 mg, 0.84 mmol, 1.2 eq) in MeCN (8 mL) was added Cs 2 CO 3 (454 mg, 1.3 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 8 (265 mg, 75%).
  • Step 5 [0427] To a stirred solution of compound 8 (146 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H 2 O 2 (30% wt in H 2 O, 0.5 mL) and K 2 CO 3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 9 (152 mg, 100 %).
  • Step 6 164 282341894 v2 PRSC-068/001WO (343170-2269) [0428] To a stirred solution of compound 9 (100 mg, 0.19 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 3 mL, 1.50 mmol, 7.9 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (3 mL) and TFA (1 mL) and the rection mixture was stirred at room temperature for 2 h.
  • Step 7 [0429] To a stirred solution of compound 10 (71 mg, 0.17 mmol, 1.0 eq) in dry pyridine (4 mL) was added MgBr 2 (37 mg, 0.2 mmol, 1.5 eq). The reaction mixture was stirred at 60°C for 4 h. After cooling to room temperature, the solvent was removed and the residue was purified by Prep- HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound A28 (46 mg, 67%).
  • Step 8 [0430] To a stirred solution of compound 9 (50 mg, 0.095 mmol, 1.0 eq) in dry MeOH (3.6 mL) was added PTSA (54 mg, 0.28 mmol, 3 eq) and 4A molecular sieve (72 mg). The reaction mixture was stirred at 135°C for 10 h. After cooling to room tempreature, the solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H 2 O, 0.1 % TFA) to give compound A29 (18 mg, 47%). Calcd. (M+H) + m/z: 404.2, Found (M+H) + m/z: 404.3 Compound A30.
  • Step 2 [0432] To a stirred solution of compound 3 (189 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h.
  • Step 8 [0433] To a stirred solution of compound 4 (64 mg, 0.095 mmol, 1.0 eq) in dry MeOH (3.6 mL) was added PTSA (54 mg, 0.28 mmol, 3 eq) and 4A molecular sieve (72 mg). The reaction mixture was stirred at 135°C for 10 h. After cooling to room tempreature, the solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H 2 O, 0.1 % TFA) to give compound A30 (15.9 mg, 41%).
  • Step 2 To a mixture of 2 (1.2 g, 1 eq) in methanol (50 mL) was added 10% Pd/C (200 mg). The mixture was stirred at 20 o C for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction.
  • Step 3 To a mixture of 3 (760 mg, 1 eq, 2.2 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.41 g, 2 eq, 4.5 mmol) and 2-chloro-6-fluorobenzonitrile (27 mg, 1.2 eq, 174 ⁇ mol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum.
  • Step 4 To a mixture of 4 (634 mg, 1 eq, 1.3 mmol) in DMSO (5.00 mL) was added potassium carbonate (366 mg, 2 eq, 2.6 mmol) at 0 o C then added hydrogen peroxide (2.3 167 282341894 v2 PRSC-068/001WO (343170-2269) mL). The mixture was stirred at 40 °C for 10 h.
  • Step 5 To a mixture of 5 (0.351 g, 1 eq, 0.71 mmol) in tolene (20 mL) was added PTSA (0.405 g, 3 eq) and molecular sieve (650 mg). The reaction mixture was refluxed for 8 h.
  • Step 6 To a solution of (methoxymethyl)triphenylphosphonium (58 mg, 0.17 mmol, 1.5 eq) in dry THF/HMPA (10/1, 3 mL) was added t BuOK (1 M in THF, 0.17 mL, 0.17 mmol, 1.5 eq).
  • Step 1 To a mixture 1 (5.00 g, 1 eq, 23.6 mmol) in 1,4-dioxane (50.0 mL) and water (10 mL), was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.73 g, 0.1 eq, 2.36 mmol), sodium carbonate (7.50 g, 3 eq, 70.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2 (10.9 g, 1.5 eq, 3
  • Step 2 To a mixture of 3 (6.70 g, 1 eq, 21.3 mmol) in methanol (50 mL) was added 10% Pd/C (1.13 g, 0.05 eq, 1.07 mmol). The mixture was stirred at 20 o C for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction.
  • Step 3 To a mixture of 4 (0.30 g, 1 eq, 0.95 mmol) and TMEDA (0.33 g, 3 eq, 2.8 mmol) in THF (10 mL) at -78 °C was added n-butyllithium (0.17 mL, 2 eq, 1.9 mmol) dropwise slowly at -78 °C, after 30 minutes, MeI (0.12 mL, 2 eq, 1.9 mmol) was added then stirred at -78 °C for 3 h.
  • Step 4 To a mixture of 5 (50.0 mg, 1 eq, 145 ⁇ mol) in acetonitrile (5 mL) was added cesium carbonate (142 mg, 3 eq, 435 ⁇ mol) and 2-chloro-6-fluorobenzonitrile 6 (27 mg, 1.2 eq, 174 ⁇ mol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum.
  • Step 5 To a mixture of 7 (50 mg, 1 eq, 104 ⁇ mol) in DMSO (5.00 mL) was added potassium carbonate (43.2 mg, 3 eq, 313 ⁇ mol) at 0 o C then added hydrogen peroxide (35.4 mg, 31.9 ⁇ L, 10 eq, 1.04 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2).
  • Step 6 To a mixture of 8 (0.199 g, 1 eq, 0.40 mmol) in tolene (4.5 mL) was added PTSA (0.11 g, 3 eq) and molecular sieve (50 mg). The reaction mixture was refluxed for 12 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated in vacuum.
  • the mixture was stirred at 80 °C for 2 h.
  • the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2).
  • the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum.
  • reaction was stirred at 80 °C for 16 hours under N 2 .
  • LCMS indicated completion of reaction.
  • the reaction mixture was concentrated under vacuum, poured into water (100 mL), extracted with ethyl acetate (50 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum.
  • LCMS indicated completion of reaction.
  • the recation was poured into water (100 mL), extracted with EA (50 mL X 3). The combined organic layers were washed brine (20 mL X 3), dried over anhydrous sodium sulfate, filtered and concerntrated under vacuum to give tert-butyl (tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)piperidine-1-carboxylate (50 mg, 81.5 ⁇ mol, 96.41%) as a white solid.
  • reaction mixture was stirred at 80 °C for 16 h. LCMS showed the reaction was complete.
  • the reaction was diluted with EA 210 282341894 v2 PRSC-068/001WO (343170-2269) (100 mL) and washed with water (200 mL). The EA layer was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • reaction mixture was stirred at 80 °C for 2 h.
  • LCMS indicated completion of reaction.
  • the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum.
  • Bio-Layer Interferometry (BLI) assays were performed using an OctetRED96 instrument from PALL/ForteBio. All assays were run at 30 °C with continuous 1000 RPM shaking. PBS with 0.1% BSA, 0.01% Tween-20 and 2% DMSO was used as the assay buffer.
  • Biotinylated DCN1 protein was tethered on Super Streptavidin (SSA) biosensors (ForteBio) by dipping sensors into 50 ⁇ g/mL protein solutions. Average saturation response level of 4-5 nm was achieved in 15 minutes.
  • SSA Super Streptavidin
  • Biotinylated blocked Super Streptavidin (SSA) biosensors were prepared as well by following the protocol provided by the manufacturer which were used as the inactive reference controls. Sensors with proteins tethered were washed in assay buffer for 10 minutes to eliminate loose nonspecific bound protein molecules and establish stable base line before starting association-dissociation cycles of compound. Different association 244 282341894 v2 PRSC-068/001WO (343170-2269) and dissociation times were used depending on the potencies of compounds being tested. DMSO only reference was included in all assays. Raw kinetic data collected were processed in the Data Analysis software provided by the manufacturer using double reference subtraction in which both DMSO only reference and inactive protein reference were subtracted.
  • bromodomain ligand 2 (peptide histone H3; sequence: ARTKQTARKSTGGKAPRKQLA (Ala-Arg-Thr-Lys-Gln-Thr- Ala-Arg-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-Lys-Gln-Leu-Ala)) for SMARCA4 or 90-fold diluted bromodomain ligand 2 for SMARCA2 was added followed by addition of diluted terbium 246 282341894 v2 PRSC-068/001WO (343170-2269) (Tb)-labeled donor and 5 uL of diluted dye-labeled acceptor (BPS Biosciences cat# 40341).
  • reaction was stirred at 25 °C for 2 hours.
  • LCMS indicated completion of reaction.
  • the reaction was pouried into water (30.0 mL) and extated with EA (50.0 mL), then washed with brine (30.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum.
  • reaction was extracted with EtOAc (20.0 mL X 3) and the combined organic layers were washed with water (20.0 mL X 3) and washed with brine (20.0 mL) dried over sodium sulfate, filtered and concentrated under vacuum.

Abstract

Described herein are compounds and conjugates of Formula II and their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as their uses (e.g., as SMARCA2 or SMARCA4 inhibitors or degraders).

Description

PRSC-068/001WO (343170-2269) COMPOUNDS AND COMPOSITIONS AS SMARCA2/4 INHIBITORS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/409,244, filed September 23, 2022; U.S. Provisional Application No. 63/476,581, filed December 21, 2022; and U.S. Provisional Application No. 63/460,719, filed April 20, 2023, the contents of each of which are incorporated herein by reference in their entireties. BACKGROUND [0002] Chromatin is a complex combination of DNA and protein that makes up chromosomes. Chromatin functions to package, strengthen, and control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications, most commonly within the "histone tails" which extend beyond the core nucleosome structure. These epigenetic modifications including acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation, are then interpreted by the cell to allow gene-specific regulation of chromatin structure and thereby transcription. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues. [0003] Bromodomains, which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs. Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. [0004] Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains 1 282341894 v2 PRSC-068/001WO (343170-2269) reside within key chromatin-modifying complexes that serve to control distinctive disease- associated transcriptional pathways. An example of such a complex is the switch/sucrose nonfermenting (“SWI/SNF”) chromatin-remodeling complex, which has been reported to be involved in gene regulation, cell lineage specification and development, and comprises a number of bromodomain containing subunits, including SWI/SNF-related matrix-associated actin- dependent regulator of chromatin subfamily A members 2 and 4 (SMARCA2 and SMARCA4) and polybromo-1 (PB1). [0005] An ongoing need exists in the art for effective treatments for disease, especially hyperplasia and cancers, e.g., lung cancer. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that modulate or inhibit the activity of target cancer-associated proteins such as SMARCA2, SMARCA4, and PB1 hold promise as therapeutic agents. Accordingly, there remains a need to find compounds that target these proteins and are useful as therapeutic agents. SUMMARY [0006] In certain aspects, the present disclosure provides compounds or conjguates of Formula II: , and pharmaceutically acceptable
Figure imgf000003_0001
thereof, wherein each of the variables in Formulae II is described, embodied, and exemplified herein. [0007] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient. [0008] In certain aspects, the present disclosure provides methods of inhibiting a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein. 2 282341894 v2 PRSC-068/001WO (343170-2269) [0009] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a SMARCA2 or SMARCA4 protein in a subject. [0010] In certain aspects, the present discloure provides compounds disclosed herein for use in inhibiting a SMARCA2 or SMARCA4 protein in a subject. [0011] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a conjugate disclosed herein. [0012] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a subject. [0013] In certain aspects, the present discloure provides conjugates disclosed herein for use in degrading a SMARCA2 or SMARCA4 protein in a subject. [0014] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount). [0015] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0016] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. [0017] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a conjugate disclosed herein (e.g., in a therapeutically effective amount). [0018] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0019] In certain aspects, the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. DETAILED DESCRIPTION [0020] The present disclosure relates to compounds and compositions that are useful as SMARCA2 or SMARCA4 protein inhibitors. The present disclosure also relates to methods of 3 282341894 v2 PRSC-068/001WO (343170-2269) inhibiting a SMARCA2 or SMARCA4 protein comprising contacting the SMARCA2 or SMARCA4 protein with a SMARCA2 or SMARCA4 protein inhibitor disclosed herein. The invention also relates to methods of treating a SMARCA2 or SMARCA4 protein-mediated disease or condition in a subject in need thereof by administering (e.g., in a therapeutically effective amount) a SMARCA2 or SMARCA4 protein inhibitor disclosed herein. The invention further relates to methods of treating a SMARCA2 or SMARCA4 protein-mediated disease or condition in a subject in need thereof, comprising administering (e.g., in a therapeutically effective amount) a pharmaceutical composition comprising an amount of a SMARCA2 or SMARCA4 protein inhibitor disclosed herein. Compounds of the Application SMARCA2/4 Inhibitors [0021] In certain aspects, the present disclosure provides compounds of Formula II: , and pharmaceutically acceptable
Figure imgf000005_0001
thereof, A1 is CRA1 or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - - -
Figure imgf000005_0002
carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; 4 282341894 v2 PRSC-068/001WO (343170-2269) each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000006_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - 5 282341894 v2 PRSC-068/001WO (343170-2269) S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or one of RE2, RE3, or RE4 is , wherein:
Figure imgf000007_0001
Ring F is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected 6 282341894 v2 PRSC-068/001WO (343170-2269) from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0022] In certain aspects, the present disclosure provides compounds of Formula II: , and pharmaceutically acceptable
Figure imgf000008_0001
thereof, wherein: A1 is CRA1 or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered 7 282341894 v2 PRSC-068/001WO (343170-2269) heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000009_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - - -
Figure imgf000009_0002
heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; 8 282341894 v2 PRSC-068/001WO (343170-2269) E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, or RE2, RE3, or RE4 is ; wherein:
Figure imgf000010_0001
Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - 9 282341894 v2 PRSC-068/001WO (343170-2269) NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0023] In certain aspects, the present disclosure provides compounds of Formula II: , and pharmaceutically acceptable
Figure imgf000011_0001
thereof, wherein: A1 is CRA1 or N; A2 is CRA2 or N; 10 282341894 v2 PRSC-068/001WO (343170-2269) A3 is CRA3 or N; A4 is CRA4 or N; RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl,-SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl,-SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C
Figure imgf000012_0001
3-12 carbocycle or 3- to 12- each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl,-SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, 11 282341894 v2 PRSC-068/001WO (343170-2269) alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl,-SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; 12 282341894 v2 PRSC-068/001WO (343170-2269) each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0024] In certain embodiments, 1) the compound is not 2) when
Figure imgf000014_0001
i) RA1 is hydrogen; and ii) E1 is CRE1, E2 is CRE2, E3 is CRE3, and E4 is CRE4; wherein RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy, then i) RC are not both optionally substituted phenyl; and ii) when one RC is optionally substituted thiophenyl, then the other RC is not optionally substituted phenyl. [0025] In certain embodiments, when two RC form an oxo, then at least one of Ring A and Ring E is substituted aryl or optionally substituted heteroaryl. [0026] In certain embodiments, the compound is a compound of Formula II-1 or II-2 13 282341894 v2 PRSC-068/001WO (343170-2269) 2), or a
Figure imgf000015_0001
each RC is - - - - 6 C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0027] The compound of claim 1, wherein the compound is a compound of Formula II-1’ or II-2’ , or a
Figure imgf000015_0002
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0028] In certain aspects, the present disclosure provides compounds of Formula II 14 282341894 v2 PRSC-068/001WO (343170-2269) or a pharmaceutically acceptable thereof, wherein 1 A1
Figure imgf000016_0001
A is CR or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - - -
Figure imgf000016_0002
carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - 15 282341894 v2 PRSC-068/001WO (343170-2269) OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000017_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or 16 282341894 v2 PRSC-068/001WO (343170-2269) one of RE2, RE3, or RE4 is ; wherein:
Figure imgf000018_0001
Ring F is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - - -
Figure imgf000018_0002
heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; 17 282341894 v2 PRSC-068/001WO (343170-2269) each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0029] In certain aspects, the present disclosure provides compounds of Formula II or a pharmaceutically acceptable
Figure imgf000019_0001
thereof, wherein A1 is CRA1 or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; 18 282341894 v2 PRSC-068/001WO (343170-2269) RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C carbocycle or 3- t
Figure imgf000020_0001
3-12 o 12- each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; 19 282341894 v2 PRSC-068/001WO (343170-2269) d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - - -
Figure imgf000021_0001
carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or RE2, RE3, or RE4 is ; wherein:
Figure imgf000021_0002
Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - - -
Figure imgf000021_0003
heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, wherein: 20 282341894 v2 PRSC-068/001WO (343170-2269) each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0030] In certain embodiments, the compound is a compound of Formula II-1-i, II-1-ii, II-1-iii, II-2-i, II-2-ii, or II-2-iii 21 282341894 v2 PRSC-068/001WO (343170-2269) i), , or a
Figure imgf000023_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. In certain embodiments, the compound is a compound of Formula II-1-iv, II-1-v, II-1-vi, II-2-iv, II-2-v, or II-2-vi 22 282341894 v2 PRSC-068/001WO (343170-2269) , , or
Figure imgf000024_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and RA1 is halogen. [0032] In certain embodiments, A1 is CRA1 or N. In certain embodiments, A1 is N. In certain embodiments, A1 is CRA1. [0033] In certain embodiments, A2 is CRA2 or N. In certain embodiments, A2 is N. In certain embodiments, A2 is CRA2. [0034] In certain embodiments, A3 is CRA3 or N. In certain embodiments, A3 is N. In certain embodiments, A3 is CRA3. 23 282341894 v2 PRSC-068/001WO (343170-2269) [0035] In certain embodiments, A4 is CRA4 or N. In certain embodiments, A4 is N. In certain embodiments, A4 is CRA4. [0036] In certain embodiments, none of A1, A2, A3, and A4 is N. In certain embodiments, one of A1, A2, A3, and A4 is N. In certain embodiments, two of A1, A2, A3, and A4 are N. In certain embodiments, three of A1, A2, A3, and A4 are N. In certain embodiments, each of A1, A2, A3, and A4 is N. [0037] In certain embodiments, A1 is CRA1, and none of A2, A3, and A4 is N (i.e., A1 is CRA1, A2 is CRA2; A3 is CRA3; and A4 is CRA4). In certain embodiments, A1 is CRA1, and one of A2, A3, and A4 is N. In certain embodiments, A1 is CRA1, and two of A2, A3, and A4 are N. In certain embodiments, A1 is CRA1, and each of A2, A3, and A4 is N. [0038] In certain embodiments, A1 is CRA1, A3 is CRA3, and one of A2 and A4 is N. In certain embodiments, A1 is CRA1, A3 is CRA3, and each of A2 and A4 is N. [0039] In certain embodiments, RA1, RA2, RA3, and RA4, when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl- i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl- n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), 24 282341894 v2 PRSC-068/001WO (343170-2269) cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0040] In certain embodiments, RA1, RA2, RA3, and RA4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0041] In certain embodiments, RA1, RA2, RA3, and RA4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0042] In certain embodiments, RA1, RA2, RA3, and RA4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0043] In certain embodiments, RA1, RA2, RA3, and RA4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 25 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0044] In certain embodiments, RA1 is halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di- i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n- butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t- butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the 26 282341894 v2 PRSC-068/001WO (343170-2269) alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0045] In certain embodiments, RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0046] In certain embodiments, RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0047] In certain embodiments, RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0048] In certain embodiments, RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0049] In certain embodiments, RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0050] In certain embodiments, RA1 is halogen, -CN, -OH, -NH2, C1-6 alkyl, or -C(=O)NRcRd. [0051] In certain embodiments, RA1 is halogen. [0052] In certain embodiments, RA1 is not hydrogen. [0053] In certain embodiments, RA1 is hydrogen. In certain embodiments, RA1 is halogen, -CN, - OH, -NH2, or C1-6 alkyl. In certain embodiments, RA1 is halogen. In certain embodiments, RA1 is - CN. In certain embodiments, RA1 is -OH. In certain embodiments, RA1 is -NH2. In certain embodiments, RA1 is C1-6 alkyl. In certain embodiments, RA2 is hydrogen. In certain embodiments, RA3 is hydrogen. In certain embodiments, RA4 is hydrogen. 27 282341894 v2 PRSC-068/001WO (343170-2269) [0054] In certain embodiments, each RC is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t- butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, 28 282341894 v2 PRSC-068/001WO (343170-2269) alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0055] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0056] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0057] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0058] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0059] In certain embodiments, each RC is independently C1-6 alkyl optionally substituted with one or more Ru. In certain embodiments, at least one RC is C1-6 alkyl optionally substituted with one or more Ru. [0060] In certain embodiments, two RC together form an oxo. [0061] In certain embodiments, two RC, together with the carbon atom to which they are attached, form Ring D .
Figure imgf000030_0001
29 282341894 v2 PRSC-068/001WO (343170-2269) [0062] In certain embodiments, Ring D is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0063] In certain embodiments, each RD is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or 30 282341894 v2 PRSC-068/001WO (343170-2269) two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0064] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0065] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0066] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0067] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0068] In certain embodiments, each RD is independently oxo, halogen, -OH, C1-6 alkylamino, or -NRbC(=O)Ra. In certain embodiments, each RD is independently oxo, halogen, or -OH. In certain embodiments, at least one RD is oxo. In certain embodiments, at least one RD is halogen. In certain embodiments, at least one RD is -OH. 31 282341894 v2 PRSC-068/001WO (343170-2269) [0069] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, d is 6. In certain embodiments, d is 7. In certain embodiments, d is 8. In certain embodiments, d is 9. In certain embodiments, d is 10. [0070] In certain embodiments, E1 is CRE1 or N. In certain embodiments, E1 is N. In certain embodiments, E1 is CRE1. [0071] In certain embodiments, E2 is CRE2 or N. In certain embodiments, E2 is N. In certain embodiments, E2 is CRE2. [0072] In certain embodiments, E3 is CRE3 or N. In certain embodiments, E3 is N. In certain embodiments, E3 is CRE3. [0073] In certain embodiments, E4 is CRE4 or N. In certain embodiments, E4 is N. In certain embodiments, E4 is CRE4. [0074] In certain embodiments, none of E1, E2, E3, and E4 is N. In certain embodiments, one of E1, E2, E3, and E4 is N. In certain embodiments, two of E1, E2, E3, and E4 are N. In certain embodiments, three of E1, E2, E3, and E4 are N. In certain embodiments, each of E1, E2, E3, and E4 is N. [0075] In certain embodiments, one or two of E1, E2, E3, and E4 is N. [0076] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl- i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl- n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino,
Figure imgf000033_0001
s- 32 282341894 v2 PRSC-068/001WO (343170-2269) butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0077] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0078] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0079] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, 33 282341894 v2 PRSC-068/001WO (343170-2269) alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0080] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0081] In certain embodiments, RE1, RE2, RE3, and RE4, when applicable, are independently hydrogen or halogen. [0082] In certain embodiments, RE1 is hydrogen. In certain embodiments, RE2 is hydrogen. In certain embodiments, RE3 is hydrogen. In certain embodiments, RE4 is hydrogen. [0083] In certain embodiments, RE2, RE3, or RE4 is . [0084] In certain embodiments, none
Figure imgf000035_0001
none of E1, E2, and E4, or none of E1, E2, and E3 is N. [0085] In certain embodiments, one of E1, E3, and E4, one of E1, E2, and E4, or one of E1, E2, and E3 is N. [0086] In certain embodiments, two of E1, E3, and E4, two of E1, E2, and E4, or two of E1, E2, and E3 are N. [0087] In certain embodiments, each of E1, E3, and E4, each of E1, E2, and E4, or each of E1, E2, and E3 is N. [0088] In certain embodiments, RE3 is one or two of E1, E2, and E4 are N.
Figure imgf000035_0002
[0089] In certain embodiments, RE2 is 282341894 v2
Figure imgf000035_0003
PRSC-068/001WO (343170-2269) one or two of E1, E3, and E4 are N. [0090] In certain embodiments, Ring F is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S). [0091] In certain embodiments, Ring F is C5-10 carbocyclyl or 5- to 10-membered heterocyclyl. [0092] In certain embodiments, Ring F is cyclohexyl, piperidinyl, 2,7-diazaspiro[3.5]nonanyl, 3,9- diazaspiro[5.5]undecanyl, or 2-azaspiro[3.5]nonanyl. [0093] In certain embodiments, each RF is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl 35 282341894 v2 PRSC-068/001WO (343170-2269) (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0094] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0095] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0096] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0097] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, 36 282341894 v2 PRSC-068/001WO (343170-2269) wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru. [0098] In certain embodiments, each RF is independently oxo, C1-6 alkyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)ORb, or -C(=O)Rb, wherein the alkyl is optionally substituted with one or more -NH2, C1-6 alkylamino, or 3- to 12-membered heterocyclyl. In certain embodiments, Rb is hydrogen or 3- to 12-membered heterocyclyl. [0099] In certain embodiments, f is 0. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, f is 7. In certain embodiments, f is 8. In certain embodiments, f is 9. In certain embodiments, f is 10. [0100] In certain aspects, the present disclosure provides compounds of Formula I: , and pharmaceutically acceptable
Figure imgf000038_0001
thereof, wherein: X1 is CRX1 or N; X2 is CRX2 or N; X3 is CRX3 or N; X4 is CRX4 or N; RX1, RX2, RX3, and RX4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; 37 282341894 v2 PRSC-068/001WO (343170-2269) each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000039_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; Y1 is CRY1 or N; Y2 is CRY2 or N; Y3 is CRY3 or N; Y4 is CRY4 or N; and RY1, RY2, RY3, and RY4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - 38 282341894 v2 PRSC-068/001WO (343170-2269) NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 39 282341894 v2 PRSC-068/001WO (343170-2269) [0101] In certain embodiments, 1) the compound is not
Figure imgf000041_0001
2) when i) RX1 is hydrogen; and ii) Y1 is CRY1, Y2 is CRY2, Y3 is CRY3, and Y4 is CRY4; RY1, RY2, RY3, and RY4 are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy, then i) RC are not both optionally substituted phenyl; and ii) when one RC is optionally substituted thiophenyl, then other RC is not optionally substituted phenyl. [0102] In certain embodiments, when two RC form an oxo, then at least one of Ring A and Ring E is substituted aryl or optionally substituted heteroaryl. [0103] In certain embodiments, the compound is a compound of Formula I-1 or I-2 2), or a
Figure imgf000041_0002
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0104] In certain embodiments, the compound is a compound of Formula I-1’ or I-2’ 40 282341894 v2 PRSC-068/001WO (343170-2269) , or a C
Figure imgf000042_0001
each R is - - - - 6 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and RX1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0105] In certain embodiments, RX1 is halogen. [0106] In certain embodiments, RY1, RY2, RY3, and RY4 are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0107] In certain embodiments, two of Y1, Y2, Y3, and Y4 is N. In certain embodiments, one of Y1, Y2, Y3, and Y4 are N. [0108] In certain embodiments, two or three of RY1, RY2, RY3, and RY4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0109] In certain embodiments, two or three of RY1, RY2, RY3, and RY4 are hydrogen. [0110] In certain embodiments, at least one of RY2 and RY3 Ring F, wherein Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle optionally substituted with one or more RF. 41 282341894 v2 PRSC-068/001WO (343170-2269) [0111] In certain embodiments, the compound is a compound of Formula I-1-i, I-1-ii, I-2-i, or I- 2-ii , ii), or a
Figure imgf000043_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - - -
Figure imgf000043_0002
heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and p is an integer selected from 0 to 10, as valency permits. 42 282341894 v2 PRSC-068/001WO (343170-2269) [0112] In certain embodiments, RX1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0113] In certain embodiments, RX1 is halogen. [0114] In certain embodiments, the compound is a compound of Formula I-1-iii, I-1-iv, I-2-iii, or I-2-iv , , or
Figure imgf000044_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and RX1 is halogen. [0115] In certain embodiments, Ring F is 3-membered heterocyclyl. In certain embodiments, Ring F is 4-membered heterocyclyl. In certain embodiments, Ring F is 5-membered heterocyclyl. In certain embodiments, Ring F is 6-membered heterocyclyl. In certain embodiments, Ring F is 7- membered heterocyclyl. In certain embodiments, Ring F is 8-membered heterocyclyl. In certain 43 282341894 v2 PRSC-068/001WO (343170-2269) embodiments, Ring F is 9-membered heterocyclyl. In certain embodiments, Ring F is 10- membered heterocyclyl. In certain embodiments, Ring F is 11-membered heterocyclyl. In certain embodiments, Ring F is 12-membered heterocyclyl. [0116] In certain embodiments, Ring F is 3- to 12-membered heterocyclyl. In certain embodiments, Ring F is 3- to 11-membered heterocyclyl. In certain embodiments, Ring F is 3- to 10-membered heterocyclyl. In certain embodiments, Ring F is 3- to 9-membered heterocyclyl. In certain embodiments, Ring F is 3- to 8-membered heterocyclyl. In certain embodiments, Ring F is 3- to 7-membered heterocyclyl. In certain embodiments, Ring F is 3- to 6-membered heterocyclyl. In certain embodiments, Ring F is 3- to 5-membered heterocyclyl. In certain embodiments, Ring F is 3- to 4-membered heterocyclyl. In certain embodiments, Ring F is 4- to 12-membered heterocyclyl. In certain embodiments, Ring F is 4- to 11-membered heterocyclyl. In certain embodiments, Ring F is 4- to 10-membered heterocyclyl. In certain embodiments, Ring F is 4- to 9-membered heterocyclyl. In certain embodiments, Ring F is 4- to 8-membered heterocyclyl. In certain embodiments, Ring F is 4- to 7-membered heterocyclyl. In certain embodiments, Ring F is 4- to 6-membered heterocyclyl. In certain embodiments, Ring F is 4- to 5-membered heterocyclyl. In certain embodiments, Ring F is 5- to 12-membered heterocyclyl. In certain embodiments, Ring F is 5- to 11-membered heterocyclyl. In certain embodiments, Ring F is 5- to 10-membered heterocyclyl. In certain embodiments, Ring F is 5- to 9-membered heterocyclyl. In certain embodiments, Ring F is 5- to 8-membered heterocyclyl. In certain embodiments, Ring F is 5- to 7-membered heterocyclyl. In certain embodiments, Ring F is 5- to 6-membered heterocyclyl. In certain embodiments, Ring F is 6- to 12-membered heterocyclyl. In certain embodiments, Ring F is 6- to 11-membered heterocyclyl. In certain embodiments, Ring F is 6- to 10-membered heterocyclyl. In certain embodiments, Ring F is 6- to 9-membered heterocyclyl. In certain embodiments, Ring F is 6- to 8-membered heterocyclyl. In certain embodiments, Ring F is 6- to 7-membered heterocyclyl. In certain embodiments, Ring F is 8- to 12-membered heterocyclyl. In certain embodiments, Ring F is 8- to 11-membered heterocyclyl. In certain embodiments, Ring F is 8- to 10-membered heterocyclyl. In certain embodiments, Ring F is 8- to 9-membered heterocyclyl. In certain embodiments, Ring F is 9- to 12-membered heterocyclyl. In certain embodiments, Ring F is 9- to 11-membered heterocyclyl. In certain embodiments, Ring F is 9- to 10-membered heterocyclyl. In certain embodiments, Ring F is 10- to 12-membered heterocyclyl. 44 282341894 v2 PRSC-068/001WO (343170-2269) In certain embodiments, Ring F is 10- to 11-membered heterocyclyl. In certain embodiments, Ring F is 11- to 12-membered heterocyclyl. [0117] In certain embodiments, Ring F is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0118] In certain embodiments, Ring F is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring F is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0119] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0120] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9. In certain embodiments, p is 10. [0121] In certain embodiments, RY1, RY2, and RY4 or RY1, RY3, and RY4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 45 282341894 v2 PRSC-068/001WO (343170-2269) [0122] In certain embodiments, each of RY1, RY2, and RY4 or each of RY1, RY3, and RY4 is hydrogen. [0123] In certain embodiments, one or two of Y1, Y2, and Y4 or one or two of Y1, Y3, and Y4 is N. [0124] In certain embodiments, one or two of RY1, RY2, and RY4 or one or two of RY1, RY3, and RY4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0125] In certain embodiments, one or two of RY1, RY2, and RY4 or one or two of RY1, RY3, and RY4 are hydrogen. [0126] In certain embodiments, each of RX2, RX3, and RX4 is independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0127] In certain embodiments, each of RX2, RX3, and RX4 is hydrogen. [0128] In certain embodiments, Ring D is 3-membered heterocyclyl. In certain embodiments, Ring D is 4-membered heterocyclyl. In certain embodiments, Ring D is 5-membered heterocyclyl. In certain embodiments, Ring D is 6-membered heterocyclyl. In certain embodiments, Ring D is 7- membered heterocyclyl. In certain embodiments, Ring D is 8-membered heterocyclyl. In certain embodiments, Ring D is 9-membered heterocyclyl. In certain embodiments, Ring D is 10- membered heterocyclyl. In certain embodiments, Ring D is 11-membered heterocyclyl. In certain embodiments, Ring D is 12-membered heterocyclyl. [0129] In certain embodiments, Ring D is 3- to 12-membered heterocyclyl. In certain embodiments, Ring D is 3- to 11-membered heterocyclyl. In certain embodiments, Ring D is 3- to 10-membered heterocyclyl. In certain embodiments, Ring D is 3- to 9-membered heterocyclyl. In certain embodiments, Ring D is 3- to 8-membered heterocyclyl. In certain embodiments, Ring D is 3- to 7-membered heterocyclyl. In certain embodiments, Ring D is 3- to 6-membered heterocyclyl. In certain embodiments, Ring D is 3- to 5-membered heterocyclyl. In certain embodiments, Ring D is 3- to 4-membered heterocyclyl. In certain embodiments, Ring D is 4- to 12-membered heterocyclyl. In certain embodiments, Ring D is 4- to 11-membered heterocyclyl. 46 282341894 v2 PRSC-068/001WO (343170-2269) In certain embodiments, Ring D is 4- to 10-membered heterocyclyl. In certain embodiments, Ring D is 4- to 9-membered heterocyclyl. In certain embodiments, Ring D is 4- to 8-membered heterocyclyl. In certain embodiments, Ring D is 4- to 7-membered heterocyclyl. In certain embodiments, Ring D is 4- to 6-membered heterocyclyl. In certain embodiments, Ring D is 4- to 5-membered heterocyclyl. In certain embodiments, Ring D is 5- to 12-membered heterocyclyl. In certain embodiments, Ring D is 5- to 11-membered heterocyclyl. In certain embodiments, Ring D is 5- to 10-membered heterocyclyl. In certain embodiments, Ring D is 5- to 9-membered heterocyclyl. In certain embodiments, Ring D is 5- to 8-membered heterocyclyl. In certain embodiments, Ring D is 5- to 7-membered heterocyclyl. In certain embodiments, Ring D is 5- to 6-membered heterocyclyl. In certain embodiments, Ring D is 6- to 12-membered heterocyclyl. In certain embodiments, Ring D is 6- to 11-membered heterocyclyl. In certain embodiments, Ring D is 6- to 10-membered heterocyclyl. In certain embodiments, Ring D is 6- to 9-membered heterocyclyl. In certain embodiments, Ring D is 6- to 8-membered heterocyclyl. In certain embodiments, Ring D is 6- to 7-membered heterocyclyl. In certain embodiments, Ring D is 8- to 12-membered heterocyclyl. In certain embodiments, Ring D is 8- to 11-membered heterocyclyl. In certain embodiments, Ring D is 8- to 10-membered heterocyclyl. In certain embodiments, Ring D is 8- to 9-membered heterocyclyl. In certain embodiments, Ring D is 9- to 12-membered heterocyclyl. In certain embodiments, Ring D is 9- to 11-membered heterocyclyl. In certain embodiments, Ring D is 9- to 10-membered heterocyclyl. In certain embodiments, Ring D is 10- to 12-membered heterocyclyl. In certain embodiments, Ring D is 10- to 11-membered heterocyclyl. In certain embodiments, Ring D is 11- to 12-membered heterocyclyl. [0130] In certain embodiments, Ring D is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0131] In certain embodiments, Ring D is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain 47 282341894 v2 PRSC-068/001WO (343170-2269) embodiments, Ring D is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring D is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0132] In certain embodiments, Ring D is C3 carbocyclyl. In certain embodiments, Ring D is C4 carbocyclyl. In certain embodiments, Ring D is C5 carbocyclyl. In certain embodiments, Ring D is C6 carbocyclyl. In certain embodiments, Ring D is C7 carbocyclyl. In certain embodiments, Ring D is C8 carbocyclyl. In certain embodiments, Ring D is C9 carbocyclyl. In certain embodiments, Ring D is C10 carbocyclyl. In certain embodiments, Ring D is C11 carbocyclyl. In certain embodiments, Ring D is C12 carbocyclyl. [0133] In certain embodiments, Ring D is C3-12 carbocyclyl. In certain embodiments, Ring D is C3- 11 carbocyclyl. In certain embodiments, Ring D is C3-10 carbocyclyl. In certain embodiments, Ring D is C3-9 carbocyclyl. In certain embodiments, Ring D is C3-8 carbocyclyl. In certain embodiments, Ring D is C3-7 carbocyclyl. In certain embodiments, Ring D is C3-6 carbocyclyl. In certain embodiments, Ring D is C3-5 carbocyclyl. In certain embodiments, Ring D is C3-4 carbocyclyl. In certain embodiments, Ring D is C4-12 carbocyclyl. In certain embodiments, Ring D is C4-11 carbocyclyl. In certain embodiments, Ring D is C4-10 carbocyclyl. In certain embodiments, Ring D is C4-9 carbocyclyl. In certain embodiments, Ring D is C4-8 carbocyclyl. In certain embodiments, Ring D is C4-7 carbocyclyl. In certain embodiments, Ring D is C4-6 carbocyclyl. In certain embodiments, Ring D is C4-5 carbocyclyl. In certain embodiments, Ring D is C5-12 carbocyclyl. In certain embodiments, Ring D is C5-11 carbocyclyl. In certain embodiments, Ring D is C5-10 carbocyclyl. In certain embodiments, Ring D is C5-9 carbocyclyl. In certain embodiments, Ring D is C5-8 carbocyclyl. In certain embodiments, Ring D is C5-7 carbocyclyl. In certain embodiments, Ring D is C5-6 carbocyclyl. In certain embodiments, Ring D is C6-12 carbocyclyl. In certain embodiments, Ring D is C6-11 carbocyclyl. In certain embodiments, Ring D is C6-10 carbocyclyl. In certain embodiments, Ring D is C6-9 carbocyclyl. In certain embodiments, Ring D is C6-8 carbocyclyl. In certain embodiments, Ring D is C6-7 carbocyclyl. In certain embodiments, Ring D is C7-12 carbocyclyl. In certain embodiments, Ring D is C7-11 carbocyclyl. In certain embodiments, Ring D is C7-10 carbocyclyl. In certain embodiments, Ring D is C7-9 carbocyclyl. In certain embodiments, Ring D is C7-8 carbocyclyl. In certain embodiments, Ring D is C8-12 carbocyclyl. In certain embodiments, Ring D is C8-11 carbocyclyl. In certain embodiments, Ring D is C8-10 48 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl. In certain embodiments, Ring D is C8-9 carbocyclyl. In certain embodiments, Ring D is C9-12 carbocyclyl. In certain embodiments, Ring D is C9-11 carbocyclyl. In certain embodiments, Ring D is C9-10 carbocyclyl. In certain embodiments, Ring D is C10-12 carbocyclyl. In certain embodiments, Ring D is C10-11 carbocyclyl. In certain embodiments, Ring D is C11-12 carbocyclyl. [0134] In certain embodiments, Ring D is C4-12 carbocycle and 3- to 12-membered heterocycle. [0135] In certain embodiments, Ring D is C4-12 carbocycle. [0136] In certain embodiments, Ring D is C5-7 carbocycle. [0137] In certain embodiments, Ring D is 3- to 12-membered heterocycle. [0138] In certain embodiments, Ring D is 5- to 7-membered heterocycle. [0139] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0140] In certain embodiments, each RD is independently oxo, halogen, or -OH. [0141] In certain embodiments, at least one RD is oxo. In certain embodiments, at least one RD is halogen. In certain embodiments, at least one RD is -OH. [0142] In certain embodiments, at least one RD is oxo. In certain embodiments, at least one RD is halogen. In certain embodiments, at least one RD is -OH. [0143] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [0144] In certain embodiments, m is 0 or 1. [0145] In certain embodiments, two RC form an oxo. [0146] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0147] In certain embodiments, at least one RC is C1-6 alkyl. 49 282341894 v2 PRSC-068/001WO (343170-2269) [0148] In certain embodiments, each of RC is C1-6 alkyl. [0149] In certain embodiments, at least one RC is methyl. [0150] In certain embodiments, each of RC is methyl. [0151] In certain embodiments, each Ra is independently C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2- butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0152] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0153] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0154] In certain embodiments, each Ra is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0155] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), 50 282341894 v2 PRSC-068/001WO (343170-2269) or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0156] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0157] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0158] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0159] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- 51 282341894 v2 PRSC-068/001WO (343170-2269) membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0160] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru. [0161] In certain embodiments, Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more Ru. [0162] In certain embodiments, Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz. [0163] In certain embodiments, Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0164] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di- i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n- butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t- butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl 52 282341894 v2 PRSC-068/001WO (343170-2269) (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - the is
Figure imgf000054_0001
optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0165] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0166] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. 53 282341894 v2 PRSC-068/001WO (343170-2269) [0167] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0168] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0169] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6- membered ring and 1-3 heteroatoms selected from N, O, and S), C6 aryl (i.e., phenyl), or 5- to 6- membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz. [0170] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Rz. [0171] In certain embodiments, two geminal Ru, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 54 282341894 v2 PRSC-068/001WO (343170-2269) 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Rz. [0172] Embodiments of the variables in any of the Formulae described herein, are described above. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, are also contemplated. [0173] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1- 6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0174] In certain embodiments, the compound is selected from the compounds in Tables 1’ and 2, or a pharmaceutically acceptable salt thereof. Table 1. Compound No. Structure Chemical Name - ne
Figure imgf000056_0001
55 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - 2- - - 2- '-
Figure imgf000057_0001
56 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - -
Figure imgf000058_0001
57 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- - 2- 2- - - - 2- - 2-
Figure imgf000059_0001
58 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - - - 2- - -
Figure imgf000060_0001
59 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - 2- - 2- 2- 2-
Figure imgf000061_0001
60 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- - - 2- - 2-
Figure imgf000062_0001
61 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- H- 2- n-
Figure imgf000063_0001
62 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 2- n- - - - - - - - 2-
Figure imgf000064_0001
63 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- 2- - '- '-
Figure imgf000065_0001
64 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - 2- 2- - 2-
Figure imgf000066_0001
Table 1’. Compound Structure Chemical Name
Figure imgf000066_0002
65 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - 2- - - 2- -
Figure imgf000067_0001
66 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - 2-
Figure imgf000068_0001
67 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- 2- - - - 2- - 2- -
Figure imgf000069_0001
68 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - - 2- - - -
Figure imgf000070_0001
69 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- - 2- 2- 2- -
Figure imgf000071_0001
70 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 2- - - 2- - 2-
Figure imgf000072_0001
71 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - 2- H- 2- n- 2- n- -
Figure imgf000073_0001
72 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name - - - - - - 2- - 2-
Figure imgf000074_0001
73 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 2- - '- '- - - 2-
Figure imgf000075_0001
74 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 2- - 2-
Figure imgf000076_0001
Table 2. Compoun d N Structure Chemical Name n- )- n- )- 4- -
Figure imgf000076_0002
75 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name - - - n- )- - - - -
Figure imgf000077_0001
76 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name - 2- - 4-
Figure imgf000078_0001
77 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name n - - - - -
Figure imgf000079_0001
78 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name - - - - zi '- -
Figure imgf000080_0001
79 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name - - - - - -
Figure imgf000081_0001
80 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name - - - - - -
Figure imgf000082_0001
81 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name -
Figure imgf000083_0003
g [0175] In certain aspects, the present disclosure provides conjugates comprising a compound disclosed herein being connected to a E3 ubiquitin ligase ligand (e.g., cereblon E3 ubiquitin ligase ligand or von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand) (e.g., via a linker). [0176] In certain aspects, the present disclosure provides conjugates of Formula II , wherein:
Figure imgf000083_0001
one of RE1, RE2, RE3, and RE4 is -L-E; or one of RE2, RE3, or RE4 is ; L is a linker; and
Figure imgf000083_0002
E is a ubiquintin ligase ligand, wherein each of the variables in Formula II is described herein. [0177] In certain embodiments, the conjugate is of Formula II-1 or II-2 82 282341894 v2 PRSC-068/001WO (343170-2269) 2), wherein each
Figure imgf000084_0001
[0178] In iii’, II-2-i’, II-2- ii’, II-2-iii’, II-3-i’, II-3-ii’, II-3-iii’, , , ,
Figure imgf000084_0002
PRSC-068/001WO (343170-2269) or wherein iii’, II-3-
Figure imgf000085_0001
i’, II-3-ii’, II-3-iii’ is described herein. [0179] L, a linker, is a divalent chemical moiety that connects the E3 ubiquitin ligase ligand with ligand of a protein (e.g., an inhibitor) disclosed herein. L configures the ligand of a protein and the E3 ubiquitin ligase ligand such that the construct functions as a bifunctional degrader which binds the E3 ubiquitin ligase and selectively degrades the target protein. [0180] In certain embodiments, L is a linker comprising C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10- membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted by one or more Ru. [0181] In certain embodiments, L is of Formula II-2 , wherein:
Figure imgf000085_0002
* denotes attachment to T and ** denotes attachment to E; each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the 84 282341894 v2 PRSC-068/001WO (343170-2269) alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 6. [0182] In certain embodiments, each L’ is independently C1-6 alkylene (e.g., methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-)), C1-6 heteroalkylene (C1-6 alkylene comprising 1-6 heteroatoms selected from O, N, and S), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6 alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (C6)), C3-12 carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C10), cyclodecenylene (C10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C10), or spiro[4.5]decanylene (C10)), 3- to 12-membered heterocyclylene (e.g., heterocyclylene comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)-, -C(=O)N(RL2)-, - C(=O)O-, -N(RL2)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru. [0183] In certain embodiments, each L’ is independently C1-6 alkylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2- 85 282341894 v2 PRSC-068/001WO (343170-2269) , wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru. [0184] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0185] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C3- 6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0186] In certain embodiments, l is 0. In certain embodiments, t is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is 6. [0187] In certain embodiments, E is E3 ubiquitin ligase ligand. [0188] In certain embodiments, E is cereblon E3 ubiquitin ligase ligand. [0189] Cereblon E3 ubiquitin ligase ligand is a ligand that binds Cereblon E3 ubiquitin ligase. Representative Cereblon E3 ubiquitin ligase ligands are disclosed in WO2018144649, 86 282341894 v2 PRSC-068/001WO (343170-2269) WO2017176958, WO2021041664, WO2022187423, US20180228907, Lu et al Science 343, 305 (2014), and Kronke et al Science 343, 301 (2014). [0190] In certain embodiments, E is von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand. [0191] Von Hippel-Lidau (VHL) E3 ubiquitin ligase ligand is a residue of a ligand that binds the von Hippel-Lidau E3 ubiquitin ligase (VHL ligand). Representative VHL ligands are disclosed in, for example, i) WO 2019/207538, WO 2020/251972, WO 2020/251971, WO 2021/155321, WO2021/086785, WO 2021/133920, and WO 2022/109396; ii) Kofink, C., Trainor, N., Mair, B. et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat Commun 13, 5969 (2022); iii) Cantley, J., Ye, X., Rousseau, E. et al. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers. Nat Commun 13, 6814 (2022); iv) WO 2022/125804 and CN112979747; and v) Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol.15, 672–680 (2019). [0192] In certain embodiments, the conjugate is selected from the conjugates in Table 3, or a pharmaceutically acceptable salt thereof. Table 3. Compound Structure Chemical Name - - 1- y- l- e- - - -
Figure imgf000088_0001
87 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 1- - - - 1- - l- e- - y- l- e- 1- y- l- e-
Figure imgf000089_0001
88 282341894 v2 PRSC-068/001WO (343170-2269) Compound No. Structure Chemical Name 1- - - o- - - - l- e- 4- 1- - l- e- 4- 1- - l- e-
Figure imgf000090_0001
Table 4. 89 282341894 v2 PRSC-068/001WO (343170-2269) * denotes that the compound is racemic at the glutarimide position. Compoun d No. Structure Chemical Name - '- - - '- - - '- - - '- - o- - '- - n-
Figure imgf000091_0001
90 282341894 v2 PRSC-068/001WO (343170-2269) Compoun d No. Structure Chemical Name n- - 7- - - - - o) 7- -
Figure imgf000092_0001
[0193] The compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known SMARCA2/4 inhibitors. For example, the compounds of the present disclosure may display more potent SMARCA2/4 activity, more 91 282341894 v2 PRSC-068/001WO (343170-2269) favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure may be measured according to methods commonly available in the art, such as methods exemplified herein. [0194] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration. [0195] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. [0196] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Forms of Compounds Disclosed Herein Pharmaceutically acceptable salts [0197] In some embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the 92 282341894 v2 PRSC-068/001WO (343170-2269) methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [0198] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [0199] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate. [0200] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- 93 282341894 v2 PRSC-068/001WO (343170-2269) hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [0201] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [0202] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0203] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the invention. [0204] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention. [0205] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present 94 282341894 v2 PRSC-068/001WO (343170-2269) disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0206] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers/Stereoisomers [0207] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” [0208] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. [0209] In some embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. [0210] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure 95 282341894 v2 PRSC-068/001WO (343170-2269) enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers [0211] In some embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [0212] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions [0213] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [0214] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [0215] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small 96 282341894 v2 PRSC-068/001WO (343170-2269) molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0216] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [0217] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. Preparation and Characterization of the Compounds [0218] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those 97 282341894 v2 PRSC-068/001WO (343170-2269) skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein (e.g., Examples). General Synthetic Method Scheme 1. General Synthetic Scheme for Preparing Compound “A” Scheme 2.
Figure imgf000099_0001
98 282341894 v2 PRSC-068/001WO (343170-2269) [0219]
Figure imgf000100_0001
of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). [0220] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. 99 282341894 v2 PRSC-068/001WO (343170-2269) (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0221] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527- 29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 100 282341894 v2 PRSC-068/001WO (343170-2269) in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0222] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Analytical Methods, Materials, and Instrumentation [0223] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays [0224] The biological activities of the compounds of the present application can be assessed with methods and assays known in the art. [0225] In some embodiments, the compounds are assessed by IC50 Measurements for binding to SMARCA2/4. The binding potency may be determined using homogeneous time-resolved 101 282341894 v2 PRSC-068/001WO (343170-2269) fluorescence (HTRF) assay technology. In a typical HTRF assay, compounds are serially diluted in certain solvent (e.g., DMSO), and incubated with certain concentration of SMARCA4 (e.g., 0/12 ng/ul) or SMARCA2 (e.g., 0.5 ng/ul) for a certain period of time (e.g., 30 min) at a certain temperature (e.g., 25 oC), followed by addition of diluted bromodomain ligand 2 (peptide histone H3; sequence: ARTKQTARKSTGGKAPRKQLA (Ala-Arg-Thr-Lys-Gln-Thr-Ala-Arg-Lys-Ser- Thr-Gly-Gly-Lys-Ala-Pro-Arg-Lys-Gln-Leu-Ala)) to SMARCA4 or SMARCA2 (e.g., 120-fold dilute for SMARCA4 or 90-fold diluted for SMARCA2). terbium-labeled donor and dye-labeled acceptor are added subsequently. After incubation for a certain period of time (e.g., 120 min) at a certain temperature (e.g., 25 oC), HTRF signals are read (e.g., on Envision reader) and data is analyzed using, e.g., XLfit using four parameters dose response curve to determine IC50s. Methods of Use [0226] In certain aspects, the present disclosure provides methods of inhibiting a SMARCA2 or SMARCA4 protein in a subject or a biological sample, comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein. [0227] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a SMARCA2 or SMARCA4 protein in a subject or a biological sample. [0228] In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a SMARCA2 or SMARCA4 protein in a subject or a biological sample. [0229] In certain embodiments, the compound selectively binds the SMARCA2 protein over the SMARCA4 protein. [0230] In certain embodiments, the compound has a dissociation constant for the SMARCA2 protein at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold lower than the dissociation constant for the SMARCA4 protein. [0231] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 or SMARCA4 protein in a subject, comprising administering to the subject a conjugate disclosed herein. [0232] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a subject. 102 282341894 v2 PRSC-068/001WO (343170-2269) [0233] In certain aspects, the present discloure provides conjugates disclosed herein for use in degrading a SMARCA2 or SMARCA4 protein in a subject. [0234] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount). [0235] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0236] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. [0237] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a conjugate disclosed herein (e.g., in a therapeutically effective amount). [0238] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0239] In certain aspects, the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. [0240] In certain embodiments, the disease or disorder is a SMARCA2 or SMARCA4 protein- mediated disease or disorder. [0241] In certain embodiments, the disease or disorder is selected from a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder. [0242] In certain embodiments, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer, glioma, breast cancer, pancreatic cancer, colorectal cancer, bladder cancer, endometrial cancer, penile cancer, esophagogastric cancer, hepatobiliary cancer soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non- 103 282341894 v2 PRSC-068/001WO (343170-2269) Hodgkin lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small bowel cancer, non-melanoma skin cancer, melanoma, leukemia, and malignant rhabdoid tumors (MRT). [0243] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS). [0244] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC). [0245] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers of Table A. Table A. adrenal cancer acinic cell carcinoma acoustic neuroma acral lentigious melanoma c l a
Figure imgf000105_0001
104 282341894 v2 PRSC-068/001WO (343170-2269) bladder cancer blastoma bone cancer Brenner tumor a i a c
Figure imgf000106_0001
105 282341894 v2 PRSC-068/001WO (343170-2269) malignant fibrous malignant peripheral malignant triton mantle cell histiocytoma nerve sheath tumor tumor lymphoma a l a
Figure imgf000107_0001
106 282341894 v2 PRSC-068/001WO (343170-2269) testicular cancer thecoma thyroid cancer transitional cell carcinoma a
Figure imgf000108_0001
, . , r is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. Table B. acute lymphocytic leukemia (ALL) acute eosinophilic leukemia
Figure imgf000108_0002
107 282341894 v2 PRSC-068/001WO (343170-2269) Richter's transformation
Figure imgf000109_0001
[0248] In certain embodiments, the subject is a human. [0249] Definitions [0250] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [0251] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. [0252] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). 108 282341894 v2 PRSC-068/001WO (343170-2269) [0253] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0254] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0255] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0256] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl 109 282341894 v2 PRSC-068/001WO (343170-2269) (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n-Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). [0257] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkelene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, - C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, - CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. [0258] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2- 10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms 110 282341894 v2 PRSC-068/001WO (343170-2269) (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. [0259] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, - CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-,-C(CH3)2- CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. [0260] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, 111 282341894 v2 PRSC-068/001WO (343170-2269) an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2- 10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl. [0261] “Alkynylene” as used herein, refers to a alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0262] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 112 282341894 v2 PRSC-068/001WO (343170-2269) alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl. [0263] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 113 282341894 v2 PRSC-068/001WO (343170-2269) heteroatom (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl. [0264] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2- 3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl. [0265] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent 114 282341894 v2 PRSC-068/001WO (343170-2269) radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0266] “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 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). [0267] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl. [0268] “Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0269] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each 115 282341894 v2 PRSC-068/001WO (343170-2269) heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. [0270] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). [0271] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6- membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted 116 282341894 v2 PRSC-068/001WO (343170-2269) heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl. [0272] Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [0273] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0274] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 117 282341894 v2 PRSC-068/001WO (343170-2269) carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. [0275] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12 carbocyclyl. 118 282341894 v2 PRSC-068/001WO (343170-2269) [0276] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3- 12 carbocyclyl. [0277] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0278] “Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded. [0279] “Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded. [0280] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or 119 282341894 v2 PRSC-068/001WO (343170-2269) the same atom of the carbocyclylene group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein. [0281] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. 120 282341894 v2 PRSC-068/001WO (343170-2269) [0282] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12- membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6- membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0283] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl. 121 282341894 v2 PRSC-068/001WO (343170-2269) [0284] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0285] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. [0286] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. [0287] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0288] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1- 6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. 122 282341894 v2 PRSC-068/001WO (343170-2269) [0289] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0290] “Oxo” refers to =O. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical. [0291] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0292] “Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl- protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid- protecting groups, respectively. [0293] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso- propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)). [0294] Common types of amino-protecting groups include but not limited to carbamates (e.g., t- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfenyl (Nps)). 123 282341894 v2 PRSC-068/001WO (343170-2269) [0295] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)). [0296] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline. [0297] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions [0298] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0299] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. 124 282341894 v2 PRSC-068/001WO (343170-2269) Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0300] The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci.66 (1):1-79 (January 77). [0301] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. [0302] “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural formula indicated herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR2 and -CH2OR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups. [0303] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution- phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. [0304] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, 125 282341894 v2 PRSC-068/001WO (343170-2269) sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. [0305] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment. [0306] “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset). [0307] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high. [0308] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease. [0309] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that only differ in the arrangement of their atoms in space are termed “stereoisomers.” 126 282341894 v2 PRSC-068/001WO (343170-2269) [0310] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”. [0311] “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. [0312] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0313] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)- compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound. 127 282341894 v2 PRSC-068/001WO (343170-2269) [0314] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)- compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0315] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)- compound in such compositions can, for example, comprise, at least about 95% by weight (R)- compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0316] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. [0317] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. [0318] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an 128 282341894 v2 PRSC-068/001WO (343170-2269) embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0319] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0320] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0321] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least 129 282341894 v2 PRSC-068/001WO (343170-2269) one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0322] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. [0323] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. [0324] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All 130 282341894 v2 PRSC-068/001WO (343170-2269) embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. EXAMPLES [0325] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. I. SMARCA2/4 Inhibitors 1.. Synthesis and Characterization Compound A1. 6'-chloro-1',2'-dihydro-5'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]quinazolin]- 5'-one
Figure imgf000132_0001
in dioxane (30 mL) was added tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (560 mg, 2.2 mmol, 1.1 equiv), Pd2(dba)3 (88 mg, 0.1 mmol, 0.05 equiv), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (116 mg, 0.2, 0.1 equiv), Cs2CO3 (1.3 g, 4.0 mmol, 2 equiv). Under protection of nitrogen, the mixture was refluxed for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product (620 mg, 73%). ESI MS m/z: 423.16 [M+H]+. [0327] Step 2. To a solution of tert-butyl 2-(3-chloro-2-(methoxycarbonyl)phenyl)-1-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (620 mg, 1.47 mmol, 1 equiv) in a mixture solution of MeOH/H2O (30/3 mL) was added NaOH (175 mg, 4.4 mmol, 3 equiv). The mixture was stirred for 3 h at room temperature. After reaction, the methanol was removed under reduce pressure. The 131 282341894 v2 PRSC-068/001WO (343170-2269) residue aqueous phase was neutralized by TFA to week acidic (pH: 3-4). Extraction with DCM twice, combined DCM phases was washed by brine once, after dried and removing, the crude product (600 mg, 99%) was obtained and can be used in the next step directly. ESI MS m/z: 409.16 [M+H]+. [0328] Step 3. To a solution of received acid product (600 mg, 1.47 mmol, 1.0 equiv) in CH3CN (20 mL) was added HATU (725 mg, 1.91 mmol, 1.3 equiv) and DIPEA (570 mg, 4.4 mmol, 3.0 equiv). under stirring, the mixture was bubbled by NH3 gas for 2 minutes. Then let mixture stirred for 30 min at room temperature. The reaction solution was purified by prepared HPLC C-18 reversal column to get target product (160 mg, 28%). ESI MS m/z: 390.16 [M+H]+. Step 4 [0329] Step 4. The obtained cyclic product (160 mg, 0.26 mmol) was dissolved into DCM (5 mL), then TFA (5 mL) was added. The mixture was stirred for 30 minutes. After concentrating, the residue was purified by prepared HPLC C-18 reversal column to get target product (60 mg, 81%). ESI MS m/z: 290.10 [M+H]+. Compound A2.4-chloro-5H-spiro[indolo[1,2-a]quinazoline-7,4'-piperidin]-5-one
Figure imgf000133_0001
added 2 (282 mg, 1.82 mmol, 1.1 equiv), Cs2CO3 (1.8 g, 3.31 mmol, 2 equiv). The mixture was refluxed for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 3 as a white solid (620 mg, 86%). ESI MS m/z: 438.15 [M+H]+. 132 282341894 v2 PRSC-068/001WO (343170-2269) [0331] Step 2. To a solution of 1 (600 mg, 1.37 mmol, 1 equiv) in mixture DMSO/H2O230% wt (10 mL/2 mL) was added K2CO3 (378 mg, 2.74 mmol, 2.0 equiv). The mixture was stirred for 16 h at 50 °C. After cooling to room temperature, the mixture was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 4 as a white solid (600 mg, 96%). ESI MS m/z: 456.16 [M+H]+. [0332] Step 3. To a solution of 4 (300 mg, 0.65 mmol, 1 equiv) in MeOH (20 mL) was added MeONa (355 mg, 6.58 mmol, 10 equiv). The mixture was refluxed for 16 h. After cooling to 0 ° C, the mixture was neutralized by TFA (0.3 mL). Then the reaction was removed solvent under rotatory evaporator. The reside was dissolved into a mixture of ethyl acetate, the organic phase was washed by brine once. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 as a white solid (90 mg, 31%). ESI MS m/z: 437.16 [M+H]+. [0333] Step 4. To a solution of 5 (50 mg, 1.37 mmol, 1 equiv) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred for 0.5 h. After removing solvent, the mixture was purified by pre- HPLC C-18 reversal column to get target product 6 as a white solid (30 mg, 78%). ESI MS m/z: 338.10 [M+H]+. Compound A3. 4-chloro-9-(piperidin-4-yl)-5H-spiro[indolo[1,2-a]quinazoline-7,4'- piperidin]-5-one 133 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000135_0001
(2.92 g, 9.40 mmol, 1.0 eq), Pd(dppf)Cl2 (692 mg, 0.94 mmol, 0.1 eq), K2CO3 (2.61 g, 18.80 mmol, 2.0 eq). Then a mixture solvent of dioxane and water (50 mL and 10 mL) was added to the flask. The suspension was protected by nitrogen and heated to reflux for 10 h. LC-MS showed the reaction completed. The reaction mixture was diluted by ethyl acetate (the formed solid was removed by celite filtration), washed by brine. After removing solvent, the residue was purified directly by C- 18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 3 (2.45 g, 86%) as a slight yellow solid. ESI MS m/z: 315.16 [M+H]+. [0335] Step 2. Under nitrogen protection, to a solution of 3 (2.40 g, 7.63 mmol, 1.0 eq) in methanol (50 mL) was added palladium on carbon (0.6 g, 50% wt water, 10% wt palladium) cautiously. Then mixture was stirred overnight under hydrogen atmosphere (1 atm). After reaction, the mixture was filtered by celite. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 4 (2.10 g, 87%) as a white solid. ESI MS m/z: 317.18 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.18 – 6.98 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 12.3 Hz, 2H), 3.53 (d, J = 1.1 Hz, 2H), 2.81 (t, J = 134 282341894 v2 PRSC-068/001WO (343170-2269) 12.7 Hz, 2H), 2.62 (tt, J = 12.0, 3.7 Hz, 1H), 1.80 (m, 2H), 1.60 (dd, J = 12.6, 4.2 Hz, 2H), 1.50 (s, 9H). [0336] Step 3. Under nitrogen protection, to a solution of 4 (2.10 g, 6.64 mmol, 1.0 eq) in dry THF (40 mL) was added LHMDS (21.9 mL, 21.9 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 5 (1.61 g, 6.64 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 6 (650 mg, 20%) as a white solid. ESI MS m/z: 486.30 [M+H]+. [0337] Step 4. To a flask was added 6 (600 mg, 1.24 mmol, 1.0 eq), 7 (211 mg, 1.36 mmol, 1.1 eq), Cs2CO3 (805 g, 2.47 mmol, 2.0 eq). Then CH3CN (80 mL and 10 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 8 (720 mg, 94%) as a slight yellow solid. ESI MS m/z: 621.28 [M+H]+. [0338] Step 5. To a solution of DMSO (10 mL) was added 8 (300 mg, 0.48 mmol, 1 eq), K2CO3 (133 mg, 0.97 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product 9 (278 mg, 90%). ESI MS m/z: 639.30 [M+H]+. [0339] Step 6. 9 (250 mg, 0.39 mmol, 1 eq) was dissolved into dry methanol (30 mL), then a MeONa (211 mg,3.9 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition, LC-MS showed about 50% conversion. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (110 mg, 45 %). ESI MS m/z: 521.28 [M˗Boc+H]+. 135 282341894 v2 PRSC-068/001WO (343170-2269) [0340] Step 7. To a solution of 10 (10 mg, 0.24 mmol, 1 equiv) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred for 0.5 h. After removing solvent, the mixture was purified by pre-HPLC C-18 reversal column to get target product 11 as a white solid (86 mg, 86%). ESI MS m/z: 421.17 [M+H]+. Compound A4. 4-chloro-9-(piperidin-4-yl)-2',3',5',6'-tetrahydro-5H-spiro[indolo[1,2- a]quinazoline-7,4'-pyran]-5-one
Figure imgf000137_0001
(40 mL) was added LHMDS (21.9 mL, 21.9 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 2 (1.54 g, 6.64 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 3 (1.6 g, 62%) as a white solid. ESI MS m/z: 387.22 [M+H]+. [0342] Step 2. To a flask was added 3 (1.60 g, 4.14 mmol, 1.0 eq), 4 (643 mg, 4.14 mmol, 1.0 eq), Cs2CO3 (2.70 g, 8.28 mmol, 2.0 eq). Then CH3CN (80 mL and 10 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 136 282341894 v2 PRSC-068/001WO (343170-2269) 10% to 100%, 0.1%TFA) to get target product 5 (1.45 g, 65%) as a slight yellow solid. ESI MS m/z: 522.21 [M+H]+. [0343] Step 3. To a solution of DMSO (4 mL) was added 5 (200 mg, 0.38 mmol, 1 eq), K2CO3 (106 mg, 0.76 mmol, 2 eq) and H2O2 (1 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product (180 mg, 87%). ESI MS m/z: 540.22 [M+H]+. [0344] Step 4.6 (500 mg, 0.96 mmol, 1 eq) was dissolved into dry methanol (50 mL), then MeONa (500 mg, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (205 mg, 48 %). ESI MS m/z: 522.21 [M+H]+. [0345] Step 5. To a solution of 7 (23 mg, 0.44 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product as a TFA salt (16 mg, 70 %). ESI MS m/z: 422.16 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.72 (d, J = 11.6 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.5, 1.8 Hz, 1H), 4.31 (ddd, J = 12.0, 8.6, 3.6 Hz, 2H), 3.89 (dt, J = 11.8, 4.6 Hz, 2H), 3.43 (d, J = 12.5 Hz, 2H), 3.14 – 2.91 (m, 3H), 2.12 – 1.76 (m, 8H). Compound A5. 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclopentane-1,7'-indolo[1,2- a]quinazolin]-5'-one 137 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000139_0001
(40 mL) was added LHMDS (5.2 mL, 5.2 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 2 (341 mg, 1.58 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 3 (420 mg, 72%) as a white solid. ESI MS m/z: 371.23 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.06 – 7.00 (m, 2H), 6.85 – 6.77 (m, 1H), 4.27 (d, J = 13.3 Hz, 2H), 2.87 – 2.76 (m, 2H), 2.63 (tt, J = 12.1, 3.6 Hz, 1H), 2.20 (ddd, J = 11.9, 9.4, 4.1 Hz, 2H), 2.15 – 1.93 (m, 4H), 1.93 – 1.79 (m, 4H), 1.63 (td, J = 12.6, 4.1 Hz, 2H), 1.51 (s, 9H). [0347] Step 2. To a flask was added 3 (400 mg, 1.08 mmol, 1.0 eq), 4 (184 mg, 1.19 mmol, 1.1 eq), Cs2CO3 (678 mg, 2.16 mmol, 2.0 eq). Then CH3CN (30 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 (510 mg, 93%) as a slight yellow solid. ESI MS m/z: 506.22 [M+H]+. [0348] Step 3. To a solution of DMSO (10 mL) was added 5 (200 mg, 0.39 mmol, 1 eq), K2CO3 (109 mg, 0.79 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: 138 282341894 v2 PRSC-068/001WO (343170-2269) CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product (170 mg, 82%). ESI MS m/z: 524.22 [M+H]+. [0349] Step 4.6 (100 mg, 0.19 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (43 mg, 45 %). ESI MS m/z: 506.21 [M+H]+. [0350] Step 5. To a solution of 7 (30 mg, 0.59 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (16 mg, 66 %). ESI MS m/z: 406.16 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.41 (dd, J = 8.7, 1.0 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 8.6, 7.9 Hz, 1H), 7.68 (dd, J = 8.0, 0.9 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 8.6, 1.9 Hz, 1H), 3.56 (d, J = 12.9 Hz, 2H), 3.20 (t, J = 12.7 Hz, 2H), 3.13 – 3.02 (m, 1H), 2.40 (dd, J = 12.3, 5.0 Hz, 2H), 2.28 (s, 2H), 2.14 (d, J = 9.3 Hz, 6H), 1.99 (qd, J = 13.3, 4.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 1H). Compound A6. 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000140_0001
dry THF (40 mL) was added LHMDS (5.2 mL, 5.2 mmol, 3.3 eq) slowly at -78 °C. Then mixture was 139 282341894 v2 PRSC-068/001WO (343170-2269) stirred 30 min. After that, 2 (363 mg, 1.58 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 3 (410 mg, 67%) as a white solid. ESI MS m/z: 385.24 [M+H]+. [0352] Step 2. To a flask was added 3 (400 mg, 1.04 mmol, 1.0 eq), 4 (178 mg, 1.11 mmol, 1.1 eq), Cs2CO3 (678 g, 2.08 mmol, 2.0 eq). Then CH3CN (30 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 (470 mg, 87%) as a slight yellow solid. ESI MS m/z: 520.23 [M+H]+. [0353] Step 3. To a solution of DMSO (10 mL) was added 5 (200 mg, 0.38 mmol, 1 eq), K2CO3 (106 mg, 0.76 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product (170 mg, 82%). ESI MS m/z: 538.24 [M+H]+. [0354] Step 4.6 (100 mg, 0.19 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (38 mg, 39 %). ESI MS m/z: 520.23 [M+H]+. [0355] Step 5. To a solution of 7 (30 mg, 0.57 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (18 mg, 74 %). ESI MS m/z: 420.18 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.35 (dd, J = 8.8, 1.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.82 (dd, J = 8.7, 7.9 Hz, 1H), 7.75 (d, J = 1.9 140 282341894 v2 PRSC-068/001WO (343170-2269) Hz, 1H), 7.61 (dd, J = 7.9, 0.9 Hz, 1H), 7.45 (dd, J = 8.5, 1.8 Hz, 1H), 3.63 – 3.54 (m, 2H), 3.22 (td, J = 12.9, 3.1 Hz, 2H), 3.08 (tt, J = 12.1, 3.7 Hz, 1H), 2.23 – 1.92 (m, 8H), 1.92 – 1.60 (m, 6H). Compound A7. 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cycloheptane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000142_0001
dry THF (40 mL) was added LHMDS (5.2 mL, 5.2 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 2 (385 mg, 1.58 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 2 h, then the mixture was heated to 50 °C for 4 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (50 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 3 (210 mg, 33%) as a white solid. ESI MS m/z: 399.27 [M+H]+. [0357] Step 2. To a flask was added 3 (400 mg, 1.04 mmol, 1.0 eq), 4 (171 mg, 1.11 mmol, 1.1 eq), Cs2CO3 (654 g, 2.08 mmol, 2.0 eq). Then CH3CN (30 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 (440 mg, 82%) as a slight yellow solid. ESI MS m/z: 534.24 [M+H]+. 141 282341894 v2 PRSC-068/001WO (343170-2269) [0358] Step 3. To a solution of DMSO (10 mL) was added 5 (200 mg, 0.37 mmol, 1 eq), K2CO3 (104 mg, 0.75 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product (180 mg, 87%). ESI MS m/z: 552.26 [M+H]+. [0359] Step 4.6 (100 mg, 0.18 mmol, 1 eq) was dissolved into dry methanol (20 mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (38 mg, 39 %). ESI MS m/z: 534.24 [M+H]+. [0360] Step 5. To a solution of 7 (30 mg, 0.56 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (19 mg, 78 %). ESI MS m/z: 434.20 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.38 (dd, J = 8.7, 1.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.89 – 7.80 (m, 1H), 7.69 – 7.62 (m, 2H), 7.46 (dd, J = 8.5, 1.9 Hz, 1H), 3.64 – 3.53 (m, 2H), 3.21 (td, J = 12.9, 3.0 Hz, 2H), 3.08 (tt, J = 12.2, 3.7 Hz, 1H), 2.25 – 2.09 (m, 6H), 2.09 – 1.70 (m, 11H). Compound A8. 4'-bromo-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000143_0001
PRSC-068/001WO (343170-2269) [0361] Step 1. To a flask was added 1 (400 mg, 1.04 mmol, 1.0 eq), was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 (470 mg, 80%) as a slight yellow solid. ESI MS m/z: 564.18 [M+H]+. [0362] Step 2. To a solution of DMSO (10 mL) was added 5 (200 mg, 0.35 mmol, 1 eq), K2CO3 (98mg, 0.71 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product (170 mg, 82%). ESI MS m/z: 582.20 [M+H]+. [0363] Step 3. 6 (100 mg, 0.17 mmol, 1.0 eq) was dissolved into dry methanol (20 mL), then MeONa (92 mg, 1.72 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry-ice, then TFA (0.5 mL) was added to neutralized the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) directly to get product (40 mg, 41 %). ESI MS m/z: 564.18 [M+H]+. [0364] Step 4. To a solution of 5 (30 mg, 0.53 mol, 1 eq) in DCM (2 mL) was added TFA (2 mL). After stirring 30 min, the solvent was removed and the reside was purified by pre-HPLC directly to get product (20 mg, 81%). ESI MS m/z: 644.14 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.40 (dd, J = 8.6, 1.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 7.9, 0.9 Hz, 1H), 7.78 – 7.72 (m, 1H), 7.72 – 7.67 (m, 1H), 7.44 (dd, J = 8.5, 1.9 Hz, 1H), 3.59 (dt, J = 11.5, 2.7 Hz, 2H), 3.22 (td, J = 12.9, 3.1 Hz, 2H), 3.08 (tt, J = 12.1, 3.7 Hz, 1H), 2.29 – 1.93 (m, 8H), 1.93 – 1.58 (m, 6H). [0365] Step 5. To a solution of 1 (5 mg, 0.9 mmol, 1 eq) in MeOH (2 mL) was added NaBH4 (2 mL). After stirring for 30 min, the solvent was purified by pre-HPLC directly to get product 2 (3 mg, 60%). ESI MS m/z: 422.20 [M+H]+. Compound A9. 4'-chloro-9'-(piperidin-4-yl)-6',6a'-dihydro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one 143 282341894 v2 PRSC-068/001WO (343170-2269) [0366] To a NaBH4 (2 mL).
Figure imgf000145_0001
After stirring for 30 min, the solvent was purified by pre-HPLC directly to get product 4'-chloro- 9'-(piperidin-4-yl)-6',6a'-dihydro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (3 mg, 60%). ESI MS m/z: 422.20 [M+H]+. Compound A10. 4-chloro-10-(piperidin-4-yl)-5H-spiro[indolo[1,2-a]quinazoline-7,4'- piperidin]-5-one
Figure imgf000145_0002
-1'- carboxylate 1 (500 mg, 1.31 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2 (487 mg, 1.57 mmol, 1.2 eq), Pd(dppf)Cl2 (96 mg, 144 282341894 v2 PRSC-068/001WO (343170-2269) 0.13 mmol, 0.1 eq), K2CO3 (363 mg, 2.62 mmol, 2.0 eq). Dioxane(10 mL) and water(1 mL) was added and the flask was flushed with nitrogen. The mixture was stirred at 100°C for 10 h. After cooling to room temperature, solvent was removed and the residue was purified by flash chromatography (0-40% Ethyl acetate in hexanes) to give compound 3 (616 mg, 97 %). [0368] Step 2: To a stirred solution of compound 3 (356 mg, 0.74 mmol, 1.0 eq) in methanol (7 mL) was added palladium on carbon (36 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature for 12 h. The mixture was filtered by celite and solvent was removed to give crude compound 4 (350 mg, 97 %) which was used in the next step without further purification. [0369] Step 3: To a stirred solution of compound 4 (70 mg, 0.14 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 5 (25 mg, 0.16 mmol, 1.1 eq) in MeCN (2 mL) was added Cs2CO3 (94 mg, 0.29 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 6 (70 mg, 78 %). [0370] Step 4: To a stirred solution of compound 6 (70 mg, 0.11 mmol, 1.0 eq) in DMSO (2 mL) was added H2O2 (30% wt in H2O, 0.3 mL) and K2CO3 (31 mg, 0.22 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 7 (52 mg, 72 %). [0371] Step 5: To a stirred solution of compound 7 (52 mg, 0.081 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (1.0 M in MeOH, 0.8 mL, 0.80 mmol, 10 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (10-90% MeCN in H2O, 0.1 % TFA) to give compound 8 (2.7 mg, 6 %).1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.90 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 4.19 (t, J = 12.0 Hz, 2H), 3.58 (d, J = 12.4 Hz, 2H), 3.46 (d, J = 12.9 Hz, 2H), 3.30 – 3.15 (m, 3H), 2.45 (t, J = 12.4 Hz, 2H), 2.20 (d, J = 14.4 Hz, 4H), 2.07 (q, J = 13.1 Hz, 2H). 145 282341894 v2 PRSC-068/001WO (343170-2269) Compound A11. 4-chloro-10-(piperidin-4-yl)-2',3',5',6'-tetrahydro-5H-spiro[indolo[1,2- a]quinazoline-7,4'-pyran]-5-one
Figure imgf000147_0001
1 (300 mg, 1.06 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate 2 (395 mg, 1.28 mmol, 1.2 eq), Pd(dppf)Cl2 (78 mg, 0.11 mmol, 0.1 eq), K2CO3 (294 mg, 2.13 mmol, 2.0 eq). Dioxane(10 mL) and water(1 mL) was added and the flask was flushed with nitrogen. The mixture was stirred at 100°C for 10 h. After cooling to room temperature, solvent was removed and the residue was purified by flash chromatography (0-100% Ethyl acetate in hexanes) to give compound 3 (90 mg, 22 %). [0373] Step 2: To a stirred solution of compound 3 (90 mg, 0.23 mmol, 1.0 eq) in methanol (10 mL) was added palladium on carbon (10 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature for 12 h. The mixture was filtered by celite and solvent was removed to give crude compound 4 (84 mg, 93 %) which was used in the next step without further purification. [0374] Step 3: To a stirred solution of compound 4 (84 mg, 0.22 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 5 (37 mg, 0.24 mmol, 1.1 eq) in MeCN (3 mL) was added Cs2CO3 (142 mg, 0.44 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 6 (102 mg, 90 %). [0375] Step 4: To a stirred solution of compound 6 (102 mg, 0.20 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (54 mg, 0.40 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified 146 282341894 v2 PRSC-068/001WO (343170-2269) by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 7 (107 mg, 100 %). [0376] Step 5: To a stirred solution of compound 7 (21.4 mg, 0.040 mmol, 1.0 eq) in dry MeOH (3 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.50 mmol, 12 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound 8 (5.2 mg, 30 %).1H NMR (400 MHz, MeOD) δ 8.44 (dd, J = 8.6, 0.9 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.92 – 7.80 (m, 2H), 7.73 – 7.62 (m, 1H), 7.42 – 7.33 (m, 1H), 4.50 – 4.42 (m, 2H), 4.00 (dt, J = 11.8, 4.8 Hz, 2H), 3.58 (d, J = 12.6 Hz, 2H), 3.28 – 3.11 (m, 3H), 2.62 (s, 1H), 2.21 (d, J = 14.1 Hz, 2H), 2.15 – 1.99 (m, 6H). Compound A12. 4-chloro-10-(piperazin-1-yl)-2',3',5',6'-tetrahydro-5H-spiro[indolo[1,2- a]quinazoline-7,4'-pyran]-5-one
Figure imgf000148_0001
3,4'-pyran]-2-one 1 (70 mg, 0.25 mmol, 1.0 eq), tert-butyl piperazine-1-carboxylate 2 (92 mg, 0.50 mmol, 2.0 eq), Pd2(dba)3 (23 mg, 0.025 mmol, 0.1 eq), XPhos (12 mg, 0.025 mmol, 0.1 eq), NaOtBu (48 mg, 0.50 mmol, 2.0 eq). Dioxane(2 mL) was added and the microwave tube was flushed with nitrogen. The mixture was stirred at 110°C in microwave reactor for 12 h. After cooling to room temperature, solvent was removed and the residue was purified by flash chromatography (0-100 % Ethyl acetate in hexanes) to give compound 3 (30 mg, 31 %). 147 282341894 v2 PRSC-068/001WO (343170-2269) [0378] Step 2: To a stirred solution of compound 3 (30 mg, 0.077 mmol, 1.0 eq) in DMF (1 mL) was added NaH (60% wt in mineral oil, 4.6 mg, 0.12 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 15 min, then 2-chloro-6-fluorobenzonitrile 5 (13 mg, 0.085 mmol, 1.1 eq) was added. The reaction mixture was stirred at 60°C for 6 h. After cooling to room temperature, the mixture was diluted with saturated NH4Cl solution (5 mL) and extracted with ethyl acetate (5 mL) 3 times. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over Na2SO4 and filtered. The solvent was removed and the residue was purified by flash chromatography (0-100 % Ethyl acetate in hexanes) to give compound 5 (28 mg, 69 %). [0379] Step 3: To a stirred solution of compound 5 (28 mg, 0.054 mmol, 1.0 eq) in DMSO (1mL) was added H2O2 (30% wt in H2O, 0.2 mL) and K2CO3 (15 mg, 0.11 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 6 (20 mg, 69 %). [0380] Step 4: To a stirred solution of compound 7 (20 mg, 0.036 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.50 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (20-100 % MeCN in H2O, 0.1 % TFA) to give compound 8 (3.1 mg, 20 %).1H NMR (400 MHz, MeOD) δ 8.40 (dd, J = 8.6, 1.0 Hz, 1H), 7.90 – 7.82 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.09 (dd, J = 8.4, 2.1 Hz, 1H), 4.62 (s, 1H), 4.45 (ddd, J = 11.9, 7.5, 4.4 Hz, 2H), 4.00 (dt, J = 11.8, 4.9 Hz, 2H), 3.58 (dd, J = 6.7, 3.6 Hz, 4H), 3.46 (dd, J = 6.6, 3.7 Hz, 4H), 2.11 – 1.93 (m, 4H). Compound A13. 4-chloro-10-(2,7-diazaspiro[3.5]nonan-7-yl)-2',3',5',6'-tetrahydro-5H- spiro[indolo[1,2-a]quinazoline-7,4'-pyran]-5-one 148 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000150_0001
of Compound A11. Compound A14. 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclopentane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000150_0002
[0382] To a flask was added tert-butyl 4-(2-oxoindolin-6-yl)piperidine-1-carboxylate 1 (200 mg, 0.63 mmol, 1.0 eq). THF (4 mL) was added and the flask was flushed with nitrogen. The mixture was kept at -78°C and LiHMDS (1 M, in THF, 1.9 mL, 1.9 mmol, 3.0 eq) was added slowly. The reaction mixture was stirred at at -78°C for 15 min and 1,4-dibromobutane 2 (137 mg, 0.63 mmol, 1.0 eq) was added dropwise. The reaction mixture was then stirred at room temperature for another 1 h and 60°C overnight. After cooling to room temperature, the mixture was diluted with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (10 mL) 3 times. The combined organic 149 282341894 v2 PRSC-068/001WO (343170-2269) layer was washed with water (20 mL) and saturated brine (20 mL), dried over Na2SO4 and filtered. The solvent was removed and the residue was purified by flash chromatography (0-50% Ethyl acetate in hexanes) to give compound 3 (132 mg, 56 %). Step 2: [0383] To a stirred solution of compound 3 (132 mg, 0.36 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 4 (61 mg, 0.39 mmol, 1.1 eq) in MeCN (4 mL) was added Cs2CO3 (231 mg, 0.71 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 5 (146 mg, 81 %). Step 3: [0384] To a stirred solution of compound 5 (146 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 6 (155 mg, 100 %). Step 4: [0385] To a stirred solution of compound 6 (155 mg, 0.29 mmol, 1.0 eq) in dry MeOH (5 mL) was added sodium methoxide solution (0.5 M in MeOH, 5 mL, 2.50 mmol, 8.5 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (3 mL) and TFA (1 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound 8 (85.2 mg, 72 %).1H NMR (400 MHz, MeOD) δ 8.41 (dd, J = 8.6, 1.0 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.86 (dd, J = 8.6, 7.9 Hz, 1H), 7.66 (dd, J = 7.9, 0.9 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.9, 1.3 Hz, 1H), 3.58 (d, J = 13.0 Hz, 2H), 3.22 (td, J = 13.1, 3.1 Hz, 2H), 3.17 – 3.09 (m, 1H), 2.42 – 2.31 (m, 2H), 2.31 – 2.17 (m, 4H), 2.17 – 2.03 (m, 4H), 2.03 – 1.96 (m, 2H). Compound A15. 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one 150 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000152_0001
of Compound A14. [0387] 1H NMR (400 MHz, MeOD) δ 8.42 (dd, J = 8.6, 1.0 Hz, 1H), 8.02 – 7.97 (s, 1H), 7.92 – 7.81 (m, 2H), 7.66 (dd, J = 8.0, 0.8 Hz, 1H), 7.36 (dd, J = 7.9, 1.4 Hz, 1H), 3.59 (d, J = 12.6 Hz, 2H), 3.28 – 3.09 (m, 3H), 2.22 (d, J = 14.2 Hz, 2H), 2.15 – 2.01 (m, 6H), 1.95 – 1.87 (m, 3H), 1.77 (q, J = 6.7, 5.7 Hz, 3H). Compound A16. 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazoline]-4,5'-dione 151 282341894 v2 PRSC-068/001WO (343170-2269) [0388]
Figure imgf000153_0001
and DMSO (7 mL). Potassium tert-butoxide (0.085 g, 0.80 mmol, 0.05 eq) was added and the mixture was stirred at room temperature for 10 minutes. The mixture was heated to 45 °C and methyl acrylate (4.00 mL, 44.4 mmol, 3.1 eq) was added dropwise over 70 minutes. After addition, the mixture was stirred at 45 °C for 1 hour and then further potassium tert-butoxide (955 mg, 8.5 mmol, 0.6 eq) was added four times over 30 minutes keeping the temperature below 50 °C. The mixture was then heated to 100 °C and stirred for 1.5 hours and water (45 mL) was added and heating was continued at 85 °C for 4 hours. After cooling to room temperature, the mixture was extracted with EtOAc (50 mL) 3 times and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over Na2SO4 and filtered. Solvent was removed and the residue was purified by column chromatography (0-60% 0-60% Ethyl acetate in hexanes) to give compound 3 (960 mg, 23%). [0389] Step 2: To a flask was added compound 3 (300 mg, 1.02 mmol, 1.0 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2 (347 mg, 1.12 mmol, 1.1 eq), Pd(dppf)Cl2 (75 mg, 0.10 mmol, 0.1 eq), K2CO3 (282 mg, 2.04 mmol, 2.0 eq). Dioxane (10 mL) and water (1 mL) was added and the flask was flushed with nitrogen. The mixture 152 282341894 v2 PRSC-068/001WO (343170-2269) was stirred at 100°C for 10 h. After cooling to room temperature, solvent was removed and the residue was purified by flash chromatography (0-100% Ethyl acetate in hexanes) to give compound 5 (415 mg, 100 %). [0390] Step 3: To a stirred solution of compound 5 (415 mg, 1.05 mmol, 1.0 eq) in EtOAc (20 mL) was added palladium on carbon (42 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature overnight. The mixture was filtered by celite and solvent was removed to give crude compound 6 (120 mg, 29 %) which was used in the next step without further purification. [0391] Step 4: To a stirred solution of compound 6 (61 mg, 0.15 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 7 (26 mg, 0.17 mmol, 1.1 eq) in MeCN (2 mL) was added Cs2CO3 (100 mg, 0.31 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 8 (48 mg, 59 %). [0392] Step 5: To a stirred solution of compound 8 (48 mg, 0.091 mmol, 1.0 eq) in DMSO (2 mL) was added H2O2 (30% wt in H2O, 0.3 mL) and K2CO3 (25 mg, 0.18 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 9 (29.2 mg, 58 %). [0393] Step 6: To a stirred solution of compound 9 (29.2 mg, 0.053 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 1.5 mL, 0.75 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (20-100% MeCN in H2O, 0.1 % TFA) to give compound 10 (12 mg, 52 %). Compound A17. 4'-chloro-4,4-difluoro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one 153 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000155_0001
mmol, 1.0 eq) in DCM (4 mL) was added (Diethylamino)sulfur trifluoride (0.17 mL, 1.30 mmol, 3.0 eq) dropwise. The mixture was stirred at room temperature overnight and then added dropwise to an ice-water mixture. After stirring for 20 minutes, saturated sodium bicarbonate solution (5 mL) was added and the mixture was extracted with DCM (5 mL) 3 times. The combined organic layer was dried over MgSO4. Solvent was removed and the residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 2 (90 mg, 64 %). [0395] Step 2: To a flask was added compound 2 (15 mg, 0.046 mmol, 1.0 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 3 (16 mg, 0.052 mmol, 1.1 eq), Pd(dppf)Cl2 (3.4 mg, 0.0046 mmol, 0.1 eq), K2CO3 (13 mg, 0.094 mmol, 2.0 eq). Dioxane (0.5 mL) and water (0.05 mL) was added and the flask was flushed with nitrogen. The mixture was stirred at 100°C for 10 h. After cooling to room temperature, solvent was removed and the residue was purified by flash chromatography (0-100% Ethyl acetate in hexanes) to give compound 4 (10 mg, 51 %). [0396] Step 3: To a stirred solution of compound 4 (105 mg, 0.25 mmol, 1.0 eq) in MeOH (3 mL) was added palladium on carbon (11 mg, 10% wt). The flask was flushed with hydrogen and the reaction mixture was stirred at room temperature overnight. The mixture was filtered by celite and solvent was removed to give crude compound 5 (95 mg, 90 %) which was used in the next step without further purification. [0397] Step 4: To a stirred solution of compound 5 (95 mg, 0.23 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 6 (39 mg, 0.25 mmol, 1.1 eq) in MeCN (3 mL) was added Cs2CO3 (148 mg, 0.45 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room 154 282341894 v2 PRSC-068/001WO (343170-2269) temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 7 (79 mg, 62 %). [0398] Step 5: To a stirred solution of compound 7 (15 mg, 0.027 mmol, 1.0 eq) in DMSO (2 mL) was added H2O2 (30% wt in H2O, 0.2 mL) and K2CO3 (7.5 mg, 0.054 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 8 (7.5 mg, 48 %). [0399] Step 6: To a stirred solution of compound 8 (7.5 mg, 0.013 mmol, 1.0 eq) in dry MeOH (0.5 mL) was added sodium methoxide solution (0.5 M in MeOH, 0.5 mL, 0.25 mmol, 20 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (20-100% MeCN in H2O, 0.1 % TFA) to give compound 9 (4 mg, 67 %). [0400] 1H NMR (400 MHz, MeOD) δ 7.95 – 7.87 (m, 1H), 7.83 (dd, J = 8.3, 1.1 Hz, 1H), 7.65 (dd, J = 7.9, 1.1 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.59 (s, 1H), 3.56 – 3.49 (m, 2H), 3.16 (td, J = 13.0, 3.0 Hz, 2H), 2.97 (tt, J = 12.3, 3.6 Hz, 1H), 2.73 – 2.56 (m, 2H), 2.30 – 2.05 (m, 8H), 1.92 (qd, J = 13.3, 4.0 Hz, 2H). Compound A18. 4'-chloro-4-hydroxy-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one
Figure imgf000156_0001
PRSC-068/001WO (343170-2269) [0401] Step 1: To a solution of tert-butyl 4-(2',4-dioxospiro[cyclohexane-1,3'-indolin]-5'- yl)piperidine-1-carboxylate (60 mg, 0.15 mmol, 1.0 eq) in MeOH (2 mL) was added sodium borohydride (11 mg, 0.30 mmol, 2.0 eq). The mixture was stirred at room temperature for 4 hours and then saturated ammonium chloride solution (4 mL) was added and the mixture was extracted with EtOAc (4 mL) 3 times. The the combined organic layer was washed with water (5 mL) and saturated brine (5 mL), dried over Na2SO4 and filtered. Solvent was removed and the residue was purified by column chromatography (0-100% Ethyl acetate in hexanes) to give compound 2 (23 mg, 39 %). [0402] Step 2: To a stirred solution of compound 2 (23 mg, 0.058 mmol, 1.0 eq), 2-chloro-6- fluorobenzonitrile 3 (10 mg, 0.064 mmol, 1.1 eq) in MeCN (1 mL) was added Cs2CO3 (38 mg, 0.12 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 4 (22 mg, 71 %). [0403] Step 3: To a stirred solution of compound 4 (22 mg, 0.040 mmol, 1.0 eq) in DMSO (1.5 mL) was added H2O2 (30% wt in H2O, 0.2 mL) and K2CO3 (11 mg, 0.080 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 5 (20 mg, 90 %). [0404] Step 4: To a stirred solution of compound 5 (20 mg, 0.036 mmol, 1.0 eq) in dry MeOH (1 mL) was added sodium methoxide solution (0.5 M in MeOH, 1 mL, 0.5 mmol, 14 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by Prep-HPLC (20-100% MeCN in H2O, 0.1 % TFA) to give compound 6 (7 mg, 43 %). Compound A19. 4'-chloro-9'-(3,9-diazaspiro[5.5]undecan-3-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one 156 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000158_0001
of Compound A12. [0406] 1H NMR (400 MHz, MeOD) δ 7.96 – 7.88 (m, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.3, 1.1 Hz, 1H), 7.63 (dd, J = 7.9, 1.1 Hz, 1H), 7.55 (dd, J = 8.6, 2.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 3.70 – 3.62 (m, 4H), 3.31 – 3.24 (m, 4H), 2.14 – 2.03 (m, 6H), 2.03 – 1.91 (m, 6H), 1.91 – 1.68 (m, 6H). Compound A20.4'-chloro-9'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000158_0002
the synthesis of Compound A12. 157 282341894 v2 PRSC-068/001WO (343170-2269) [0408] 1H NMR (400 MHz, MeOD) δ 7.87 (t, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.3, 1.1 Hz, 1H), 7.59 (dd, J = 8.0, 1.1 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.5, 2.4 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3.45 – 3.34 (m, 8H), 2.11 – 2.02 (m, 2H), 2.01 – 1.88 (m, 2H), 1.87 – 1.77 (m, 2H), 1.77 – 1.66 (m, 6H). Compound A21.4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrido[3',2':4,5]pyrrolo[1,2-a]quinazolin]-5'-one [0409]
Figure imgf000159_0001
of Compound A14. [0410] 1H NMR (400 MHz, MeOD) δ 9.84 (dd, J = 8.7, 1.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.7, 7.9 Hz, 1H), 7.65 (dd, J = 7.9, 1.1 Hz, 1H), 3.68 – 3.55 (m, 2H), 3.29 – 3.09 (m, 3H), 2.26 – 1.94 (m, 8H), 1.94 – 1.68 (m, 6H). Compound A22. 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrido[2',3':4,5]pyrrolo[1,2-a]quinazolin]-5'-one 158 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000160_0001
of Compound A14. [0412] 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 8.6 Hz, 1H), 8.32 (dd, J = 8.7, 1.0 Hz, 1H), 7.88 (dd, J = 8.6, 7.9 Hz, 1H), 7.68 (dd, J = 8.0, 0.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 3.68 – 3.54 (m, 2H), 3.23 (ddt, J = 12.7, 8.0, 4.4 Hz, 3H), 2.42 – 2.03 (m, 8H), 1.88 (dd, J = 32.5, 11.3 Hz, 5H), 1.74 – 1.62 (m, 1H). Compound A23. 4'-bromo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrimido[5',4':4,5]pyrrolo[1,2-a]quinazolin]-5'-one 159 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000161_0001
of Compound A14. [0414] 1H NMR (400 MHz, MeOD) δ 8.75 (t, J = 2.1 Hz, 1H), 7.92 (dt, J = 8.3, 1.9 Hz, 1H), 7.75 (td, J = 8.0, 4.2 Hz, 1H), 7.65 (dt, J = 8.1, 1.8 Hz, 1H), 3.40 (dt, J = 13.0, 4.0 Hz, 2H), 3.27 (d, J = 3.6 Hz, 1H), 3.16 – 3.01 (m, 3H), 2.16 (d, J = 14.6 Hz, 2H), 2.07 – 1.89 (m, 6H), 1.76 (dd, J = 21.2, 9.4 Hz, 4H), 1.60 (d, J = 10.6 Hz, 1H). Compound A24. 4'-bromo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one 160 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000162_0001
of Compound A14. [0416] Calcd. (M+H)+ m/z: 464.1, Found (M+H)+ m/z: 464.3 Compound A25. 4'-bromo-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrido[3',2':4,5]pyrrolo[1,2-a]quinazolin]-5'-one
Figure imgf000162_0002
of Compound A14. [0418] Calcd. (M+H)+ m/z: 465.1, Found (M+H)+ m/z: 465.0 Compound A26. 4'-bromo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrido[3',2':4,5]pyrrolo[1,2-a]quinazolin]-5'-one 161 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000163_0001
of Compound A14. [0420] Calcd. (M+H)+ m/z: 465.1, Found (M+H)+ m/z: 465.3 Compound A27. 4'-bromo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- pyrido[2',3':4,5]pyrrolo[1,2-a]quinazolin]-5'-one
Figure imgf000163_0002
of Compound A14. [0422] Calcd. (M+H)+ m/z: 465.1, Found (M+H)+ m/z: 465.2 Compound A28. 4'-hydroxy-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one Compound A29. 4'-fluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one 162 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000164_0001
[0423] To a flask was added 6-bromoindolin-2-one 1 (10 g, 47 mmol, 1.0 eq). THF (300 mL) was added and the flask was flushed with nitrogen. The mixture was kept at -78°C and LiHMDS (1 M, in THF, 141 mL, 141 mmol, 3.0 eq) was added slowly. The reaction mixture was stirred at at - 78°C for 15 min and 1,5-dibromopentane 2 (6.4 mL, 47 mmol, 1.0 eq) was added dropwise. The reaction mixture was then stirred at room temperature for another 1 h and 60°C overnight. After cooling to room temperature, the mixture was diluted with saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (100 mL X 3). The combined organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over Na2SO4 and filtered. The solvent was removed, 163 282341894 v2 PRSC-068/001WO (343170-2269) and the residue was purified by flash chromatography (0-50% Ethyl acetate in hexanes) to give compound 3 (7.3 g, 55 %). Step 2: [0424] To a flask was added 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one 3 (2.66 g, 9.40 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate 4 (2.92 g, 9.40 mmol, 1.0 eq), Pd(dppf)Cl2 (692 mg, 0.94 mmol, 0.1 eq), K2CO3 (2.61 g, 18.80 mmol, 2.0 eq). Then a mixture solvent of dioxane and water (50 mL and 10 mL) was added to the flask. The suspension was protected by nitrogen and heated to reflux for 10 h. LC- MS showed the reaction completed. The reaction mixture was diluted by ethyl acetate (the formed solid was removed by celite filtration), washed by brine. After removing solvent, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 5 (3.06 g, 85%) as a slight yellow solid. Step 3: [0425] Under nitrogen protection, to a solution of 5 (3.06 g, 8.0 mmol, 1.0 eq) in methanol (80 mL) was added palladium on carbon (0.6 g, 50% wt water, 10% wt palladium) cautiously. Then mixture was stirred overnight under hydrogen atmosphere (1 atm). After reaction, the mixture was filtered by celite. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 6 (2.77 g, 90%) as a white solid. Step 4: [0426] To a stirred solution of compound 6 (268 mg, 0.70 mmol, 1.0 eq), 2,6-difluorobenzonitrile 7 (116 mg, 0.84 mmol, 1.2 eq) in MeCN (8 mL) was added Cs2CO3 (454 mg, 1.3 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered by celite and solvent was removed. The residue was purified by flash chromatography (0-60% Ethyl acetate in hexanes) to give compound 8 (265 mg, 75%). Step 5: [0427] To a stirred solution of compound 8 (146 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 9 (152 mg, 100 %). Step 6: 164 282341894 v2 PRSC-068/001WO (343170-2269) [0428] To a stirred solution of compound 9 (100 mg, 0.19 mmol, 1.0 eq) in dry MeOH (2 mL) was added sodium methoxide solution (0.5 M in MeOH, 3 mL, 1.50 mmol, 7.9 eq). The reaction mixture was stirred at 65°C for 12 h. After cooling to -78°C, TFA was added to adjust pH to 3 and the solvent was removed. The residue was dissolved in DCM (3 mL) and TFA (1 mL) and the rection mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to give compound 10 (71 mg, 90 %). Step 7: [0429] To a stirred solution of compound 10 (71 mg, 0.17 mmol, 1.0 eq) in dry pyridine (4 mL) was added MgBr2 (37 mg, 0.2 mmol, 1.5 eq). The reaction mixture was stirred at 60°C for 4 h. After cooling to room temperature, the solvent was removed and the residue was purified by Prep- HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound A28 (46 mg, 67%).1H NMR (400 MHz, MeOD) δ 8.10 (s, 1H), 7.91 (dd, J = 13.0, 4.5 Hz, 2H), 7.85 (t, J = 8.3 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.1, 0.9 Hz, 1H), 3.59 (d, J = 12.8 Hz, 2H), 3.29 – 3.11 (m, 4H), 2.23 (d, J = 13.9 Hz, 2H), 2.17 – 1.99 (m, 5H), 1.94 (t, J = 15.1 Hz, 3H), 1.84 – 1.70 (m, 3H). Step 8: [0430] To a stirred solution of compound 9 (50 mg, 0.095 mmol, 1.0 eq) in dry MeOH (3.6 mL) was added PTSA (54 mg, 0.28 mmol, 3 eq) and 4A molecular sieve (72 mg). The reaction mixture was stirred at 135°C for 10 h. After cooling to room tempreature, the solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound A29 (18 mg, 47%). Calcd. (M+H)+ m/z: 404.2, Found (M+H)+ m/z: 404.3 Compound A30. 4'-amino-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one
Figure imgf000166_0001
[0431] To a stirred solution of compound 1 (200 mg, 0.397 mmol, 1.0 eq), 2 (119 μL, 0.79 mmol, 2.0 eq) in DDMF (2 mL) was added DIPEA (310 μL, 2.0 mmol, 5.0 eq). The reaction mixture was 165 282341894 v2 PRSC-068/001WO (343170-2269) stirred at 90°C for 12 h. After cooling to room temperature, the mixture was purified by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to give compound 3 (243 mg, 93 %). Step 2: [0432] To a stirred solution of compound 3 (189 mg, 0.29 mmol, 1.0 eq) in DMSO (4 mL) was added H2O2 (30% wt in H2O, 0.5 mL) and K2CO3 (80 mg, 0.58 mmol, 2.0 eq). The reaction mixture was stirred at 50°C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase flash chromatography (10-100% MeCN in H2O, 0.1% TFA) to give compound 4 (112 mg, 58 %). Step 8: [0433] To a stirred solution of compound 4 (64 mg, 0.095 mmol, 1.0 eq) in dry MeOH (3.6 mL) was added PTSA (54 mg, 0.28 mmol, 3 eq) and 4A molecular sieve (72 mg). The reaction mixture was stirred at 135°C for 10 h. After cooling to room tempreature, the solvent was removed and the residue was purified by Prep-HPLC (15-75% MeCN in H2O, 0.1 % TFA) to give compound A30 (15.9 mg, 41%). Calcd. (M+H)+ m/z: 401.2, Found (M+H)+ m/z: 401.3 [0434] Compound A31 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 504.2, Found (M+H)+ m/z: 504.3 [0435] Compound A32 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 460.2, Found (M+H)+ m/z: 460.4 [0436] Compound A35 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 403.2, Found (M+H)+ m/z: 403.7 [0437] Compound A36 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 403.2, Found (M+H)+ m/z: 403.6 [0438] Compound A37 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 400.2, Found (M+H)+ m/z: 400.1 [0439] Compound A38 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 414.2, Found (M+H)+ m/z: 414.4 [0440] Compound A39 was synthesized using similar procedures as used in the synthesis of Compound A14. Calcd. (M+H)+ m/z: 410.2, Found (M+H)+ m/z: 410.0 166 282341894 v2 PRSC-068/001WO (343170-2269) Compound A33.4'-chloro-10'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one Compound A34.4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclohexane-1-carbaldehyde
Figure imgf000168_0001
5.4 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.1 g, 7.9 mmol, 1.5 eq), Pd(dppf)Cl2 (388 mg, 0.54 mmol, 0.1 eq), K2CO3 (1.46 g, 10.6 mmol, 2.0 eq). Then a mixture solvent of dioxane and water (40 mL and 8 mL) was added to the flask. The suspension was protected by nitrogen and heated to 95 °C for 6 h. LC-MS showed the reaction completed. The reaction mixture was cooled to room temperature. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane) to obtained product to get target product 2 (1.2 g, 65%). [0442] Step 2: To a mixture of 2 (1.2 g, 1 eq) in methanol (50 mL) was added 10% Pd/C (200 mg). The mixture was stirred at 20 oC for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated to afford 3 (1.2 g) as a yellow solid. [0443] Step 3: To a mixture of 3 (760 mg, 1 eq, 2.2 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.41 g, 2 eq, 4.5 mmol) and 2-chloro-6-fluorobenzonitrile (27 mg, 1.2 eq, 174 µmol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-20% ethyl acetate/hexane to afford 4 (634 mg, 60%) as a white solid. [0444] Step 4: To a mixture of 4 (634 mg, 1 eq, 1.3 mmol) in DMSO (5.00 mL) was added potassium carbonate (366 mg, 2 eq, 2.6 mmol) at 0 oC then added hydrogen peroxide (2.3 167 282341894 v2 PRSC-068/001WO (343170-2269) mL). The mixture was stirred at 40 °C for 10 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to afford 5 (351 mg, 55%) as a white solid. [0445] Step 5: To a mixture of 5 (0.351 g, 1 eq, 0.71 mmol) in tolene (20 mL) was added PTSA (0.405 g, 3 eq) and molecular sieve (650 mg). The reaction mixture was refluxed for 8 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated in vacuum. The residue was purified by reverse-phase chromatography to afford A33 (172 mg, 56%) as a white solid. Calcd. (M+H)+ m/z: 433.2, Found (M+H)+ m/z: 433.6 [0446] Step 6: To a solution of (methoxymethyl)triphenylphosphonium (58 mg, 0.17 mmol, 1.5 eq) in dry THF/HMPA (10/1, 3 mL) was added tBuOK (1 M in THF, 0.17 mL, 0.17 mmol, 1.5 eq). The mixture was stirred for 30 min and followed by addition of A33 (50 mg, 0.115 mmol, 1.0 eq). The mixture was stirred for 3 h at rt. The reaction was quenched by 2N HCl (3 mL) and stirred for 40 min. After removing solvent, the mixture was subjected to Prep-HPLC (25-100% MeCN in H2O, 0.1 % TFA) to give compound A34 (15 mg, 29 %). Calcd. (M+H)+ m/z: 447.2, Found (M+H)+ m/z: 447.4 Compound A40. 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one 168 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000170_0001
[0447] Step 1: To a mixture 1 (5.00 g, 1 eq, 23.6 mmol) in 1,4-dioxane (50.0 mL) and water (10 mL), was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.73 g, 0.1 eq, 2.36 mmol), sodium carbonate (7.50 g, 3 eq, 70.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2 (10.9 g, 1.5 eq, 35.4 mmol) and stirred at 90 °C for 12 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate and concentrated under vacuum. The crude was purified by silica gel column chromatography (0-30% of ethyl acetate in petroleum ether) to afford 3 (6.50 g, 20.7 mmol, 87.7%) as a yellow solid. [0448] Step 2: To a mixture of 3 (6.70 g, 1 eq, 21.3 mmol) in methanol (50 mL) was added 10% Pd/C (1.13 g, 0.05 eq, 1.07 mmol). The mixture was stirred at 20 oC for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated to afford 4 (6.50 g, 20.5 mmol, 96.4 %) as a yellow solid. [0449] Step 3: To a mixture of 4 (0.30 g, 1 eq, 0.95 mmol) and TMEDA (0.33 g, 3 eq, 2.8 mmol) in THF (10 mL) at -78 °C was added n-butyllithium (0.17 mL, 2 eq, 1.9 mmol) dropwise slowly at -78 °C, after 30 minutes, MeI (0.12 mL, 2 eq, 1.9 mmol) was added then stirred at -78 °C for 3 h. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mLx2). The combined organic layer was washed with brine (50 mL), dried 169 282341894 v2 PRSC-068/001WO (343170-2269) over sodium sulfate, filtered and concentrated in vacuum. The mixture was concentrated and the residue was purified by column chromatography on silica gel using 0-20% ethyl acetate/hexane to afford 5 (67.0 mg, 195 µmol, 21%) as a yellow solid. [0450] Step 4: To a mixture of 5 (50.0 mg, 1 eq, 145 µmol) in acetonitrile (5 mL) was added cesium carbonate (142 mg, 3 eq, 435 µmol) and 2-chloro-6-fluorobenzonitrile 6 (27 mg, 1.2 eq, 174 µmol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-20% ethyl acetate/hexane to afford 7 (83.3 µmol, 57.4%) as a white solid. [0451] Step 5: To a mixture of 7 (50 mg, 1 eq, 104 µmol) in DMSO (5.00 mL) was added potassium carbonate (43.2 mg, 3 eq, 313 µmol) at 0 oC then added hydrogen peroxide (35.4 mg, 31.9 µL, 10 eq, 1.04 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to afford 8 (43.4 mg, 80 µmol, 77.3%) as a white solid. [0452] Step 6: To a mixture of 8 (0.199 g, 1 eq, 0.40 mmol) in tolene (4.5 mL) was added PTSA (0.11 g, 3 eq) and molecular sieve (50 mg). The reaction mixture was refluxed for 12 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated in vacuum. The residue was purified by reverse-phase chromatography to afford A40 (101 mg, 265 µmol, 66%) as a white solid. Calcd. (M+H)+ m/z: 380.2, Found (M+H)+ m/z: 380.2 Compound A41.4-bromo-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one [0453] Compound A41 was synthesized using similar procedures as used in the synthesis of Compound A40. Calcd. (M+H)+ m/z: 424.1, Found (M+H)+ m/z: 424.8 Compound A42.4'-chloro-10'-(piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one 170 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000172_0001
of Compound A3. [0455] 1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 11.4 Hz, 1H), 8.66 (d, J = 11.2 Hz, 1H), 8.44 (dd, J = 8.7, 0.9 Hz, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.89 – 7.79 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.31 (dd, J = 7.9, 1.3 Hz, 1H), 3.40 (dd, J = 24.1, 11.9 Hz, 2H), 3.31 – 3.08 (m, 2H), 2.98 (d, J = 11.7 Hz, 1H), 2.17 – 1.49 (m, 14H). LC-MS = 420.18 (M+H). Compound A43.4'-chloro-10'-(pyrrolidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one 171 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000173_0001
of Compound A3. [0457] 1H NMR (400 MHz, DMSO) δ 8.97 (s, 2H), 8.45 (dd, J = 8.7, 1.0 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.88 – 7.79 (m, 2H), 7.65 (dd, J = 7.9, 0.8 Hz, 1H), 7.37 (dd, J = 7.8, 1.3 Hz, 1H), 3.69 – 3.58 (m, 3H), 3.51 (tdt, J = 8.4, 5.5, 3.4 Hz, 1H), 3.34 – 3.22 (m, 1H), 2.49 – 2.39 (m, 1H), 2.16 – 2.02 (m, 3H), 1.90 (td, J = 9.9, 9.2, 5.4 Hz, 2H), 1.83 – 1.61 (m, 6H). LC-MS = 406.18 (M+H). Compound A44, 4-chloro-7,7-diethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one 172 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000174_0001
of Compound A3. LC-MS = 408.18 (M+H). Compound A45, 4'-bromo-10'-(4-(piperazin-1-ylmethyl)cyclohexyl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one 173 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000175_0001
one 1 (1.80 g, 6.42 mmol, 1.0 eq), 2 (2.22 g, 8.35 mmol, 1.3 eq), Pd(dppf)Cl2 (470 mg, 0.64 mmol, 0.1 eq), K2CO3 (1.78 g, 12.85 mmol, 2.0 eq). Then a mixture solvent of dioxane and water (50 mL and 10 mL) was added to the flask. The suspension was protected by nitrogen and heated to reflux for 16 h. LC-MS showed the reaction completed. The reaction mixture was diluted by ethyl acetate (the formed solid was removed by celite filtration), washed by brine. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product to get target product 3 (1.10 g, 40%) as a slight yellow solid. ESI MS m/z: 296.16 [M+H]+. [0460] Synthesis of 4. Under nitrogen protection, to a solution of 3 (0.90 g, 3.05 mmol, 1.0 eq) in methanol (50 mL) was added palladium on carbon (0.6 g, 50% wt water, 10% wt palladium) cautiously. Then mixture was stirred overnight under hydrogen atmosphere (1 atm). After reaction, the mixture was filtered by celite. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 4 (0.75 g, 83%) as a white solid. ESI MS m/z: 298.18 [M+H]+. [0461] Synthesis of 6. To a flask was added 4 (600 mg, 2.02 mmol, 1.0 eq), 5 (605 mg, 3.03 mmol, 1.5 eq), Cs2CO3 (1.30 g, 4.03 mmol, 2.0 eq). Then CH3CN (80 mL and 10 mL) was added to the 174 282341894 v2 PRSC-068/001WO (343170-2269) flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the mixture was filtered by celite. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to get target product 6 (620 mg, 64%) as a slight yellow solid. ESI MS m/z: 477.12 [M+H]+. [0462] Synthesis of 9, to a suspension of 7 (718 mg, 2.09 mmol, 2.0 eq) in dry THF (20 mL) was added t-BuOK (235 mg, 2.09 mmol, 2.0 eq), then the mixture was stirred for 30 min. after that a solution of 6 (500 mg, 1.05 mmol, 1.0 eq) in THF (3 mL) was added the reaction solution. The mixture was stirred for 6 h at rt. A saturated aqueous solution NH4Cl (10 mL) was added to quench the reaction, then HCl (5 mL, 1 N) was added. The mixture was stirred for 1 h. The organic phase was collected and the aqueous phase was extracted by ethyl acetate once. Combined layers were washed by brine once. After removing solvent, the residue was purified by directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 9 (210 mg, 41%) as a slight yellow solid. ESI MS m/z: 491.13 [M+H]+. [0463] Synthesis of 11, to a solution of 9 (200 mg, 0.41 mmol, 1.0 eq) in dry DCE/DCM (3/3 mL) was added 10 (113 mg, 0.61 mmol, 1.5 eq), and NaBH(OAc)3 (258 mg, 1.22 mmol, 3.0 eq). then the mixture was stirred for 3 h. After that, the reaction solution was purified by directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 11 (160 mg, 59%). ESI MS m/z: 663.28 [M+H]+. [0464] Synthesis of 12, To a solution of DMSO (10 mL) was added 11 (120 mg, 0.18 mmol, 1 eq), K2CO3 (50 mg, 0.36 mmol, 2 eq) and H2O2 (2 mL). The mixture was warmed to 50 °C and stirred for 16 h. after reaction, the mixture was transferred to C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to purify directly to get product 12 (90 mg, 72%). ESI MS m/z: 681.30 [M+H]+. [0465] Synthesis of A45, To a solution of toluene (10 mL) was added 12 (90 mg, 0.13 mmol, 1 eq), TsOH (90 mg, 0.53 mmol, 4 eq) and 4A molecular sieves (2.0 g). The mixture was refluxed for 16 h. after reaction, the solvent was removed under reduced pressure. The residue was redissolved into MeOH and filtered. the mixture solution was purified pre-HPLC to get product 13 (35 mg, 47%). ESI MS m/z: 561.22 [M+H]+. 175 282341894 v2 PRSC-068/001WO (343170-2269) Compound A46, 4'-chloro-10'-(4-((dimethylamino)methyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one Synthesis of A46 [0466] To a solution of A34 (7 mg, 0.015 mmol, 1 equiv.) in DCE/DMF (0.8/0.8 mL) was added dimethylamine (0.045 mmol, 3.0 equiv.). The mixture was stirred for 30 min. then NaBH(OAc)3 (2.8 mg, 0.045 mmol, 3 equiv.) was added. The resulting reaction mixture stirred for additional 3 h. The mixture solution was purified directly by pre-HPLC to get product A46 (4 mg, 56%). ESI MS m/z: 477.08 [M+H]+. [0467] Compounds A47-50 were synthesized using the similar procedures as used in the synthesis of Compound A46. Compound No. ESI MS m/z [M+H]+
Figure imgf000177_0001
Compound A51, 10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one [0468] Synthesis of A51, to a solution of A24 (42 mg, 0.075 mmol, 1 equiv.) in isopropyl alcohol (1 mL) was added CsOAc (22 mg, 0.112 mmol, 1.5 equiv.) and [RuCl2(cymene)]2 (6.9 mg, 0.011 mmol, 0.15 equiv.). The mixture was stirred for 20 h at °C. The mixture solution was purified directly by pre-HPLC to get product A51 (11 mg, 31%). ESI MS m/z: 386.32 [M+H]+. [0469] Compounds A53-55 were synthesized using the similar procedures as used in the synthesis of Compound A40. 176 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000178_0001
Figure imgf000178_0002
Compound A56, 4'-chloro-10'-(4-((dimethylamino)methyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one 177 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000179_0001
[0470] To a solution of A15 (255 mg, 0.477 mmol, 1 equiv.) in DCE/DMF (2.5/2.5 mL) was tert- butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (251 mg, 1.19 mmol, 3.0 equiv.). The mixture was stirred for 30 min. then NaBH(OAc)3 (303 mg, 1.43 mmol, 3 equiv.) was added. The resulting reaction mixture stirred for additional 6 h. The mixture solution was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get intermediate 2. intermediate 2 was dissolved in DCM (50 mL) and followed by addition of TFA (10 mL). The mixture was stirred for 3 h, and then removed the solvent by air. The residue was purified directly by pre-HPLC to get product A56 (189 mg, 63% for 2 steps). ESI MS m/z: 515.37 [M+H]+. [0471] Compounds A57 and A58 were synthesized using the similar procedures as used in the synthesis of Compound A56. Compound No. ESI MS m/z [M+H]+
Figure imgf000179_0002
[0472] Compounds A59 and A60 were synthesized using the similar procedures as used in the synthesis of Compound A12. 178 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000180_0001
Figure imgf000180_0003
ompoun , - romo- -(-(pperazn--yme y)pper n--y)- - spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one [0473]
Figure imgf000180_0002
, 4.28 mmol, 1.5 equiv.), Pd2(dba)3 (261 mg, 0.28 mmol, 0.1 equiv.), Xphos (272 mg, 0.57 mmol, 0.2 equiv) in 179 282341894 v2 PRSC-068/001WO (343170-2269) dioxane was added Cs2CO3 (1.86 g, 5.7 mmol, 2.0 equiv.). The suspension was refluxed overnight. After filtration, the solution was concentrated and the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 4 (0.76 g, 74%) as a white solid. ESI MS m/z: 359.23 [M+H]+. [0474] Synthesis of 5, 6, 7, and 10 ware similar to the general procedure A45. [0475] Compound A61 was synthesized using similar procedures as used in the synthesis of Compound A45. LC-MS = 662.26 (M+H). Compound B1.4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000181_0001
(Intermediate 3) [0476] To a mixture 5-bromoindolin-2-one (5.00 g, 1 eq, 23.6 mmol) in 1,4-dioxane (50.0 mL) and water (10 mL), was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.73 g, 0.1 eq, 2.36 mmol), sodium carbonate (7.50 g, 3 eq, 70.7 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10.9 g, 1.5 eq, 35.4 mmol) and stirred at 90 °C for 12 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate and concentrated under vacuum. The crude was purified 180 282341894 v2 PRSC-068/001WO (343170-2269) by silica gel column chromatography (0-30% of ethyl acetate in petroleum ether) to afford tert- butyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.50 g, 20.7 mmol, 87.7%) as a yellow solid. LC purity (0.1%FA): 77.33 % (UV at 254 nm)/MS: 356.3 [M+42]; Retention time: 1.198 min. Synthesis of tert-butyl 4-(2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 4) [0477] To a mixture of tert-butyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.70 g, 1 eq, 21.3 mmol) in methanol (50 mL) was added 10% Pd/C (1.13 g, 0.05 eq, 1.07 mmol). The mixture was stirred at 20 oC for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated to afford tert-butyl 4-(2-oxoindolin-5- yl)piperidine-1-carboxylate (6.50 g, 20.5 mmol, 96.4 %) as a yellow solid . LC purity (0.1 %TFA): 85.53% (UV at 254 nm)/MS: 358.2 [M+42]; Retention time: 1.053 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0478] To a mixture of tert-butyl 4-(2-oxoindolin-5-yl)piperidine-1-carboxylate (0.30 g, 1 eq, 0.95 mmol) and TMEDA (0.33 g, 3 eq, 2.8 mmol) in THF (10 mL) at -78 °C was added n-butyllithium (0.17 mL, 2 eq, 1.9 mmol) dropwise slowly at -78 °C, after 30 minutes, MeI (0.12 mL, 2 eq, 1.9 mmol) was added then stirred at -78 °C for 3 h. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mLx2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The mixture was concentrated and the residue was purified by column chromatography on silica gel using 0-20% ethyl acetate/hexane to afford tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (67.0 mg, 195 µmol, 21%) as a yellow solid. LC purity (0.03 %FA): 85.68 % (UV at 254 nm)/MS: 386.1 [M+42]; Retention time: 1.298 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 1-carboxylate (Intermediate 7) [0479] To a mixture of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 145 µmol) in acetonitrile (5 mL) was added cesium carbonate (142 mg, 3 eq, 435 µmol) and 2-chloro-6-fluorobenzonitrile (27.1 mg, 1.2 eq, 174 µmol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column 181 282341894 v2 PRSC-068/001WO (343170-2269) chromatography using 0-20% ethyl acetate/hexane to afford tert-butyl 4-(1-(3-chloro-2- cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (40.0 mg, 83.3 µmol, 57.4%) as a white solid. LC purity (0.1%FA): 62.31 % (UV at 254 nm)/MS: 502.3 [M+23]; Retention time: 1.546 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0480] To a mixture of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 104 µmol) in DMSO (5.00 mL) was added potassium carbonate (43.2 mg, 3 eq, 313 µmol) at 0 oC then added hydrogen peroxide (35.4 mg, 31.9 µL, 10 eq, 1.04 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to afford tert- butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1- carboxylate (40.0 mg, 80 µmol, 77.3%) as a white solid. LC purity (0.1%FA): 88.62 % (UV at 254 nm)/MS: 520.1 [M+23]; Retention time: 1.354 min. Synthesis of tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carboxylate (Intermediate 9) [0481] To a mixture of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (0.20 g, 1 eq, 0.40 mmol) in methanol (5 mL) was added sodium methoxide (0.11 g, 5 eq, 2.0 mmol). The reaction mixture was stirred at 70 °C for 3 h. The mixture was poured into HCl（1M） (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase chromatography to afford tert-butyl 4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carboxylate (50.0 mg, 104 µmol, 26%) as a white solid. LC purity (0.1%FA): 31.93 % (UV at 254 nm)/MS: 480.3 [M+1]; Retention time: 1.465 min. Synthesis of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0482] A mixture of tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carboxylate (0.05 g, 1 eq, 0.1 mmol) in HCl/dioxane (3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give 4-chloro-7,7-dimethyl-9- 182 282341894 v2 PRSC-068/001WO (343170-2269) (piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (18.0 mg, 47.4 µmol, 50 %) as a white solid. LC purity (0.1%FA): 97.98 % (UV at 254 nm)/MS: 380.2 [M+1]; Retention time: 0.869 min.1H NMR (400 MHz, DMSO) δ 9.10 (b, 1H), 8.92-8.94 (b, 1H), 8.40-8.42 (d, J = 8.8 Hz, 1H), 8.14- 8.16 (d, J = 8.4Hz, 1H), 7.81-7.85 (m, 1H), 7.63-7.65 (d, J = 8.0 Hz, 1H), 7.57-7.58 (m, 1H), 7.34- 7.36 (d, J = 8.4 Hz, 1H), 3.37-3.39 (m, 2H), 2.94-3.06 (m, 3H), 1.92-2.02 (m, 4H), 1.53 (s, 9H). Compound B2.4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000184_0001
Synthesis of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 1-carboxylate (Intermediate 3) [0483] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (2.00 g, 1 eq, 5.81 mmol) in MeCN (30 mL) were added 2-chloro-6-fluorobenzonitrile (2.32 g, 2 eq, 11.6 mmol) and 2-chloro-6-fluorobenzonitrile (5.68 g, 3 eq, 17.4 mmol) at room temperature. The reaction was stirred at 80 °C for 16 hours under N2. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum, poured into water (100 mL), extracted with ethyl acetate (50 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 40% of EtOAc in PE) to give tert-butyl 4- (1-(3-bromo-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (2.00 g, 3.81 mmol, 65.6 %) as a yellow solid. LC purity (0.1 % FA): 58.03 % (UV at 254 nm)/MS: 524.1 [M+H]; Retention time: 1.560 min. 183 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 4) [0484] To a solution of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (2.0 g, 1 eq, 3.81 mmol) in DMSO (40 mL) were added K2CO3 (1.05 g, 2 eq, 7.63 mmol) and H2O2 (30 %) (14.0 mL, 120 eq, 457 mmol). The reaction was stirred 50 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL X 2). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3,3-dimethyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (1.90 g, 3.50 mmol, 91.8 %) as a yellow solid. LC purity (0.1 % FA): 100 % (UV at 254 nm)/MS: 486.0 [M-tBu+H]; Retention time: 1.166 min. Synthesis of 4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (Compound B2) [0485] To a solution of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3,3-dimethyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (1.8 mg, 1 eq, 3.32 mmol) in toluene (20 mL) was added TsOH (1.26 g, 2 eq, 6.64 mmol). The reaction was stirred 120 °C for 24 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacumn, diluted with sat. NaHCO3 aq (200 mL), and extracted with MeOH / DCM (1/20, 100 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to give the crude product (1.31 g, 3.09 mmol, 92.78%) as a yellow solid. The crude product (25.0 mg) was further purified by prep- HPLC, eluted with MeCN in H2O from 90: 10 to 5: 95, (0.1% NH4HCO3) to afford 4-bromo-7,7- dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (10.0 mg, 96.35 % purity) as a white solid. LC purity (0.1 % NH4HCO3): 80.76 % (UV at 254 nm)/MS: 424.2 [M+H]; Retention time: 1.652 min.1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.92 – 7.87 (m, 1H), 7.77 – 7.70 (m, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.42 (m, 1H), 3.26 (d, J = 12.4 Hz, 2H), 2.86 (t, J = 12.4 Hz, 3H), 1.92 (t, J = 12.0 Hz, 2H), 1.78 (m, 2H), 1.61 (s, 6H). Compound B3.4-bromo-7,7-diethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one 184 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis
Figure imgf000186_0001
[0486] To a solution of 5-bromoindolin-2-one (5.00 g, 1 eq, 23.60 mmol) in THF (150 mL) was added n-BuLi (28.3 mL, 2.5 M, 3 eq, 70.7 mmol) dropwise -10 °C, and the reaction was stirred for 30 min. Then TMEDA (8.22 g, 3 eq, 70.7 mmol) was added , followed by iodoethane (11.0 g, 3 eq, 70.7 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was quenched by satuted NH4Cl (aq.) (200 mL), extracted with ethyl acetate (150 mL X 3). The combine organic layers were dried over sodium sulfate, concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 5-bromo-3,3-diethylindolin-2-one (1.5 g, 2.54 mmol, 10.8 %) as a red solid. LC purity (0.1 % FA): 40.54 % (UV at 254 nm)/MS: 268.1 [M+H]; Retention time: 1.530 min. Synthesis of tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 4) [0487] To a solution of 5-bromo-3,3-diethylindolin-2-one (1.50 g, 1 eq, 5.60 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.59 g, 1.5 eq, 8.40 mmol) in 1,4-dioxane (5 mL) and H2O (15 mL) was added Pd(dppf)Cl2 (406 mg, 0.1 185 282341894 v2 PRSC-068/001WO (343170-2269) eq, 0.56 mmol) and K2CO3 (1.55 g, 2 eq, 11.2 mmol). The mixture was stirred at 100 °C for 16 hours under N2. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.68 g, 4.53 mmol, 81.1 %) as a white solid. LC purity (0.1 % FA): 55.53 % (UV at 254 nm)/MS: 371.2 [M+H]; Retention time: 1.189 min. Synthesis of tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0488] To a solution of tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.21 g, 1 e q, 3.27 mmol) in methanol (20 mL) was added Pd/C (10%).The mixture was stirred at 25 °C for 16 hours under H2 atmoshpere. LCMS indicated completion of reaction. The reaction solution was filtered and the filtrate was concentrated under vacuum to give tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.14 g, 3.06 mmol, 93.7 %) as a yellow solid. LC purity (0.1 % FA): 96.9 % (UV at 254 nm)/MS: 373.2 [M+H]; Retention time: 1.68 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3,3-diethyl-2-oxoindolin-5-yl)piperidine-1- carboxylate(Intermediate 7) [0489] To a solution of tert-butyl 4-(3,3-diethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.14 g, 1 eq, 3.06 mmol) in acetonitrile (12 mL) was added 2-bromo-6-fluorobenzonitrile (734 mg, 1.2 eq, 3.67 mmol). The mixture was stirred at 90 °C for 16 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and then poured into water (20 mL). The mixture was extracted with ethyl acetate (80 mL X 2). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to give tert-buty 4-(1-(3-bromo-2-cyanophenyl)-3,3-diethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (1.20 g, 2.17 mmol, 71.04 %) as a white solid. LC purity (0.1 % FA): 96.39 % (UV at 254 nm)/MS: 496.0 [M-tBu+1]; Retention time: 1.91 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3,3-diethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0490] To a solution of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3,3-diethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (1.20 g, 1 eq, 2.17 mmol) in DMSO (30 mL) was added potassium carbonate (900 mg, 3 eq, 6.52 mmol), hydrogen peroxide (5.48 g, 5.00 mL, 74.2 eq, 161.0 mmol). The mixture was stirred at 60 °C for 16 hours. LCMS indicated completion of reaction. The 186 282341894 v2 PRSC-068/001WO (343170-2269) reaction was poured into water (100 mL), extracted with ethyl acetate (60 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 20% of EtOAc in PE) to give tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)- 3,3-diethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.14 g, 1.7 mmol, 77%) as a white soild. LC purity (0.1 % FA): 87.94 % (UV at 254 nm)/MS: 514.2 [M-tBu+1]; Retention time: 1.72 min. Synthesis of 4-bromo-7,7-diethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0491] To a solution of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3,3-diethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (900 mg, 1 eq, 1.58 mmol) in toluene (20 mL)was added TsOH (600 mg, 2 eq, 3.15 mmol) at room temperature. The reaction was stirred 120 °C for 24 hours under N2. The reaction was concentracted in vacumn, poured into saturated NaHCO3 (aq.) (200 mL), extracted with MeOH / DCM (1 / 20, 100 mL X 3). The comnined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95%, (0.1% NH3 .H2O) to give 4-bromo-7,7-diethyl-9-(piperidin- 4-yl)indolo[1,2-a]quinazolin-5(7H)-one (135.7 mg, 0.27 mmol, 16.9 %, 89 % purity) as a yellow solid. LC purity (0.1 % FA): 100 % (UV at 254 nm)/MS: 452.2 [M+H]; Retention time: 1.12 min. 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 8.4 Hz, 1H), 8.09 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.75 (m, 1H), 7.46 (d, J = 8.8 Hz, 2H), 3.20 (d, J = 12.0 Hz, 2H), 2.81 (m, 8.2 Hz, 3H), 2.16 (m, 4H), 1.91 (d, J = 12.0 Hz, 2H), 1.74 (m, 2H), 0.46 (t, J = 7.2 Hz, 6H). Compound B4. 4-bromo-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin- 5(7H)-one 187 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000189_0001
[0492] To a solution of 5-bromo-3-methylindolin-2-one (2.00 g, 1 eq, 8.85 mmol) in THF (20 mL) was added TMEDA (3.08 g, 3.98 mL, 3 eq, 26.5 mmol). The mixture was cooled to -10 °C, and n-butyllithium (1.70 g, 3 eq, 26.5 mmol) was added dropwise and stirred at -10 °C for 30 min. Then 2-iodopropane (2.26 g, 1.5 eq, 13.3 mmol) was added. The mixture was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The reaction mixture was poured into water (100 mL), extracted with EA (100 mL X 3). The combined organics were washed with saturated brine (30 mL X 3), dried over sodium sulfate, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 5-bromo-3-isopropyl-3-methylindolin-2-one (900 mg, 2.3 mmol, 27 % yield) as a colourless oil. LC purity (0.1% FA): 88.05 % (UV at 254 nm)/MS: 268.0;270.0 [M+H]; Retention time: 1.54 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)- carboxylate (Intermediate 4) 188 282341894 v2 PRSC-068/001WO (343170-2269) [0493] To a solution of 5-bromo-3-isopropyl-3-methylindolin-2-one (800 mg, 1 eq, 2.98 mmol) i n 1,4-dioxane (8.00 mL) and H2O (1.60 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.38 g, 1.5 eq, 4.48 mmol), K2CO3 (1. 24 g, 3 eq, 8.95 mmol), and 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (218 mg, 0.1 eq, 298 µmol). The mixture was stirred at 100 °C for 16 hours under N2. LCMS indicated completion of reaction. The reaction mixture was poured into water (100 mL), extracted with EA (100 mL X 3). The combined organic layers were washed with saturated brine (30 mL X 3), drie d over sodium sulfate, and concentrated under vacuum. The resulting residue was purified by sili ca gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford tert-butyl 4-(3-i sopropyl-3-methyl-2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.10 g, 2.1 mmol, 70 %) as a yellow soild. LC purity (0.1% FA): 99.90% (UV at 254 nm)/MS: 371.2 [M+H]; Rete ntion time: 1.24 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0494] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (900 mg, 1 Eq, 2.43 mmol) in meOH (10 mL) was added Pd/C (200 mg, 10% Wt) under N2 atmosphere. The mixture was stirred under H2 atmosphere at 25 °C for 1 hour. LCMS indicated completion of reaction. The reaction mixture was filtered and the filtrate was concentrated unver vacuum to give tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (780 mg, 1.5 mmol, 60 %) as a yellow solid. LC purity (0.1% FA): 65.00% (UV at 254 nm)/MS: 373.2 [M+H]; Retention time: 1.69 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 7) [0495] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1- carboxylate (680.0 mg, 1 eq, 1.83 mmol) in CH3CN (2.00 mL) was added 2-bromo-6- fluorobenzonitrile (365.0 mg, 1 eq, 1.83 mmol) and Cs2CO3 (1.78 g, 3 eq, 5.48 mmol), and the reaction was stirred at 80 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered, and the organic layer was concerned under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to give tert- butyl 4-(1-(3-bromo-2-cyanophenyl)-3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1- 189 282341894 v2 PRSC-068/001WO (343170-2269) carboxylate (720 mg, 1.2 mmol, 64 %) as a yellow solid.LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 496.2 [M-tBu+H]; Retention time: 1.89 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0496] To a solution of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3-isopropyl-3-methyl-2- oxoindolin-5-yl)piperidine-1-carboxylate (760 mg, 1 eq, 1.38 mmol) in DMSO (6 mL) was added K2CO3 (228 mg, 1.2 eq, 1.65 mmol) and H2O2 (140 mg, 126 µL, 3 eq, 4.13 mmol), and the reaction was stirred at 50 °C for 16 hours. LCMS indicated completion of reaction. The recation was poured into water (100 mL), extracted with EA (50 mL X 3). The combined organics were washed brine (20 mL X 3), dried over anhydrous sodium sulfate and concerntrated under vacuum to give tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (700 mg, 1.1 mmol, 80 %) as a yellow solid. LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 514 [M-tBu+H]; Retention time: 1.72 min. Synthesis of 4-bromo-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0497] To a solution of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3-isopropyl-3-methyl-2- oxoindolin-5-yl)piperidine-1-carboxylate (700 mg, 1 eq, 1.23 mmol) in toluene (15 mL) was added p-toluenesulfonic acid (1.06 g, 950 µL, 5 eq, 6.13 mmol) , and the reaction was stirred at 100 °C for 24 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by Combi-flash, elutied with 0-30% CH3CN in H2O (0.05% NH4HCO3) to give 4-bromo-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo [1,2- a]quinazolin-5(7H)-one (2.15 mg, 4.61 µmol, 0.376 %, 97.04% purity) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 452.2 [M+H]; Retention time: 1.24 min. 1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.60 – 7.43 (m, 2H), 3.52 (t, J = 16.3 Hz, 2H), 3.18 (t, J = 12.1 Hz, 2H), 3.11 – 3.01 (m, 1H), 2.38 (dt, J = 13.7, 6.8 Hz, 1H), 2.16 (d, J = 14.4 Hz, 2H), 1.96 (dd, J = 26.4, 13.1 Hz, 2H), 1.64 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H). Compound B5.4-chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one 190 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000192_0001
9- yl)piperidine-1-carbonyl)piperidine-1-carboxylate (Intermediate 3) [0498] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol)in DMF (2 mL) were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (120 mg, 1.2 eq, 316 μmol), 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (72.4 mg, 1.2 eq, 316 μmol), N-ethyl-N- isopropylpropan-2-amine (102 mg, 3 eq, 790 μmol) and the reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The recation was poured into water (100 mL), extracted with EA (50 mL X 3). The combined organic layers were washed brine (20 mL X 3), dried over anhydrous sodium sulfate, filtered and concerntrated under vacuum to give tert-butyl (tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)piperidine-1-carboxylate (50 mg, 81.5 μmol, 96.41%) as a white solid. LC purity (0.1% TFA): 96.41% (UV at 254 nm)/MS: 590.3[M+H]; Retention time: 1.69 min. Synthesis of 4-chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one [0499] To a solution of tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (50.0 mg, 1 eq, 84.6 μmol) in DCM (2.00 mL) was added TFA (0.4 mL, 5.2 mmol), and the reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum, and purified by prep-HPLC, eluted with MeCN in H2O from 10% to 85% (0.1% FA) to afford 4- chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (2.06 mg, 4.17 μmol, 4.93% yield, 99.33% purity) as a white solid. LC purity (0.1% FA): 90.18% (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 1.21 min. 1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 8.4 Hz,1H), 4.70-4.74 (m, 1H), 4.20-4.24 (m, 1H), 3.1-3.49 (m, 2H), 3.14 – 3.30 (m, 1H), 3.07 – 3.14 (m, 3H), 2.96-3.06(m, 1H), 2.78-2.81(m, 1H), 1.70-2.00 (m, 6H), 1.60-1.68(m, 2H), 1.20 (s, 6H). 191 282341894 v2 PRSC-068/001WO (343170-2269) Compound B6. 4-bromo-7-ethyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one
Figure imgf000193_0001
[0500] To a solution of 3-methylindolin-2-one (10.0 g, 1 eq, 67.9 mmol) in CH3CN (113 mL) was added 1-bromopyrrolidine-2,5-dione (14.5 g, 1.2 eq, 81.5 mmol) at -15 °C. The mixture was stirred at -15 °C for 1 hour. LCMS indicated completion of reaction. The reaction was poured into H2O (500 mL) and extracted with EA (200 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford 5-bromo-3-methylindolin-2-one (18.0 g, 64 mmol, 94 % yiled) as a white solid. LC purity (0.03% TFA): 100% (UV at 254 nm)/MS: 226.0 [M+H]; Retention time: 0.47 min. Synthesis of 5-bromo-3-ethyl-3-methylindolin-2-one (Intermediate 3) [0501] To a solution of 5-bromo-3-methylindolin-2-one (2.00 g, 1 eq, 8.85 mmol) in THF (20 mL) was added n-butyllithium (1.70 g, 2.37 mL, 3 eq, 26.50 mmol) at -10 °C, the mixture stirred at - 10 °C for 30 minutes, then TMEDA (3.08 g, 3.98 mL, 3 eq, 26.50 mmol) was added, followed by iodoethane (4.14 g, 3 eq, 26.50 mmol) and the reaction was stirred at room temperature for 1 hour. 192 282341894 v2 PRSC-068/001WO (343170-2269) LCMS indicated completion of reaction. The reaction was quenched by satuated NH4Cl (aq.) (200 mL), extracted with EA (80 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 5-bromo-3-ethyl-3- methylindolin-2-one (1.80 g, 7.08 mmol, 80.1 %) as a white solid. LC purity (0.1% TFA): 96.1% (UV at 254 nm)/MS: 254.0 [M+H]; Retention time: 1.46 min. Synthesis of tert-butyl 4-(3-ethyl-3-methyl-2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)- carboxylate (Intermediate 5) [0502] To a solution of 5-bromo-3-ethyl-3-methylindolin-2-one (1.00 g, 1 eq, 3.93 mmol) in 1,4- dioxane (1.00 mL) and H2O (0.2 mL) were added K2CO3 (1.63 g, 3 eq, 11.80 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.83 g, 1.5 eq, 5.90 mmol), and1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (288.0 mg, 0.1 eq, 0.39 mmol). The mixture was stirred at 100 °C for 16 hours under N2. LCMS indicated completion of reaction. The reaction was poured into water (100 mL), extracted with EA (50 mL X 3), washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford tert-butyl 4-(3-ethyl-3-methyl-2-oxoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.10 g, 2.8 mmol, 71 % yield) as a yellow soild. LC purity (0.1% FA): 80.8% (UV at 254 nm)/MS: 301.2 [M-tBu+H]; Retention time: 1.63 min. Synthesis of tert-butyl 4-(3-ethyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 6) [0503] To a solution of tert-butyl 4-(3-ethyl-3-methyl-2-oxoindolin-5-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (1.00 g, 1 eq, 2.81 mmol) in MeOH (40 mL) was added Pd/C (280 mg) under N2. The mixture was stirred under H2 at 25 °C for 1 hour. LCMS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated under vacuum to afford tert-butyl 4-(3- ethyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (0.97 g, 2.7 mmol, 96 %) as a brown solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 359.2 [M+H]; Retention time: 1.64 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3-ethyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0504] To a solution of tert-butyl 4-(3-ethyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.00 g, 1 eq, 2.79 mmol) in CH3CN (10 mL)was added Cs2CO3 (2.73 g, 3 eq, 8.37 mmol), 2- 193 282341894 v2 PRSC-068/001WO (343170-2269) bromo-6-fluorobenzonitrile (670 mg, 1.2 eq, 3.35 mmol) and the reaction was stirred at 80 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added H2O (100 mL), extracted with EA (40 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford tert-butyl 4-(1-(3- bromo-2-cyanophenyl)-3-ethyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.30 g, 2.42 mmol, 86.6% yield %) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 438.2 [M-Boc+H]; Retention time: 1.86 min. Synthesis of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3-ethyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 9) [0505] To a solution of tert-butyl 4-(1-(3-bromo-2-cyanophenyl)-3-ethyl-3-methyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (1.27 g, 1 eq, 2.36 mmol) in DMSO (25 mL)was added H2O2 (6.99 g, 6.30 mL, 87.2 eq, 206 mmol), K2CO3 (652 mg, 2 eq, 4.72 mmol) and the reaction was stirred at 50 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added H2O (100 mL), extracted with EA (40 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 60% of EtOAc in PE) to afford tert-butyl 4-(1-(3-bromo-2- carbamoylphenyl)-3-ethyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (1.20 g, 2.15 mmol, 91.1% yield) as a white solid. LC purity (0.1% FA): 96.66% (UV at 254 nm)/MS: 456.2 [M-Boc+H]; Retention time: 1.67 min. Synthesis of 4-bromo-7-ethyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0506] To a solution of tert-butyl 4-(1-(3-bromo-2-carbamoylphenyl)-3-ethyl-3-methyl-2- oxoindolin-5-yl)piperidine-1-carboxylate (100 mg, 1 eq, 180 μmol) in toluene (5 mL) was added p-toluenesulfonic acid (92.8 mg, 83.5 μL, 3 eq, 539 μmol), and the reaction was stirred at 100 °C for 24 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.3% NH4CO3) to afford 4- bromo-7-ethyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (22.0 mg, 45.7 μmol, 25.4 %, 91.10% purity) as a white solid. LC purity (0.1% FA): 92.45% (UV at 254 nm)/MS: 438.2 [M+H]; Retention time: 0.94 min.1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J 194 282341894 v2 PRSC-068/001WO (343170-2269) = 8.5 Hz, 1H), 3.30 – 3.26 (s, 2H), 2.88 (t, J = 11.8 Hz, 3H), 2.25 – 2.07 (m, 2H), 1.96 (d, J = 13.2 Hz, 2H), 1.83 – 1.77 (m, 2H), 1.60 (s, 3H), 0.48 (t, J = 7.4 Hz, 3H). Compound B7.4-chloro-7,7-dimethyl-8-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0507] Compound B7 was synthesized employing a procedure analogous to the procedure described for Comopund B1. LC purity (0.03% TFA): 100% (UV at 254 nm)/MS: 380.2 [M+H]; Retention time: 1.19 min. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.82 (m, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.55 (m, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.39 (d, J = 12.0 Hz, 2H), 3.26 – 3.18 (m, 2H), 2.03 – 1.92 (m, 2H), 1.86 (d, J = 13.2 Hz, 2H), 1.66 (s, 6H), 1.23 (s, 1H). Compound B8.4-chloro-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin- 5(7H)-one
Figure imgf000196_0001
(2H)- carboxylate (Intermediate 2) [0508] To a solution of 5-bromo-3-methylindolin-2-one (2.00 g, 1 eq, 8.85 mmol) in THF (20 mL) was added TMEDA (3.08 g, 3 eq, 26.5 mmol). The mixture was cooled to -10 °C, and n- butyllithium (1.70 g, 3 eq, 26.5 mmol) was dropwise added and stirred at -10 °C for 30 min. Then 2-iodopropane (2.26 g, 1.5 eq, 13.3 mmol) was added. The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 30% of EtOAc in PE) to get 5-bromo-3-isopropyl-3-methylindolin-2-one 195 282341894 v2 PRSC-068/001WO (343170-2269) (1.55 g, 5.2 mmol, 59 %, 90% Purity) as a colorless oil. LC purity (0.1%FA): 62.5 % (UV at 254 nm)/MS: 268.2 [M+H]; Retention time: 1.370 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 4) [0509] To a solution of 5-bromo-3-isopropyl-3-methylindolin-2-one (1.50 g, 1 eq, 5.59 mmol) in 1,4-dioxane (1 mL) and H2O (200 μL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.59 g, 1.5 eq, 8.39 mmol), K2CO3 (2.32 g, 3 eq, 16.8 mmol), and 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (409 mg, 0.1 eq, 559 μmol). The mixture was stirred at 100 °C for 16 h under N2. LCMS indicated completion of reaction. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 40% of EtOAc in PE) to get tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.55 g, 3.8 mmol, 67 %) as a yellow oil. LC purity (0.1%FA): 100.00 % (UV at 254 nm)/MS: 371.2 [M+H]; Retention time: 1.659 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0510] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.55 g, 1 eq, 4.18 mmol) in MeOH (200 mL) was added Pd/C (445 mg, 0.1 eq, 418 μmol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum to afford tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (1.40 g, 3.4 mmol, 81 %) as a white solid. LC purity (0.1%FA):100 % (UV at 254 nm)/MS: 373.2 [M+H]; Retention time: 1.72 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 7) [0511] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1- carboxylate (1.40 g, 1 eq, 3.76 mmol) in ACN (30 mL) was added 2-chloro-6-fluorobenzonitrile (585 mg, 1 eq, 3.76 mmol). The mixture was stirred at 80 °C for 3 h. LCMS indicated completion of reaction. The reaction was quenched with water and extracted with EA. The organic layer was 196 282341894 v2 PRSC-068/001WO (343170-2269) washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to get tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-isopropyl-3-methyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (1.60 g, 2.8 mmol, 75 %, 90% Purity) as a white soild. LC purity (0.1%FA): 89.7 % (UV at 254 nm)/MS: 452.2 [M-56+H]; Retention time: 1.840 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl-3-methyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0512] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-isopropyl-3-methyl-2- oxoindolin-5-yl)piperidine-1-carboxylate (1.60 g, 1 eq, 3.15 mmol) in DMSO (32 mL) was added K2CO3 (870 mg, 2 eq, 6.30 mmol) and H2O2 (8.88 g, 8.00 mL, 30% Wt, 24.9 Eq, 78.3 mmol). The mixture was stirred at 50 °C for 5 h under N2. LCMS indicated completion of reaction. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to get tert- butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl-3-methyl-2-oxoindolin-5-yl)piperidine-1- carboxylate (1.50 g, 2.6 mmol, 81 %) as a white soild. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 470.2 [M-56+H]; Retention time: 1.390 min. Synthesis of 4-chloro-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (B8) [0513] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl-3-methyl-2- oxoindolin-5-yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 95.0 μmol) in toluene (3 mL) was added p-toluenesulfonic acid (49.1 mg, 3 eq, 285 μmol).The mixture was stirred at 110 °C for 24 h under N2. LCMS indicated completion of reaction. The solvent was removed under vacuum. The resulting residue was purified by prep-HPLC, eluted wit MeCN in H2O from 15% to 70% (0.1% FA) to get 4-chloro-7-isopropyl-7-methyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (2.03 mg, 4.85 μmol, 5.10 %) as a white soild. LC purity (0.1%FA): 85.85 % (UV at 254 nm)/MS: 408.2 [M+H]; Retention time: 1.153 min.1H NMR (400 MHz, MeOD) δ 8.38-8.40 (d, J =8.4 Hz, 1H), 8.05-8.07 (d, J =8.4 Hz, 1H), 7.79-7.83 (m, 1H), 7.61-7.63 (d, J =8.0 Hz, 1H), 7.47 (s, 1H), 7.35-7.37 (d, J =8.4 Hz, 1H), 3.04-3.07 (d, J =12 Hz, 2H), 2.58-2.71 (m, 4H), 2.24-2.30 (m, 1H), 1.73-1.76 (m, 2H), 1.54-1.62 (m, 5H), 0.92-0.94 (m, 3H), 0.58-0.60 (m, 3H). 197 282341894 v2 PRSC-068/001WO (343170-2269) Compound B9.9-bromo-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000199_0001
Synthesis of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzonitrile (Intermediate 3) [0514] To a solution of 5-bromo-3,3-dimethylindolin-2-one (1.00 g, 1 eq, 4.16 mmol) in CH3CN (10 mL) was added 2-chloro-6-fluorobenzonitrile (777 mg, 1.2 eq, 5.00 mmol) and cesium carbonate (2.71 g, 2 eq, 8.33 mmol) and the reaction was stirred at 80 °C for 2 h. LCMS indicated completion of reaction. To the resulting mixture was added EA (30 mL), washed with H2O (10 mL X 3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzonitrile (1.08 g, 2.8 mmol, 66 %) as a white solid. LC purity (0.1%FA): 96.56 % (UV at 254 nm)/MS: 375.0 [M+H]; Retention time: 2.105 min. Synthesis of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzamide (Intermediate 4) [0515] To a solution of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzonitrile (1.00 g, 1 eq, 2.66 mmol) in DMSO (20 mL) was added potassium carbonate (736 mg, 2 eq, 5.32 mmol) and H2O2 (5 mL), and the reaction was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. To the resulting mixture was EA (60 mL), washed with H2O (30 mL X 3) and brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzamide (1.10 g, 2.7 mmol, 100 %) as a white soild. LC purity (0.1%FA): 96.47 % (UV at 254 nm)/MS: 393.0 [M+H]; Retention time: 0.51 min. 198 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of 9-bromo-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (B9) [0516] To a solution of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzamide (1.20 g, 1 eq, 3.05 mmol) in toluene (40 mL) was added Ts-OH (1.74 g, 3 eq, 9.14 mmol), and the reaction was stirred at 110 °C for 16 h. LCMS indicated completion of reaction. The mixture was diluted with DCM (150 mL), washed with NaHCO3 (80 mL X 3) and H2O (60 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 9-bromo-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (300 mg, 789 μmol, 25.9 %) as a gray solid. LC purity (0.1%FA): 98.76% (UV at 254 nm)/MS: 375.0 [M+H]; Retention time: 1.948 min.1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.67-7.63 (m, 2H), 1.54 (s, 6H). Compound B10.10-(1-(4-aminobutyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]qui nazolin-5(7H)-one
Figure imgf000200_0001
[0517] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (150 mg, 1 eq, 0.395 mmol) in DMF (10 mL) was added sodium bicarbonate (332 mg, 0.15 mL, 10 eq, 3.95 mmol) and tert-butyl (4-bromobutyl)carbamate (149 mg, 1.5 eq, 0.59 mmol). The reaction was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. To the mixture was added water (20 mL), extracted with MeOH/DCM=1/10 (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by prep-TLC (MeOH/DCM=1/10) to get tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butyl)carbamate (160 mg, 290 mmol, 73.5 %) as a yellow solid. LC purity (0.03% TFA): 84.81 % (UV at 254 nm)/MS: 551.4 [M+H]; Retention time: 0.901 min. Synthesis of 10-(1-(4-aminobutyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (B10) 199 282341894 v2 PRSC-068/001WO (343170-2269) [0518] To a bottle was added (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butyl)carbamate (10.0 mg, 1 eq, 0.02 mmol) and HCl/EA (4M, 2 mL). Concentrated under vacuum, the resulting residue was purified by prep-HPLC, eluted with MeCN in H2O from 15% to 75% (0.1% FA) to get 10-(1-(4-aminobutyl)piperidin-4-yl)-4-chloro- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (2.11 mg, 4.59 μmol, 25.3 %) as a white solid. LC purity (0.1% FA): 97.51 % (UV at 254 nm)/MS: 451.4 [M+H]; Retention time: 0.16 min.1H NMR (400 MHz, MeOD) δ 8.62-8.41 (m, 3H), 7.93-7.85 (m, 1H), 7.62-7.49 (m, 1H), 7.39-6.96 (dd, J = 30.4, 6.4 Hz, 1H), 3.40-3.15 (d, J = 11.6 Hz, 2H), 2.98-2.56 (m, 3H), 2.79-2.35 (d, J = 6.8 Hz, 2H), 2.64-2.51 (m, 2H), 2.16-1.98 (m, 4H), 1.77-1.32 (s, 4H), 1.59-1.12 (s, 6H). Compound B11.10-(1-(2-aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one
Figure imgf000201_0001
tert- oxo- 10-yl)piperidin-1-yl)ethyl)carbamate (Intermediate 3) [0519] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 0.53 mmol) in MeOH (4 mL) was added tert-butyl formylcarbamate (153 mg, 2 eq, 1.05 mmol), TEA (107 mg, 2 eq, 1.05 mmol) and stirred at 25 oC for 0.5 h. Then NaCNBH3 (165 mg, 5 eq, 2.63 mmol) was added to the above mixture. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of PE in EA) to afford tert-butyl (2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)ethyl)carbamate (120 mg, 0.22 mmol, 41 %) as a yellow oil. LC purity (0.03%TFA): 40.56 % (UV at 254 nm)/MS: 523.3 [M+H]; Retention time: 0.441 min. Synthesis of 10-(1-(2-aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (B11) 200 282341894 v2 PRSC-068/001WO (343170-2269) [0520] A solution of tert-butyl (2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)ethyl)carbamate (120 mg, 1 eq, 0.23 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting residue was purified by prep- HPLC, eluted with MeCN in H2O from 20% to 55% (0.1% FA) to afford 10-(1-(2- aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (3.00 mg, 0.071 mmol, 3.08 %) as a white solid. LC purity (0.1%FA): 99.60 % (UV at 254 nm)/MS: 423.2 [M+H]; Retention time: 0.915 min.1H NMR ((400 MHz, MeOD-d4) δ 8.42 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 4.27 (s, 1H), 3.10 (t, J = 5.9 Hz, 4H), 2.69 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 9.8 Hz, 2H), 1.93 (d, J = 21.9 Hz, 4H), 1.59 (s, 6H). Compound B12.4-chloro-7,7-dimethyl-10-(1H-pyrazol-4-yl)indolo[1,2-a]quinazolin-5(7H)- one 2-
Figure imgf000202_0001
[0521] The solution of 6-bromo-3,3-dimethylindolin-2-one (200 mg, 1 eq, 833 μmol),1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (255 mg, 1.1 eq, 916 μmol), K2CO3 (288 mg, 2.5 eq, 2.08 mmol) and 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (30.5 mg, 0.05 eq, 41.6 μmol) in 1,4- dioxane (4 mL) and Water (0.4 mL) was stirred at 100 °C for 3 h under Ar. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum, diluted with water and extracted with EA. The organic layer was washed with saturated brine, dried with anhydrous 201 282341894 v2 PRSC-068/001WO (343170-2269) sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 70% of EtOAc in PE) to give 3,3-dimethyl-6- (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-2-one (220 mg, 707 μmol, 84.8 %) as a yellow solid. LC purity (0.03%TFA): 96.50 % (UV at 254 nm)/MS: 312.2 [M+H]; Retention time: 0.441 min. Synthesis of tert-butyl 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzonitrile (Intermediate 5) [0522] A solution of 3,3-dimethyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-2- one (220 mg, 1 eq, 707 μmol) , 2-chloro-6-fluorobenzonitrile (132 mg, 1.2 eq, 848 μmol) and Cs2CO3 (575 mg, 2.5 eq, 1.77 mmol) in ACN (3 mL) was was stirred at 85 °C for 16 h. LCMS indicated completion of reaction. The reaction was diluted with water (5 mL) and extracted with EA (10 mL X 2). The organic layer was washed with saturated saline (5 mL X 2) and dried with anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 70% of EtOAc in PE) to give2-chloro-6- (3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-1-yl)benzonitrile (293 mg, 656 μmol, 92.8 %) as a yellow solid. LC purity (0.03%TFA): 100.00 % (UV at 254 nm)/MS: 447.1 [M+H]; Retention time: 1.51 min. 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.72 (dd, J = 9.5, 6.7 Hz, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.45 (dd, J = 7.9, 2.3 Hz, 1H), 7.29 (t, J = 6.5 Hz, 2H), 6.67 (s, 1H), 5.40 (dd, J = 12.0, 4.6 Hz, 1H), 4.10-4.04 (m, 1H), 3.71 (t, J = 10.1 Hz, 1H), 2.13-2.02 (m, 3H), 1.73-1.59 (m, 3H), 1.57 (s, 3H), 1.53 (s, 3H). Synthesis of tert-butyl 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzamide (Intermediate 6) [0523] To a solution of 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzonitrile (290 mg, 1 eq, 649 μmol) in DMSO (3 mL) was added K2CO3 (179 mg, 2 eq, 1.30 mmol) and H2O2 (736 mg, 6.49 mmol) at 0 °C. The reaction was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with the saturated NaHCO3 aqueous solution, filtered, washed with water (5 mL X 2) and the filter cake was dried to get 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)indolin-1-yl)benzamide (230 mg, 491 μmol, 75.7 %) as a white solid. LC purity (0.03%TFA): 99.00 % (UV at 254 nm)/MS: 487.3 [M+Na]; Retention time: 1.86 min. 202 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of tert-butyl 4-chloro-7,7-dimethyl-10-(1H-pyrazol-4-yl)indolo[1,2-a]quinazolin- 5(7H)-one (B12) [0524] To a solution of 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzamide (230 mg, 1 eq, 495 μmol) in toluene (3 mL) was added p- toluenesulfonic acid (170 mg, 2 eq, 989 μmol), and the reaction was stirred at 110 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by prep-HPLC (0.1%FA) to get 4-chloro-7,7-dimethyl-10-(1H- pyrazol-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (160 mg, 441 μmol, 89.1 %) as a white solid. LC purity (0.03%TFA): 100.00 % (UV at 254 nm)/MS: 363.0 [M+H]; Retention time: 1.15 min.1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.55 (d, J = 8.3 Hz, 1H), 8.44 (s, 1H), 8.16 (s, 2H), 7.85 (t, J = 8.3 Hz, 1H), 7.73-7.57 (m, 3H), 1.53 (s, 6H). B13.4-chloro-7,7-dimethyl-10-(1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000204_0001
Synthesis of tert-butyl4-chloro-7,7-dimethyl-10-(1-(pyrazolo[1,5-a]pyrimidine-3- carbonyl)piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (B13) [0525] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30.0 mg, 1 eq, 184 μmol) in DMF (1 mL) was added HATU (105 mg, 1.5 eq, 276 μmol), DIEA (71.3 mg, 96.1 μL, 3 eq, 552 μmol), 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (105 mg, 1.5 eq, 276 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1%FA) to get 4- chloro-7,7-dimethyl-10-(1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one (4.55 mg, 8.42 μmol, 4.58 %) as a white solid. LC purity (0.1%FA): 97.13 % (UV at 254 nm)/MS: 525.2 [M+H]; Retention time: 1.400 min.1H NMR (400 MHz, MeOD) δ 7.61 (dd, J = 7.9, 1.4 Hz, 1H), 7.26-7.11 (m, 1H), 7.09 (s, 1H), 6.95-6.79 (m, 2H), 3.75-3.71 (s, 203 282341894 v2 PRSC-068/001WO (343170-2269) 4H), 3.45-3.33 (m, 3H), 3.22 (dd, J = 11.5, 5.5 Hz, 1H), 3.16-3.05 (m, 2H), 3.05-2.95 (m, 1H), 2.22-2.09 (m, 1H), 2.03-1.90 (m, 1H), 1.88-1.61 (m, 4H). Compound B14.4-chloro-7,7-dimethyl-9-(1H-pyrazol-4-yl)indolo[1,2-a]quinazolin-5(7H)- one
Figure imgf000205_0001
2- one (Intermediate 3) [0526] To a solution of 6-bromo-3,3-dimethylindolin-2-one (2.30 g, 1 eq, 9.58 mmol) in 1,4- dioxane (20 mL) and H2O (4 mL) was added PdCl2(dppf) (710 mg, 0.10 eq, 970 μmol), 1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.70 g, 1.01 eq, 9.71 mmol) and K2CO3 (2.70 g, 2.04 eq, 19.5 mmol). The mixture was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 40% EtOAc in PE) to afford 3,3-dimethyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-2-one (1.60 g, 4.9 mmol, 51 %) as yellow oil. LC purity (0.1%TFA): 100 % (UV at 254 nm)/MS: 312 [M+H]; Retention time: 1.31 min. Synthesis of tert-butyl 2-chloro-6-(3,3-dimethyl-2-oxo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzonitrile (Intermediate 5) [0527] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-1H-pyrazole-1-carboxylate (1.60 g, 1 eq, 4.89 mmol) in CH3CN (10 mL) was added Cs2CO3 (1.59 g, 1 eq, 4.89 mmol), 2- 204 282341894 v2 PRSC-068/001WO (343170-2269) chloro-6-fluorobenzonitrile (760 mg, 1 eq, 4.89 mmol). The mixture was stirred at 80 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 40% of EtOAc in PE) to afford 2- chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-1- yl)benzonitrile (2.00 g, 4.3 mmol, 87 %) as yellow oil. LC purity (0.1%TFA): 100% (UV at 254 nm)/MS: 447.2 [M+H]; Retention time: 1.62 min. Synthesis of tert-butyl 2-chloro-6-(3,3-dimethyl-2-oxo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzamide (Intermediate 6) [0528] To a solution of 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzonitrile (100 mg, 1 eq, 224 μmol) in DMSO (2 mL) was added K2CO3 (55.0 mg, 1.8 eq, 398 μmol), H2O2 (0.56 g, 0.50 mL, 73 eq, 16 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (50% of EtOAc in PE) to afford 2-chloro-6-(3,3- dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-1-yl)benzamide (55.0 mg, 0.11 mmol, 50 %) as a white solid. LC purity (0.03% TFA in ACN): 100 % (UV at 254 nm)/MS: 465.2 [M+H]; Retention time: 1.032 min. Synthesis of tert-butyl 4-chloro-7,7-dimethyl-9-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (Intermediate 7) [0529] To a solution of 2-chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)indolin-1-yl)benzamide (1.80 g, 1 eq, 3.87 mmol) in toluene (23 mL) was added 2- chloro-6-(3,3-dimethyl-2-oxo-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolin-1- yl)benzamide (1.80 g, 1 eq, 3.87 mmol), p-toluenesulfonic acid (2.00 g, 3 eq, 11.6 mmol). The mixture was stirred at 110 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1%FA) to afford 4-chloro-7,7-dimethyl-10-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolo[1,2- 205 282341894 v2 PRSC-068/001WO (343170-2269) a]quinazolin-5(7H)-one (300 mg, 0.54 mmol, 14 %) as a white solid. LC purity (0.1%FA): 100% (UV at 254 nm)/MS: 447.2 [M+H]; Retention time: 1.322 min. Synthesis of tert-butyl 4-chloro-7,7-dimethyl-9-(1H-pyrazol-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (B14) [0530] To 4-chloro-7,7-dimethyl-9-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)indolo[1,2- a]quinazolin-5(7H)-one (9.00 mg, 1 eq, 20.1 μmol) was added HCl/MeOH (0.50 mL). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.3% NH4HCO3) to afford 4-chloro-7,7-dimethyl-9-(1H-pyrazol-4-yl)indolo[1,2-a]quinazolin-5(7H)- one as a white solid. LC purity (0.1% FA): 93.34% (UV at 254 nm)/MS: 363.1 [M+H]; Retention time: 0.94 min.1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 3.30-3.26 (s, 2H), 2.88 (t, J = 11.8 Hz, 3H), 2.25-2.07 (m, 2H), 1.96 (d, J = 13.2 Hz, 2H), 1.83-1.77 (m, 2H), 1.60 (s, 3H), 0.48 (t, J = 7.4 Hz, 3H). Compound B15.4-chloro-7-isopropyl-7-methyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin- 5(7H)-one
Figure imgf000207_0001
Synthesis of 6-bromo-3-methylindolin-2-one (Intermediate 2) 206 282341894 v2 PRSC-068/001WO (343170-2269) [0531] To a solution of 6-bromoindolin-2-one (2.00 g, 1 eq, 9.43 mmol) in toluene (20 mL) was added sodium formaldehydesulfoxylate (2.19 g, 2 eq, 18.9 mmol), K2CO3 (2.61 g, 2 eq, 18.9 mmol) and H2O (3 mL). The mixture was stirred at 100 °C for 3 h. LCMS indicated completion of reaction. The reaction was poured into H2O and extracted with EA. The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) purification to get 6-bromo-3-methylindolin-2-one (660 mg, 2.8 mmol, 29 %) as yellow solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 226.1 [M+1]; Retention time: 1.37 min. Synthesis of 6-bromo-3-isopropyl-3-methylindolin-2-one (Intermediate 3) [0532] To a solution of 6-bromo-3-methylindolin-2-one (5.00 g, 1 eq, 22.1 mmol) in THF (20 mL) was added n-butyllithium (4.25 g, 5.92 mL, 3 eq, 66.4 mmol), TMEDA (7.71 g, 9.95 mL, 3 eq, 66.4 mmol), and 2-iodopropane (7.52 g, 2 eq, 44.2 mmol) on N2. The mixture was stirred at -78 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O and extracted with EA. The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 15% of EtOAc in PE) to get 6-bromo-3-isopropyl-3- methylindolin-2-one (2.10 g, 3.9 mmol, 18 %) as yellow oil. LC purity (0.03%TFA): 52.87 % (UV at 254 nm)/MS: 268.1 [M+1]; Retention time: 1.59 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate (Intermediate 5) [0533] To a solution of 6-bromo-3-isopropyl-3-methylindolin-2-one (2.00 g, 1 eq, 3.73 mmol) in 1,4-dioxane (20 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.50 g, 1.3 eq, 4.85 mmol), PdCl2(dppf) (273 mg, 0.1 eq, 373 μmol), K2CO3 (1.55 g, 3 eq, 11.2 mmol) and H2O (4 mL) under N2. The mixture was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O and extracted with EA. The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to get tert-butyl 4-(3-isopropyl- 3-methyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 1.9 mmol, 51 %) as 207 282341894 v2 PRSC-068/001WO (343170-2269) white solid. LC purity (0.03%TFA): 52.87 % (UV at 254 nm)/MS: 371.2 [M+1]; Retention time: 1.59 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (Intermediate 6) [0534] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-6-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.00 g, 70% wt, 1.89 mmol) in MeOH (10 mL) was added Pd/C (201 mg, 10% wt, 189 μmol), and under H2. The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 20% of EtOAc in PE) to get tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin- 6-yl)piperidine-1-carboxylate (600 mg, 1.5 mmol, 82 %) as a white solid. LC purity (0.1%FA): 94.26 % (UV at 254 nm)/MS: 317.1 [M-56+H]; Retention time: 1.71 min. Synthesis of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (Intermediate 7) [0535] To a solution of tert-butyl 4-(3-isopropyl-3-methyl-2-oxoindolin-6-yl)piperidine-1- carboxylate (600 mg, 1 eq, 1.55 mmol) in CH3CN (15 mL) was added Cs2CO3 (1.51 g, 3 eq, 4.64 mmol), 2-chloro-6-fluorobenzonitrile (313 mg, 1.3 eq, 2.01 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (30 mL X 3). The combined organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to get tert- butyl 4-(1-(3-chloro-2-cyanophenyl)-3-isopropyl-3-methyl-2-oxoindolin-6-yl)piperidine-1- carboxylate (800 mg, 1.5 mmol, 97 %) as white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 452.2 [M-56+H]; Retention time: 1.96 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl-3-methyl-2-oxoindolin-6- yl)piperidine-1-carboxylate (Intermediate 8) [0536] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-isopropyl-3-methyl-2- oxoindolin-6-yl)piperidine-1-carboxylate (800 mg, 1 eq, 1.57 mmol) in DMSO (10 mL) was added K2CO3 (435.2 mg, 2 eq, 3.15 mmol) and H2O2 (4.44 g, 27.4 eq, 43.1 mmol). The mixture was stirred at 60 °C for 3 h. LCMS indicated completion of reaction. The reaction was poured into H2O and extracted with EA. The organic layer was washed brine and dried over anhydrous sodium 208 282341894 v2 PRSC-068/001WO (343170-2269) sulfate, filtered and concentrated to get tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl- 3-methyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (800 mg, 1.4 mmol, 92 %) as white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 426 [M-100+H]; Retention time: 1.76 min. Synthesis of 4-chloro-7-isopropyl-7-methyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (B15) [0537] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-isopropyl-3-methyl-2- oxoindolin-6-yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 95.0 μmol) in toluene was added Ts-OH (90.4 mg, 5 eq, 475 μmol). The mixture was stirred at 110 °C for 72 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O from 30% to 40%( 0.1% NH3.H2O); Retention Time: 6.44-8.48 min of 16 min). LC purity (0.1% FA): 78.58% (UV at 254 nm)/MS: 408.2 [M+H]; Retention time: 1.12 min.1H NMR (400 MHz, DMSO-d6) δ 8.44-8.42 (m, 1H), 7.94 (s, 1H), 7.87-7.83 (m, 1H), 7.65 (d, J=8, 1H), 7.57 (d, J= 8, 1H), 7.26 (d, J=8, 1H), 3.24-3.20 (m, 2H), 2.92-2.77 (m, 3H), 2.33-2.22 (m, 1H), 1.92-1.74 (m, 4H), 1.52 (s, 3H), 1.23 (s, 1H), 0.94 (d, J=7.23H), 0.59 (d, J=8, 3H). Compound B16.10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one
Figure imgf000210_0001
10-yl)piperidin-1-yl)cyclohexyl)carbamate (Intermediate 3) [0538] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 0.53 mmol) in MeOH (4 mL) was added tert-butyl (4-oxocyclohexyl)carbamate (337 mg, 3 eq, 1.58 mmol) and sodium cyanoborohydride (49.62 mg, 1.5 eq, 0.79 mmol) at room temperature. The reaction was stirred 80 °C for 5 h under N2. LCMS indicated completion of reaction. The mixture was added water, extracted with EA (30 mL X 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of DCM in MeOH) to get tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- 209 282341894 v2 PRSC-068/001WO (343170-2269) a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)carbamate (99.9 mg, 0.17 mmol, 32.9 %) as a yellow oil. LC purity (0.1 %FA): 60.0% (UV at 214 nm)/MS: 577.3 [M+H]; Retention time: 0.93 min. Synthesis of methyl 10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (B16) [0539] To a solution of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)carbamate (100 mg, 1 e, 0.17 mmol) in ethyl acetate (2 mL) was added HCl/EA (2 mL) at room temperature. The reaction was stirred at 25 °C for 0.5 h. LCMS indicated completion of reaction. To the mixture was added EA (20 mL) and concentrated under vacuum to give the crude product (70.0 mg, 0.17 mmol, 84.7 %). The crude product (15 mg) was purified by silica gel prep-HPLC, eluted with MeCN in H2O (0.1%FA) to get 10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (4.23 mg, 0.01 mmol, 5.10 %) as a white solid. LC purity (0.1 %TFA): 93.35 % (UV at 214 nm)/MS: 477.2 [M+H]; Retention time: 0.88 min.1H NMR (400 MHz, MeOD) δ 8.42-8.47 (m, 1H), 7.99-8.00 (d, J = 5.6 Hz, 1H), 7.84-7.88 (t, J = 8.0 Hz, 1H), 7.59-7.66 (m, 2H), 7.33-7.38 (m, 1H), 3.52-3.63 (m, 3H), 3.01-3.17 (m, 4H), 2.03-2.31 (m, 9H), 1.95-2.06 (m, 2H), 1.68-1.79 (m, 1H), 1.59 (s, 6H). Compound B17.10-(1-(4-(aminomethyl)cyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000211_0001
Synthesis of tert-butyl ((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)methyl)carbamate (Intermediate 3) [0540] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (300 mg, 1 eq, 790 μmol) in MeOH (3 mL) was added tert-butyl ((4- oxocyclohexyl)methyl)carbamate (215 mg, 1.2 eq, 948 μmol), TEA (240 mg, 3 eq, 2.37 mmol) and sodium cyanoborohydride (149 mg, 3 eq, 2.37 mmol). The reaction mixture was stirred at 80 °C for 16 h. LCMS showed the reaction was complete. The reaction was diluted with EA 210 282341894 v2 PRSC-068/001WO (343170-2269) (100 mL) and washed with water (200 mL). The EA layer was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford the tert-butyl ((4-(4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexyl)methyl)carbamate (237 mg, 0.33 mmol, 42 %) as a white liquid. LC purity (0.1%FA): 82 % (UV at 254 nm)/MS: 591.4 [M+ H]; Retention time: 1.35 min. Synthesis of 10-(1-(4-(aminomethyl)cyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (B17) [0541] To a solution of tert-butyl ((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)carbamate (50.0 mg, 1 eq, 84.6 μmol) in EA (1 mL) was added HCl/EA (1 mL, 4M), and the reaction was stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The mixture was purified by prep-HPLC, eluted with MeCN in H2O from 30% to 95% (0.1%TFA) to give 10-(1-(4-(aminomethyl)cyclohexyl)piperidin-4-yl)- 4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (15.85 mg, 32.08 μmol, 37.9 %) as a white solid. LC purity (0.1%FA): 99.39% (UV at 254 nm)/MS: 981.5 [2M +H]; Retention time: 0.992 min. 1H NMR (400 MHz, DMSO) δ 8.46–8.48 (m, 1H), 9.19 (s, 1H), 7.95-7.96 (m, 1H), 7.82-7.86 (m, 1H), 7.61-7.65(m, 2H), 7.27-7.29 (m, 1H), 3.21-3.25 (m, 2H), 3.02-3.14 (m, 1H), 2.78-2.80 (m, 1H), 2.72-2.75 (m, 1H), 2.64-2.66 (m, 1H), 2.23-2.33 (m, 1H), 1.78-1.91 (m, 6H), 1.60-1.66 (m, 2H), 1.43-1.50 (m, 8H), 1.23-1.30 (m, 3H), 0.97-1.00 (m, 1H). Compound B18.9-(1-(4-aminocyclohexane-1-carbonyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one O OH O NH
Figure imgf000212_0001
Synthesis of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)cyclohexyl)carbamate (lntermediate 3) [0542] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (50 mg, 1 eq, 0.13 mmol) in DMF (3 mL) were added 4-((tert- butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (48 mg, 1.5 eq, 0.19 mmol), HATU (75.1 211 282341894 v2 PRSC-068/001WO (343170-2269) mg, 1.5 eq, 0.19 mmol) and DIEA (40 mg, 0.05 mL, 3 eq, 0.39 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (20 mL) and extracted with EA (20 mL X 3). The combined organics was washed brine (20 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (4% of MeOH in DCM) to afford tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)carbamate (70 mg, 0.12 mmol, 74.7 %) as a white oil. LC purity (0.1% FA): 85.03% (UV at 254 nm)/MS: 605.3 [M+1]; Retention time: 1.66 min. Synthesis of 9-(1-(4-aminocyclohexane-1-carbonyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (B18) [0543] A mixture of tert-butyl tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)carbamate (70 mg, 1 eq, 0.12 mmol) and HCl/MeOH (4 mL, 4N) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. The resulting residue was purified by prep- HPLC, eluted with MeCN in H2O from 20% to 50% (0.1%FA) to get 9-(1-(4-aminocyclohexane- 1-carbonyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50 mg, 0.10 mmol, 84.1 %) as a yellow solid. LC purity (0.1%FA): 100.0% (UV at 254 nm)/MS: 505.3 [M+1]; Retention time: 1.43 min.1H NMR (400 MHz, MeOD) δ 8.4-8.26 (d, J = 8.0 Hz, 1H), 8.07-8.12 (m, 1H), 7.79-7.89 (m, 1H), 7.58-7.63 (m, 1H), 7.47-7.52 (m, 1H), 7.42-7.45 (m, 1H), 4.63-7.73 (m, 2H), 4.01-4.12 (m, 1H), 3.25-3.32 (m, 1H), 2.98-3.02 (m, 1H), 2.64-2.72 (m, 3H), 1.88-1.92 (m, 4H), 1.83-1.85 (m, 2H), 1.6-1.74 (m, 2H), 1.60 (s, 6H), 1.46-1.52 (m, 1H), 1.21-1.31 (m, 2H). Compound B19.10-bromo-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one
Figure imgf000213_0001
[0544] To a solution of 5-bromo-3,3-dimethylindolin-2-one (900 mg, 1 eq, 3.75 mmol) in acetonitrile (14 mL) was added 2-chloro-6-fluorobenzonitrile (1.75 g, 3 eq, 11.2 mmol) and Cs2CO3 (7.33 g, 6 eq, 22.5 mmol) at rt. The reaction was stirred 80 °C for 16 h under N2. LCMS 212 282341894 v2 PRSC-068/001WO (343170-2269) indicated completion of reaction. The mixture was added H2O (100 mL), extracted with EA (50 mL X 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford 2-(5-bromo-3,3-dimethyl- 2-oxoindolin-1-yl)-6-chlorobenzonitrile (1.20 g, 3.19 mmol, 85.2 %) as a yellow oil. LC purity (0.1% TFA): 93.87% (UV at 254 nm)/MS: 375.0 [M+H]; Retention time: 1.686min. Synthesis of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzamide (Intermediate 4) [0545] To a solution of 2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzonitrile (1.20 g, 1 eq, 3.19 mmol) in DMSO (12 mL) was added H2O2 (6.66 g, 6 mL, 61.3 eq, 196 mmol) and K2CO3 (883 mg, 2 eq, 6.39 mmol) at room temperature. The reaction was stirred 80 °C for 16 h under N2. LCMS indicated completion of reaction. To the mixture was added H2O (100 mL) and extracted with EA (50 mL X 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of EA in PE) to afford 2-(5-bromo-3,3-dimethyl- 2-oxoindolin-1-yl)-6-chlorobenzamide (1.20 g, 3.05 mmol, 95.4 %) as a yellow oil. LC purity (0.1% TFA): 93.42% (UV at 254 nm)/MS: 393.0 [M+H]; Retention time: 1.436 min. Synthesis of 10-bromo-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (B19) [0546] To a solution of 2-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-6-chlorobenzamide (1.2 g, 1 eq, 3.05 mmol) in toluene (12 mL) was added p-toluenesulfonic acid (1.58 g, 1.42 mL, 3 eq, 9.15 mmol) at rt. The reaction was stirred 120 °C for 16 h under N2. LCMS indicated completion of reaction. The reaction mixture was quenched with NaHCO3 (40 mL). To the resulting mixture was added H2O (100 mL) and extracted with EA (50 mL X 3). The combined organics was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford 10-bromo- 4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one. The resulting product was further purified by prep-HPLC, eluted with MeCN in H2O from 20% to 70% (0.1%FA) to get 10-bromo- 4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (830 mg, 2.20 mmol, 72.3 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.34 (m, 2H), 7.83 (m, 1H), 7.58-7.69 (m, 3H), 1.52 (s, 6H). LC purity (0.1% FA): 99.88% (UV at 254 nm)/MS: 375.0 [M+H]; Retention time: 1.562 min. 213 282341894 v2 PRSC-068/001WO (343170-2269) Compound B20. 4-chloro-7-methyl-9-(piperidin-4-yl)-7-(trifluoromethyl)indolo[1,2- a]quinazolin-5(7H)-one
Figure imgf000215_0001
[0547] To a solution of 5-bromo-3-methylindolin-2-one (5.50 g, 1 eq, 24.3 mmol) in THF (30 mL) were added sodium carbonate (23.2 g, 14.1 mL, 9 eq, 219 mmol) and di-tert-butyl dicarbonate (13.3 g, 13.6 mL, 2.5 eq, 60.8 mmol). The mixture was stirred at 70 °C for 5 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 3% of EA in PE) to get tert-butyl 5-bromo-3-methyl-2- oxoindoline-1-carboxylate (3.20 g, 9.0 mmol, 37 %) as a colorless oil. LC purity (0.1%FA): 96.16 % (UV at 254 nm)/MS: 350 [M+23]; Retention time: 1.78 min. Synthesis of tert-butyl 5-bromo-3-methyl-2-oxo-3-(trifluoromethyl)indoline-1-carboxylate (Intermediate 4) [0548] To a solution of tert-butyl 5-bromo-3-methyl-2-oxoindoline-1-carboxylate (3.20 g, 1 eq, 9.81 mmol) in DCM (40 mL) were added HMPA (5.27 g, 5.12 mL, 3 eq, 29.4 mmol), sodium 2- methylpropan-2-olate (1.41 g, 1.5 eq, 14.7 mmol) and 1-Trifluoromethyl-1,2-benziodoxol-3-(1H)- one (4.65 g, 1.5 eq, 14.7 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 214 282341894 v2 PRSC-068/001WO (343170-2269) mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 2% of EA in PE) to obtain tert-butyl 5-bromo-3-methyl- 2-oxo-3-(trifluoromethyl)indoline-1-carboxylate (1.20 g, 2.7 mmol, 28%) as a colorless oil. LC purity (0.1%FA): 24.50 % (UV at 254 nm)/MS: 394.1 [M+H]; Retention time: 1.56 min. Synthesis of 5-bromo-3-methyl-3-(trifluoromethyl)indolin-2-one (Intermediate 6) [0549] To a solution of tert-butyl 5-bromo-3-methyl-2-oxo-3-(trifluoromethyl)indoline-1- carboxylate (1.20 g, 1 eq, 3.04 mmol) in HCl/EA (8 mL), The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of EA in PE) to get 5-bromo-3- methyl-3-(trifluoromethyl)indolin-2-one (580 mg, 1.9 mmol, 62%) as a white solid. LC purity (0.1%FA): 85.96 % (UV at 254 nm)/MS: 294 [M+H]; Retention time: 1.56 min. Synthesis of tert-butyltert-butyl 4-(3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (Intermediate 7) [0550] To a solution of 5-bromo-3-methyl-3-(trifluoromethyl)indolin-2-one (580 mg, 1 eq, 1.97 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) were added potassium acetate (968 mg, 616 μL, 5 eq, 9.86 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (732 mg, 1.2 eq, 2.37 mmol). The mixture was stirred at 90 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 20% of EA in PE) to get tert-butyl 4- (3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (620 mg, 1.4 mmol, 73 %, 92% Purity) as a white solid. LC purity (0.1%FA): 87.14 % (UV at 254 nm)/MS: 341 [M-56+H]; Retention time: 1.69 min. Synthesis of tert-butyl 4-(3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)piperidine-1-carboxylate (Intermediate 8) [0551] To a solution of tert-butyl 4-(3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (600.0 mg, 1 eq, 1.51 mmol) in MeOH (8 mL) was 215 282341894 v2 PRSC-068/001WO (343170-2269) added Pd/C (134.2 mg, 60% wt., 0.5 eq, 756.8 μmol). The mixture was stirred at 25 °C for 2 h under H2. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get tert-butyl 4-(3-methyl-2-oxo-3- (trifluoromethyl)indolin-5-yl)piperidine-1-carboxylate (580 mg, 1.4 mmol, 92 %) as a white solid. LC purity (0.1%FA): 97.10 % (UV at 254 nm)/MS: 343.2 [M-56+H]; Retention time: 1.65 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-methyl-2-oxo-3-(trifluoromethyl)indolin- 5-yl)piperidine-1-carboxylate (Intermediate 9) [0552] To a solution of tert-butyl 4-(3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)piperidine- 1-carboxylate (580.0 mg, 1 eq, 1.46 mmol) in CH3CN (10 mL) were added Cs2CO3 (948.6 mg, 2 eq, 2.91 mmol) and 2-chloro-6-fluorobenzonitrile (271.7 mg, 1.2 eq, 1.75 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50% of EA in PE) to obtain tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-methyl-2-oxo-3-(trifluoromethyl)indolin-5- yl)piperidine-1-carboxylate (510 mg, 0.92 mmol, 63 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 556.3 [M+Na]; Retention time: 1.87 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-methyl-2-oxo-3- (trifluoromethyl)indolin-5-yl)piperidine-1-carboxylate (Intermediate 10) [0553] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3-methyl-2-oxo-3- (trifluoromethyl)indolin-5-yl)piperidine-1-carboxylate (500 mg, 1 eq, 936 μmol) in DMSO (10 mL) were added K2CO3 (259 mg, 2 eq, 1.87 mmol) and H2O2 (3.50 g, 33 eq, 30.9 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get tert-butyl 4-(1-(2- carbamoyl-3-chlorophenyl)-3-methyl-2-oxo-3-(trifluoromethyl)indolin-5-yl)piperidine-1- carboxylate (500 mg, 0.86 mmol, 92 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 574 [M+Na]; Retention time: 1.71 min. 216 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of 4-chloro-7-methyl-9-(piperidin-4-yl)-7-(trifluoromethyl)indolo[1,2-a]quinazolin- 5(7H)-one (B20) [0554] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3-methyl-2-oxo-3- (trifluoromethyl)indolin-5-yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 90.6 μmol) in toluene (1 mL) was added p-toluenesulfonic acid (93.6 mg, 6 eq, 543 μmol). The mixture was stirred at 110 °C for 72 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with CH3CN in H2O from 70% to 85% (0.1% NH4HCO3) to get 4-chloro-7- methyl-9-(piperidin-4-yl)-7-(trifluoromethyl)indolo[1,2-a]quinazolin-5(7H)-one (2.37 mg, 5.22 μmol, 5.76 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=8.8, 1H), 8.17(d, J=8.8, 1H), 7.88-7.84 (m, 1H), 7.69-7.66 (m, 2H), 7.51 (d, J= 8.4, 1H), 3.38 (s, 1H), 3.08 (d, J=12, 2H), 2.799-2.74 (m, 1H), 2.68-2.62 (m, 2H), 1.86 (s, 3H), 1.76 (s, 2H), 1.23 (s, 1H), 1.67-1.57 (m, 2H). Compound B21. Synthesis of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one
Figure imgf000218_0001
[0555] To a solution of 6-bromoindolin-2-one (20 g, 1 eq, 94.3 mmol) in THF (200 mL) was added LDA (30.3 g, 3 eq, 283.0mmol). The mixture was stirred at -75 °C for 30 min. To the resulting mixture was added methyl iodide (26.8 g, 2 eq, 189.0 mmol). The mixture was stirred at 217 282341894 v2 PRSC-068/001WO (343170-2269) room temperature for 2 h. LCMS indicated completion of reaction. The reaction was quenched with water (200 mL) and extracted with EA (200 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of EA in PE) to afford 6-bromo-3,3-dimethylindolin-2-one (9.0 g, 33 mmol, 35.0%) as a yellow solid. LC purity (0.1% FA): 87.93 % (UV at 254 nm)/MS: 239.9 [M+H]; Retention time: 1.29 min.1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.24-7.26 (m, 1H), 7.13-7.15 (m, 1H), 6.97-6.99 (dd, J = 10.9, 1.7 Hz, 1H), 1.24 (s, 6H). Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (lntermediate 4) [0556] To a solution of 6-bromo-3,3-dimethylindolin-2-one (9.0 g, 1 eq, 33 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (13.7 g, 3 eq, 99 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20.4 g, 2 eq, 66 mmol) and PdCl2(dppf) (1.21 g, 0.05 eq, 1.65 mmol). The reaction was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 20% of EA in PE) to afford tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate (10.6 g, 30.9 mmol, 92.8 %) as a yellow solid. LC purity (0.1%FA): 96.66 % (UV at 254 nm)/MS: 343.1 [M+H]; Retention time: 1.49 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (lntermediate 5) [0557] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate (10.6 g, 1 eq, 30.9 mmol) in MeOH (200 mL) was added Pd/C (1.1 g, 0.32 eq, 9.9 mmol). The reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was filtered and concentrated under vacuum to afford tert-butyl 4-(3,3-dimethyl-2- oxoindolin-6-yl)piperidine-1-carboxylate (10.6 g, 30.8 mmol, 99.6 %) as a yellow solid. LC purity (0.1%FA): 96.47 % (UV at 254 nm)/MS: 345.1 [M+H]; Retention time:1.48 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperidine- 1-carboxylate (lntermediate 7) [0558] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (10.6 g, 1 eq, 30.8 mmol) in ACN (150 mL) was added cesium carbonate (30.1 g, 3 eq, 92.4 218 282341894 v2 PRSC-068/001WO (343170-2269) mmol) and 2-chloro-6-fluorobenzonitrile (9.58 g, 2 eq, 61.6 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (150 mL) and extracted with EA (150 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 30% of EA in PE) to afford tert-butyl 4-(1-(3- chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (13.0 g, 27.1 mmol, 88.3 %) as a yellow solid. LC purity (0.1%FA): 92.49 % (UV at 254 nm)/MS: 424.1 [M+H- 56]; Retention time: 1.71 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperidine-1-carboxylate (lntermediate 8) [0559] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperidine-1-carboxylate (13.0 g, 1 eq, 27.1 mmol) in DMSO (120 mL) was added K2CO3 (7.49 g, 2 eq, 54.2 mmol) and H2O2 (60 mL). The reaction was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (500 mL), extracted with EA (200 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford tert-butyl 4-(1-(2- carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (12.1 g, 24.30 mmol, 87.9 %) as a yellow solid. LC purity (0.1%FA): 98.11 % (UV at 254 nm)/MS: 498.2 [M+H]; Retention time: 1.48 min. Synthesis of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (B21) [0560] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 6-yl)piperidine-1-carboxylate (10.0 g, 1 eq, 20.1 mmol) in toluene (150 mL) was added Ts-OH (11.5 g, 3 eq, 60.3 mmol). The mixture was stirred at 120 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. To the resulting residue was added NaHCO3 aqueous (100 mL) and extracted with DCM/MeOH=10/1 (100 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4-chloro- 7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (6.86 g, 18.1 mmol, 90 %) as a yellow solid. LC purity (0.1%FA): 100.00 % (UV at 254 nm)/MS: 380.1 [M+H]; Retention time: 0.85 min.1H NMR (400 MHz, MeOD) δ 8.44-8.46 (d, J = 8.8 Hz, 1H), 7.94-8.03 (m, 1H), 7.80- 219 282341894 v2 PRSC-068/001WO (343170-2269) 7.85 (m, 1H), 7.62-7.68 (m, 2H), 7.14-7.25 (d, J = 7.8 Hz, 1H), 2.49-2.54 (m, 2H), 2.29 (m, 3H), 1.95-1.96 (m, 4H), 1.51 (s, 6H). Compound B22. 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2- a]quinazolin-5(7H)-one PHBP, t-BuOH Br Br Zn, AcOH LDA, CH I O N O H N Cl 25 °C, 1 h N H N Cl 25 °C, 1 h N O H N Cl THF, -78 °C, 2 h N H N Cl Boc
Figure imgf000221_0001
Synthesis of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (Intermediate 2) [0561] To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (10.0 g, 1 eq, 65.5 mmol) in t-BuOH (50 mL) was added Pyridinium bromide perbromide (62.9 g, 3 eq, 197 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (100 mL) and extracted with DCM (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get 3,3-dibromo-6-chloro-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one (20.0 g, 55 mmol, 84 %) as a yellow solid. LC purity (0.1%FA): 91.02% (UV at 254 nm)/MS: 325.0 [M+H]; Retention time: 1.40 min. Synthesis of 6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (Intermediate 3) [0562] To a solution of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (8.00 g, 1 eq, 24.5 mmol) in AcOH (100 mL) was added zinc (16.0 g, 10 eq, 245 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was 220 282341894 v2 PRSC-068/001WO (343170-2269) purified by silica gel column chromatography (100-200 mesh silica gel, 40% of EA in PE) to get 6- chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (5.80 g, 28 mmol, 110 %, 80% Purity) as a red solid. LC purity (0.1%FA): 88.66% (UV at 254 nm)/MS: 169.0 [M+H]; Retention time: 0.62 min. Synthesis of 6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (Intermediate4 ) [0563] To a solution of 6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (5.10 g, 1 eq, 30.3 mmol) in THF (120 mL) was added LDA (45.4 mL, 3 eq, 90.8 mmol) at -70 oC and stirred for 2 h. Then, methyl iodide (12.9 g, 5.87 mL, 3 eq, 90.8 mmol) was added to the mixture. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (100 mL) and extracted with EA (300 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 20% of EA in PE) to get 6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (980 mg, 4.7 mmol, 16%, 95% Purity) as a white solid. LC purity (0.1%FA): 100% (UV at 254 nm)/MS: 197.0[M+H]; Retention time: 1.218 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6- dihydropyridine-1(2H)-carboxylate (Intermediate 6) [0564] To a solution of 6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.00 g, 1 eq, 5.09 mmol) in 1,4-dioxane (15 mL) were added PdCl2(dppf) (372 mg, 0.1 eq, 509 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.89 g, 1.2 eq, 6.10 mmol) and K2CO3 (2.11 g, 3 eq, 15.3 mmol). The mixture was stirred at 100 °C for 6 h. LCMS indicated completion of reaction. The reaction was poured into H2O (50 mL) and extracted with EA (200 mL). The organic layer washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 30% of EA in PE) to obtain tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6- dihydropyridine-1(2H)-carboxylate (780 mg, 2.2 mmol, 42 %) as a white solid. LC purity (0.1%FA): 100% (UV at 254 nm)/MS: 344.2 [M+H]; Retention time: 1.564 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6- yl)piperidine-1-carboxylate (Intermediate 7) 221 282341894 v2 PRSC-068/001WO (343170-2269) [0565] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6- yl)-3,6-dihydropyridine-1(2H)-carboxylate (760.0 mg, 1 eq, 2.21 mmol) in MeOH (10 mL) was added Pd/C (1.96 g, 11.06 mmol) under H2. The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction mixture was filtered and concentrated under vacuum to get tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6- yl)piperidine-1-carboxylate (680 mg, 1.9 mmol, 85 %) as a white solid. LC purity (0.1%FA): 94.11 % (UV at 254 nm)/MS: 346.2 [M+H]; Retention time: 1.541 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (Intermediate 9) [0566] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6- yl)piperidine-1-carboxylate (650.0 mg, 1 eq, 1.88 mmol) in CH3CN (20 mL) were added Cs2CO3 (1.84 g, 3 eq, 5.64 mmol) and 2-chloro-6-fluorobenzonitrile (380.5 mg, 1.3 eq, 2.45 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 25% of EA in PE) to get tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (420 mg, 0.84 mmol, 45 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 425.2 [M-56+H]; Retention time: 1.76 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (Intermediate 10) [0567] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (400 mg, 1 eq, 831.6 μmol) in DMSO (10 mL) were added K2CO3 (229.9 mg, 2 eq, 1.66 mmol) and H2O2 (1.11 g, 1.00 mL, 30% wt, 11.8 eq, 9.79 mmol). The mixture was stirred at 45 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to get tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (400 mg, 0.69 mmol, 83 %) as a white solid. LC purity (0.1%FA): 95.59 % (UV at 254 nm)/MS: 517.2 [M+18]; Retention time: 1.67 min. 222 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]quinazolin- 5(7H)-one (B22) [0568] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 100 μmol) in toluene (2 mL) was added Ts-OH (76.2 mg, 4 eq, 401 μmol). The mixture was stirred at 110 °C for 72 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL), then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1%NH4HCO3/H2O) to get 4-chloro-7,7-dimethyl-10-(piperidin-4- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]quinazolin-5(7H)-one (6.50 mg, 16.7 μmol, 16.7 %) as a white solid. LC purity (0.1%FA): 86.55 % (UV at 254 nm)/MS: 381.2 [M+H]; Retention time: 1.14 min.1H NMR (400 MHz, CD3OD) δ 9.92 (d, J=8.4Hz, 1H), 7.97 (d, J=7.6,1H), 7.871-7.830 (m, 1H), 7.67-7.65 (m, 1H), 7.32 (d, J=7.6Hz, 1H), 4.58 (s,2H), 3.13-3.08 (m, 1H), 2.96-2.89 (m, 2H), 2.08-1.99 (m,4H), 1.623 (s, 6H). Compound B23.4-chloro-7,7-dimethyl-10-(piperazin-1-yl)indolo[1,2-a]quinazolin-5(7H)- one
Figure imgf000224_0001
Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperazine-1-carboxylate e (Intermediate 3) [0569] To a solution of 6-bromo-3,3-dimethylindolin-2-one (1.00 g, 1 eq, 4.16 mmol) in 1,4- dioxane (10 mL) were added 2-(Dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (199 223 282341894 v2 PRSC-068/001WO (343170-2269) mg, 0.1 eq, 416 μmol), sodium 2-methylpropan-2-olate (800 mg, 898 μL, 2 eq, 8.33 mmol), tert- butyl piperazine-1-carboxylate (1.55 g, 2 eq, 8.33 mmol) and Pd2(dba)3 (381 mg, 0.1 eq, 416 μmol). The mixture was stirred at 80 °C for 12 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL) and extracted with EA (20 mL X 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 30% of EA in PE) to get tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6- yl)piperazine-1-carboxylate (1.17 g, 3.39 mmol, 81.3%) as a yellow solid. LC purity (0.1% FA): 86.41% (UV at 254 nm)/MS: 346.2 [M+1]; Retention time: 1.504 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperazine- 1-carboxylate (Intermediate 5 ) [0570] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperazine-1-carboxylate (1.00 g, 1 eq, 2.89 mmol) in MeCN (4 mL) were added Cs2CO3 (2.83 g, 3 eq, 8.68 mmol) and 2- chloro-6-fluorobenzonitrile (901 mg, 2 eq, 5.79 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL) and extracted with EA (20 mL X 3). The combined organic layer washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to get tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperazine-1-carboxylate (1.18 g, 2.45 mmol, 84.7 %) as a yellow solid. LC purity (0.1% FA): 97.07% (UV at 254 nm)/MS: 481.2 [M+1]; Retention time: 1.745 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperazine-1-carboxylate (Intermediate 6) [0571] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperazine-1-carboxylate (1.18 g, 1 eq, 2.45 mmol) in DMSO (4 mL) were added H2O2 (6.66 g, 6.00 mL, 79.8 eq, 196 mmol) and K2CO3 (678 mg, 2 eq, 4.91 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL) and extracted with EA (20 mL X 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 40% of EA in PE) to get tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-6- 224 282341894 v2 PRSC-068/001WO (343170-2269) yl)piperazine-1-carboxylate (1.10 g, 2.20 mmol, 89.9 %) as a yellow solid. LC purity (0.01%NH4HCO3): 89.39% (UV at 254 nm)/MS: 499.2 [M+1]; Retention time: 1.965 min. Synthesis of 4-chloro-7,7-dimethyl-10-(piperazin-1-yl)indolo[1,2-a]quinazolin-5(7H)-one (B23) [0572] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 6-yl)piperazine-1-carboxylate (1.10 g, 1 eq, 2.20 mmol) in toluene (3 mL) was added p- Toluenesulfonic acid (759 mg, 683 μL, 2 eq, 4.41 mmol). The mixture was stirred at 120 °C for 12 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and the resulting residue was purified by prep-HPLC, eluting with MeCN in H2O (0.1%NH4HCO3) from 30% to 70% to get 4-chloro-7,7-dimethyl-10-(piperazin-1-yl)indolo[1,2-a]quinazolin-5(7H)- one (800 mg, 2.04 mmol, 92.6 %) as a yellow solid. LC purity (0.1% FA): 95.63% (UV at 254 nm)/MS: 380.8 [M+1]; Retention time: 1.084 min.1H NMR (400 MHz, DMSO-d6) δ 8.38-8.36 (m, 1H), 7.83-7.79 (m, 1H), 7.63-7.61 (m, 1H), 7.51-7.49 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 3.25 (s, 4H), 2.99 (s, 4H), 1.48 (s, 6H). Compound B24.4'-chloro-10'-(1-((1r,4r)-4-ethynylcyclohexane-1-carbonyl)piperidin-4- yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000226_0001
[0573] To a solution of methyl (1r,4r)-4-ethynylcyclohexane-1-carboxylate (400 mg, 1 eq, 2.41 mmol) in THF (5 mL) Water (5 mL) was added LiOH (231 mg, 4 eq, 9.63 mmol). The reaction was stirred at 25 °C for 1 h. TLC indicated completion of reaction. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EA in PE) to afford (1r,4r)-4-ethynylcyclohexane-1-carboxylic acid (165 mg, 1.08 mmol, 45.1 %, 225 282341894 v2 PRSC-068/001WO (343170-2269) 100% Purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 2.83-2.86 (d, J = 2.3 Hz, 1H), 2.15-2.30 (m, 2H), 1.83-1.92 (m, 4H), 1.30-1.33 (t, J = 10.2 Hz, 4H). Synthesis of 4'-chloro-10'-(1-((1r,4r)-4-ethynylcyclohexane-1-carbonyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (B24) [0574] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (60.0 mg, 1 eq, 0.14 mmol) in DMF (3 mL) were added (1r,4r)-4- ethynylcyclohexane-1-carboxylic acid (32.6 mg, 1.5 eq, 0.21 mmol)，DIEA (185 mg, 0.25 mL, 10 eq, 1.43 mmol) and BOP (126 mg, 2 eq, 0.29 mmol). The mixture was stirred at 25 °C for 16 h under N2. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL). The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel prep-TLC (PE:EA=1:1) to get 4'-chloro-10'-(1-((1r,4r)-4-ethynylcyclohexane-1-carbonyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (2.52 mg, 4.29 μmol, 3.01 %) as a white solid. LC purity (0.03%TFA): 100.00% (UV at 254 nm)/MS: 554.3 [M+H]; Retention time: 1.978 min. 1H NMR (400 MHz, CD3OD) δ 8.41-8.43 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.82-7.85 (m, 2H), 7.63-7.65 (d, J = 7.6 Hz, 1H), 7.30-7.32 (d, J = 7.2 Hz, 1H), 4.73-4.76 (d, J = 12.8 Hz, 1H), 4.20-4.23 (d, J = 13.6 Hz, 1H), 3.24-3.26 (d, J = 11.2 Hz, 1H), 3.02-3.04 (m, 1H), 2.68-2.72 (m, 2H), 2.30-2.32 (m, 2H), 1.98-2.13 (m, 8H), 1.69-1.89 (m, 10H), 1.40-1.53 (m, 4H). Compound B25.4'-chloro-10'-(1-(4-ethynylpiperidine-1-carbonyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000227_0001
[0575] To a mixture of 4-ethynylpiperidine hydrochloride (25.0 mg, 1 eq, 172 μmol) and TEA (52.1 mg, 71.8 μL, 3 eq, 515 μmol) in DCM (5 mL) was added triphosgene (19.1 mg, 0.37 eq, 64.4 226 282341894 v2 PRSC-068/001WO (343170-2269) μmol) at 0 °C. To the above mixture was added 4'-chloro-10'-(piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (72.1 mg, 1 eq, 172 μmol) at 0 °C. The resulting mixture was stirred for 18 h at 25 °C. LCMS indicated completion of reaction. The resulting mixture was concentrated under vacuum. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95% (0.1%FA) to afford 4'-chloro-10'-(1-(4-ethynylpiperidine-1-carbonyl)piperidin-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (30.0 mg, 53.9 μmol, 31.4 %) as a white solid. LC purity (0.1% FA): 99 % (UV at 254 nm)/MS: 555.2 [M+H]; Retention time: 1.72 min. 1H NMR (400 MHz, CDCl3) δ 8.15-8.00 (m, 1H), 7.82-7.64 (m, 3H), 7.50-7.57 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.48-3.61 (m, 2H), 3.18- 3.04 (m, 2H), 2.92-2.98 (t, J = 12.1 Hz, 2H), 2.70-2.75 (m, 1H), 2.55-2.69 (m, 1H), 2.02-2.22 (m, 4H), 2.01 (s, 1H), 1.56-1.94 (m, 14H). Compound 26.4'-chloro-10'-(1-(piperidine-4-carbonyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000228_0001
indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (Intermediate 3) [0577] To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (164 mg, 1.5 eq, 714 μmol) in DMF (4.8 mL) was added HATU (181 mg, 1 eq, 476 μmol) and DIEA (61.6 mg, 83.0 μL, 1 eq, 476 μmol) and 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (200 mg, 1 eq, 476 μmol). The reaction was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford tert-butyl 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1- 227 282341894 v2 PRSC-068/001WO (343170-2269) carbonyl)piperidine-1-carboxylate (180 mg, 0.16 mmol, 34 %, 57% Purity) as a white solid. LC purity (0.1%FA): 94.02 % (UV at 254 nm)/MS: 631.2 [M+H]; Retention time: 1.798 min. Synthesis of tert-butyl 4'-chloro-10'-(1-(piperidine-4-carbonyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (B26) [0578] To a solution of tert-butyl 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (180 mg, 1 eq, 285 μmol) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by silica gel prep-HPLC, eluted with CH3CN H2O from 10% to 95% (0.1%FA) to get 4'- chloro-10'-(1-(piperidine-4-carbonyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (2.73 mg, 5.06 μmol, 1.78 %) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 8.44 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.62 (d, J = 13.0 Hz, 1H), 4.10 (s, 1H), 2.96 (s, 4H), 1.98 (d, J = 41.8 Hz, 3H), 1.84 (d, J = 39.6 Hz, 5H), 1.79-1.44 (m, 14H), 1.47-1.37 (m, 1H). Compound B27.4'-chloro-10'-(4-((1r,4r)-4-ethynylcyclohexane-1-carbonyl)piperazin-1-yl)- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000229_0001
Synthesis of 4'-chloro-10'-(4-((1r,4r)-4-ethynylcyclohexane-1-carbonyl)piperazin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (B27) [0579] To a solution of (1r,4r)-4-ethynylcyclohexane-1-carboxylic acid (20.0 mg, 1 eq, 131 μmol) in DMF (0.5 mL) was added DIEA (102 mg, 137 μL, 6 eq, 788 μmol) and HATU (75.0 mg, 1.5 eq, 197 μmol). The mixture was stirred at 25 °C for 10 mins, and 4'-chloro-10'-(piperazin-1-yl)- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (55.3 mg, 1 eq, 131 μmol) was added in the mixture and stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined 228 282341894 v2 PRSC-068/001WO (343170-2269) organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95%, (0.1%FA) to afford 4'-chloro-10'-(4-((1r,4r)-4-ethynylcyclohexane-1- carbonyl)piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (2.16 mg, 3.63 μmol, 2.76 %) as a white solid. LC purity (0.1%FA): 99 % (UV at 254 nm)/MS: 555.4 [M+H]; Retention time: 1.61min.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.6 Hz, 1H), 7.84-7.80(m, 1H), 7.69-7.62 (m, 2H), 7.54 (d, J = 1.6 Hz, 1H), 6.95-6.92 (m, 1H), 3.66 (d, J = 18.4 Hz, 4H), 3.25 (d, J = 17.4 Hz, 4H), 2.86 (d, J = 2.3 Hz, 1H), 2.71-2.63 (m, 1H), 2.31-2.20 (m, 1H), 2.07- 1.84 (m, 6 H), 1.70 (d, J = 8.4 Hz, 8H), 1.48-1.30 (m, 4H). Compound B28.4'-chloro-10'-(4-(((1r,4r)-4-ethynylcyclohexyl)methyl)piperazin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000230_0001
Synthesis of 4'-chloro-10'-(4-(((1r,4r)-4-ethynylcyclohexyl)methyl)piperazin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (B28) [0580] To a solution of (1r,4r)-4-ethynylcyclohexane-1-carbaldehyde (50.0 mg, 1 eq, 367 μmol) in MeOH (2 mL) was added 4'-chloro-10'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (155 mg, 1 eq, 367 μmol), TEA (111 mg, 154 μL, 3 eq, 1.10 mmol) and NaCNBH3 (46.1 mg, 2 eq, 734 μmol). The mixture was stirred at 25 °C for 3 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95%, (0.1% FA) to afford 4'-chloro-10'-(4-(((1r,4r)-4- ethynylcyclohexyl)methyl)piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (2.48 mg, 4.55 μmol, 1.24 %, 99.2% purity) as a white solid. LC purity (0.1%FA): 99 % (UV at 254 nm)/MS: 541.4 [M+H]; Retention time: 1.17 min.1H NMR (400 MHz, MeOD) δ 8.37 (d, J = 8.6 Hz, 1H), 7.93-7.71 (m, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 3.40- 229 282341894 v2 PRSC-068/001WO (343170-2269) 3.55 (m, 4H), 2.96-3.11 (m, 4H), 2.61 (d, J = 6.9 Hz, 2H), 2.31 (d, J = 2.3 Hz, 1H), 2.20-2.23 (m, 1H), 2.01-2.09 (m, 6H), 1.80-1.93 (m, 5H), 1.63-1.78 (m, 4H), 1.35-1.51 (m, 2H), 0.98-1.16 (m, 2H) Compound B29: 4'-chloro-10'-(4-(4-ethynylpiperidine-1-carbonyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000231_0001
Synthesis of tert-butyl 1-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-4-carboxylate (Intermediate 3) [0581] To a solution of 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (3.00 g, 1 eq, 10.7 mmol) in 1,4-dioxane (30 mL) were added tert-butyl piperidine-4-carboxylate (1.98 g, 1 eq, 10.7 mmol), Pd2(dba)3 (981 mg, 0.1 eq, 1.07 mmol), 2-(Dicyclohexylphosphanyl)-2',4',6'- tris(isopropyl)biphenyl (1.02 g, 0.2 eq, 2.14 mmol) and sodium 2-methylpropan-2-olate (3.09 g, 3.46 mL, 3 eq, 32.1 mmol). The reaction was stirred at 110 °C under microwave irradiation for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 1-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'- yl)piperidine-4-carboxylate (1.70 g, 3.8 mmol, 36 %) as brown oil. LC purity (0.1%FA): 86 % (UV at 254 nm)/MS: 385.2 [M+H]; Retention time: 1.64 min. Synthesis of tert-butyl 1-(1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-6'- yl)piperidine-4-carboxylate (Intermediate 5) 230 282341894 v2 PRSC-068/001WO (343170-2269) [0582] To a solution of tert-butyl 1-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-4- carboxylate (1.70 g, 1 eq, 4.42 mmol) in MeCN (20 mL) were added Cs2CO3 (4.32 g, 3 eq, 13.3 mmol) and 2-chloro-6-fluorobenzonitrile (688 mg, 1 eq, 4.42 mmol). The mixture was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100- 200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 1-(1'-(3-chloro-2-cyanophenyl)-2'- oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-4-carboxylate (1.70 g, 3.27 mmol, 73.9 %) as yellow oil. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 520.0 [M+H]; Retention time: 1.84 min. Synthesis of tert-butyl 1-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-6'-yl)piperidine-4-carboxylate (Intermediate 6) [0583] To a solution of tert-butyl 1-(1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-6'-yl)piperidine-4-carboxylate (1.60 g, 1 eq, 3.08 mmol) in DMSO (15 mL) were added K2CO3 (850 mg, 2 eq, 6.15 mmol) and H2O2 (209 mg, 189 μL, 2 eq, 6.15 mmol). The mixture was stirred at 50 °C for 16 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (80 mL) and extracted with ethyl acetate (80 mL X 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 1-(1'-(2- carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl) piperidine-4-carboxylate (500 mg, 0.74 mmol, 24 %) as a yellow oil. LC purity (0.1%NH4HCO3): 94.80 % (UV at 254 nm)/MS: 538.1 [M+H]; Retention time: 1.91 min. Synthesis of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidine-4-carboxylic acid (Intermediate 7) [0584] To a solution of tert-butyl 1-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane- 1,3'-indolin]-6'-yl)piperidine-4-carboxylate (450 mg, 1 eq, 836 μmol) in toluene (5 mL) was added p-toluenesulfonic acid (720 mg, 648 μL, 5 eq, 4.18 mmol) under N2. The mixture was stirred at 110 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with 231 282341894 v2 PRSC-068/001WO (343170-2269) brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EA in PE) to afford 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidine-4-carboxylic acid (20.0 mg, 39 μmol, 23 %) as a white soild. LC purity (0.1%FA): 95.4% (UV at 254 nm)/MS: 464.2 [M+H]; Retention time: 1.54 min. Synthesis of 4'-chloro-10'-(4-(4-ethynylpiperidine-1-carbonyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (B29) [0585] To a solution of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidine-4-carboxylic acid (20 mg, 1 eq, 43.1 μmol) in DMF (1 mL) were added DIEA (11.1 mg, 15.0 μL, 2 eq, 86.2 μmol), HATU (32.8 mg, 2 eq, 86.2 μmol) and 4-ethynylpiperidine hydrochloride (9.42 mg, 1.5 eq, 64.7 μmol). The mixture was stirred at 25 °C for 4 h under N2. LCMS indicated completion of reaction. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O from 10% to 95%(0.1% FA) to afford 4'-chloro-10'-(4-(4-ethynylpiperidine- 1-carbonyl)piperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (13.29 mg, 23.64 μmol, 54.8 %) as a yellow solid. LC purity (0.1%FA): 100.00 % (UV at 254 nm)/MS: 555.2 [M+H]; Retention time: 1.71 min. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.7 Hz, 1H), 7.85-7.81 (m, 1H), 7.66-7.61 (m, 2H), 7.49 (s, 1H), 6.91 (d, J = 7.0 Hz, 1H), 3.87-3.76 (m,4H), 3.32-3.30 (m, 1H), 2.99-2.98 (m, 1H), 2.92-2.78 (m, 3H), 2.73-2.67 (m, 1H), 2.07-1.95 (m, 2H), 1.89-1.84 (m, 3H), 1.72 (s, 10H), 1.63-1.23 (m, 4H). Compound B30.10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one Synthesis of
Figure imgf000233_0001
a]quinazolin]-5'-one (B30) [0586] To a solution of 4'-bromo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.215 mmol) in MeOH (20 mL) was added Pd(OH)2 (30 mg, 232 282341894 v2 PRSC-068/001WO (343170-2269) 1 eq, 0.22 mmol). The mixture was stirred at 25 °C for 16 h under H2. LCMS indicated completion of reaction. The mixture was filtered. The filtrate was purified by prep-HPLC, eluting with MeCN in H2O from 10% to 95%(0.1%NH4CO3) to afford 10'-(piperidin-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (18.0 mg, 0.04 mmol, 20.6 %) as a white solid. LC purity (0.03%NH3.H2O): 94.86% (UV at 214 nm)/MS: 386.2 [M+H]; Retention time: 8.645 min. 1H NMR (400 MHz, MeOD) δ 8.55-8.53 (m, 1H), 8.37-8.36 (m, 1H), 8.07 (s, 1H), 8.02-7.98 (m, 1H), 7.88-7.86 (m, 1H), 7.67-7.63 (m, 1H), 7.34-7.33 (m, 1H), 3.34 (s, 1H), 3.03-2.91 (m, 3H), 2.14- 1.98 (m, 6H), 1.94-1.73 (m, 9H). Compound B31.5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazoline]-4'-carboxamide
Figure imgf000234_0001
- 10'-yl)piperidine-1-carboxylate (Intermediate 2) [0587] To a solution of tert-butyl 4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (80.0 mg, 1 eq, 142 μmol) in NMP (5 mL) were added XPhos Pd-G3 (12.0 mg, 0.1 eq, 14.2 μmol)，Zinc cyanide (49.9 mg, 3 eq, 425 μmol) and 2-(Dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (13.5 mg, 0.2 eq, 28.3 μmol). The mixture was stirred at 150 °C for 5 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting mixture was purified by silica gel chromatography (100- 200 mesh silica gel, 10% of DCM in MeOH) to give tert-butyl 4-(4'-cyano-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (40.0 mg, 85 μmol, 61 %) as a yellow oil. LC purity (0.1% FA): 97.7% (UV at 254 nm)/MS: 411.2 [M+1]; Retention time: 1.75 min. Synthesis of 5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazoline]-4'- carboxamide (B31) 233 282341894 v2 PRSC-068/001WO (343170-2269) [0588] A solution of tert-butyl 4-(4'-cyano-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (50 mg, 1 eq, 97.9 μmol) in H2SO4 (1 mL) was stirred at 50 °C for 6 h. LCMS indicated completion of reaction. The mixture was poured into ice water (20 mL) and extracted with DCM (20 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O from 10% to 95% (0.1%FA) to afford 5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazoline]-4'-carboxamide (2.00 mg, 4.60 μmol, 4.75 %) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 429.2 [M+1]; Retention time: 1.15 min. 1H NMR (400 MHz, MeOD) δ 8.54 (d, J = 8.6 Hz, 1H), 8.04 (s, 1H), 8.01-7.95 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 3.56 (d, J = 12.4 Hz, 2H), 3.25-3.07 (m, 3H), 2.29- 1.95 (m, 8H), 1.94-1.61 (m, 6H). Compound B32.4'-chloro-3-hydroxy-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one
Figure imgf000235_0001
Synthesis of 2-((1,3-dibromopropan-2-yl)oxy)tetrahydro-2H-pyran (Intermediate 2) [0589] To a solution of 1,3-dibromopropan-2-ol (5 g, 1 eq, 22.9 mmol) in THF (50 mL) was added PPTS (577 mg, 0.1 eq, 2.29 mmol) and 3,4-dihydro-2H-pyran (1.93 g, 1 eq, 22.9 mmol) and the reaction was stirred at 25 °C for 3 h. TLC indicated completion of reaction. The mixture was 234 282341894 v2 PRSC-068/001WO (343170-2269) poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 2-((1,3-dibromopropan-2-yl)oxy)tetrahydro-2H-pyran (3.70 g, 12.3 mmol, 53.4 %) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.79 (t, J = 3.6 Hz, 1H), 3.71- 3.63 (M, 2H), 3.59-3.52 (M, 5H), 1.70-1.49 (m, 6H). Synthesis of 6'-bromo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Intermediate 4) [0590] To a solution of 6-bromoindolin-2-one (1.00 g, 1 eq, 4.72 mmol) in THF (10 mL) was added LiHMDS (2.60 g, 3.3 eq, 15.6 mmol) at -78 °C and the reaction was stirred for 1 h. To the resulting mixture 2-((1,3-dibromopropan-2-yl)oxy)tetrahydro-2H-pyran (1.42 g, 1 eq, 4.72 mmol) in THF (6 mL) was added dropwise. The reaction was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 6'-bromo- 3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (150 mg, 426 μmol, 9.03 % yiled) as a yellow solid and 6'-bromo-3-hydroxyspiro[cyclobutane-1,3'-indolin]-2'-one (90.0 mg, 336 μmol, 7.12 %) as a white solid. LC purity (0.1%FA): 97.36% (UV at 254 nm)/MS: 374.0 [M+23]. Retention time: 1.55 min. Synthesis of tert-butyl 4-(2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'- indolin]-6'-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 6) [0591] To a solution of 6'-bromo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'- indolin]-2'-one (400 mg, 1 eq, 795 μmol) in 1,4-dioxane (4 mL) and H2O (1 mL) were added tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (295 mg, 1.2 eq, 954 μmol), PdCl2(dppf) (58.2 mg, 0.1 eq, 79.5 μmol) and K2CO3 (330 mg, 3 eq, 2.38 mmol). The reaction was stirred at 100 °C for 2 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 60% of EtOAc in PE) to afford tert-butyl 4-(2'-oxo-3- 235 282341894 v2 PRSC-068/001WO (343170-2269) ((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (330 mg, 0.36 mmol, 46 %) as a white solid. LC purity (0.1 %FA): 43.67% (UV at 214 nm)/MS: 477.2 [M+Na]. Retention time: 2.11 min. Synthesis of tert-butyl 4-(2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'- indolin]-6'-yl)piperidine-1-carboxylate (Intermediate 7) [0592] To a solution of tert-butyl 4-(2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane- 1,3'-indolin]-6'-yl)-3,6-dihydropyridine-1(2H)-carboxylate (330 mg, 1 eq, 363 μmol) in MeOH (8 mL) was added Pd/C (20 mg) under N2 and the reaction was stirred at 20 °C for 2 h under H2. LCMS indicated completion of reaction. The reaction was filtered. The filtrate was concentrated under vacuum to give tert-butyl 4-(2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane- 1,3'-indolin]-6'-yl)piperidine-1-carboxylate (320 mg, 0.35 mmol, 97%) as a yellow solid. LC purity (0.1 %FA): 44.7% (UV at 214 nm)/MS: 457.3[M+H]. Retention time: 2.11 min. Synthesis of tert-butyl 4-(1'-(3-chloro-2-cyanophenyl)-2'-oxo-3-((tetrahydro-2H-pyran-2- yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (Intermediate 9) [0593] To a solution of tert-butyl 4-(2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane- 1,3'-indolin]-6'-yl)piperidine-1-carboxylate (320 mg, 1 eq, 350 μmol) in DMF (3 mL) were added 2-chloro-6-fluorobenzonitrile (81.8 mg, 1.5 eq, 526 μmol) and Cs2CO3 (343 mg, 3 eq, 1.05 mmol). The reaction mixture was stirred at 80 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford tert-butyl 4-(1'-(3-chloro-2- cyanophenyl)-2'-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'- yl)piperidine-1-carboxylate (200 mg, 0.32 mmol, 92 %) as a white solid. LC purity (0.1 % TFA): 97.72 % (UV at 214 nm)/MS: 614.4 [M+23]. Retention time: 1.84 min. Synthesis of tert-butyl 4-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxo-3-((tetrahydro-2H-pyran-2- yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (Intermediate 10) [0594] To a solution of tert-butyl 4-(1'-(3-chloro-2-cyanophenyl)-2'-oxo-3-((tetrahydro-2H- pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (210 mg, 1 eq, 355 μmol) in DMSO (3 mL) were added K2CO3 (98.0 mg, 2 eq, 709 μmol) and H2O2 (1.11 g, 1.00 mL, 92.0 eq, 32.6 mmol). The reaction mixture was stirred at 50 °C for 6 h. LCMS indicated 236 282341894 v2 PRSC-068/001WO (343170-2269) completion of reaction. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (50% of EtOAc in PE) to afford tert-butyl 4-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxo- 3-((tetrahydro-2H-pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (95.0 mg, 0.14 mmol, 40%) as a white solid. LC purity (0.1%FA): 87.56 % (UV at 254 nm)/MS: 510.2 [M-100+H]. Retention time: 1.67 min. Synthesis of 4'-chloro-3-hydroxy-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-5'-one (B32) [0595] To a solution of tert-butyl 4-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxo-3-((tetrahydro-2H- pyran-2-yl)oxy)spiro[cyclobutane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (95 mg, 1 eq, 156 μmol) in toluene (6 mL) was added p-toluenesulfonic acid (80.4 mg, 3 eq, 467 μmol). The reaction mixture was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The mixture was filtered and concnentrated. The resulting black oil was purified by prep-HPLC, eluted with MeCN in H2O from 20% to 80% (0.1% NH4HCO3) to afford 4'-chloro-3-hydroxy-10'-(piperidin-4-yl)- 5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-5'-one (10.26 mg, 23.72 μmol, 15.2 % yield) as a white solid. LC purity (0.1%FA): 97.89 % (UV at 254 nm)/MS: 408.2 [M+H]; Retention time: 1.15min. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.6 Hz, 1H), 7.92-7.89 (m, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.81-7.73 (m, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.33-7.27 (m, 1H), 5.68-5.50 (m, 1H), 4.81-4.69 (m, 1H), 3.13 (d, J = 10.9 Hz, 2H), 2.96-2.54 (m, 7H), 1.82-1.69 (m, 4H). Compound B33.4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazoline]-3,5'-dione
Figure imgf000238_0001
a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 2) 237 282341894 v2 PRSC-068/001WO (343170-2269) [0596] To a solution of 4'-chloro-3-hydroxy-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one (800 mg, 1 eq, 981 μmol) in DCM (10 mL) were added TEA (298 mg, 410 μL, 3 eq, 2.94 mmol) and (Boc)2O (278 mg, 1.3 eq, 1.27 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (100 mL). The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50%THF in PE) to afford tert-butyl 4-(4'-chloro-3-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (560 mg, 0.99 mmol, 100 %) as a yellow solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 508.2 [M+1]; Retention time: 1.60 min. Synthesis of tert-butyl 4-(4'-chloro-3,5'-dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 3) [0597] To a solution of tert-butyl 4-(4'-chloro-3-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (400 mg, 1 eq, 787.4 μmol) in DCM (10 mL) was added DMP (2.00 g, 6 eq, 4.72 mmol). The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 4-(4'-chloro-3,5'- dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (270.0 mg, 0.51 mmol, 65 %) as a white solid. LC purity (0.1%FA): 85.59 % (UV at 254 nm)/MS: 506.1 [M+H]; Retention time: 1.56 min. Synthesis of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazoline]-3,5'-dione (B33) [0598] A solution of tert-butyl 4-(4'-chloro-3,5'-dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (20 mg, 1 eq, 39.5 μmol) in TFA/DCM (2 mL) was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction was filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O from 20% to 80% (0.1% FA) to get 4'-chloro-10'-(piperidin-4-yl)-5'H- spiro[cyclobutane-1,7'-indolo[1,2-a]quinazoline]-3,5'-dione (2.25 mg, 4.74 μmol, 12.0 %) as a 238 282341894 v2 PRSC-068/001WO (343170-2269) white solid. LC purity (0.1%FA): 93.80 % (UV at 254 nm)/MS: 406.2 [M+H]; Retention time: 1.21 min.1H NMR (400 MHz, MeOD) δ 8.55-8.63 (m, 1H), 8.38-8.41 (m, 1H), 8.03 (s, 1H) 7.81- 7.97 (m, 2H), 7.64-7.68 (m, 1H), 7.36-7.42 (m, 1H), 3.85-3.90 (m, 1H), 3.69-3.73 (m, 1H), 3.54- 3.59 (m, 2H), 3.13-3.24 (m, 3H), 2.17-2.21 (m, 2H), 2.02-2.09 (m, 2H), 1.26-1.33 (m, 2H). Compound B34.4'-chloro-3-(dimethylamino)-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane- 1,7'-indolo[1,2-a]quinazolin]-5'-one
Figure imgf000240_0001
indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 2) [0599] To a solution of tert-butyl 4-(4'-chloro-3,5'-dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (20 mg, 1 eq, 39.5 μmol) in MeOH (1 mL) were added dimethylamine (17.8 mg, 10 eq, 395 μmol), sodium cyanoborohydride (10.0 mg, 4.0 eq, 158 μmol) and DCM (0.2 mL). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl 4-(4'-chloro-3-(dimethylamino)-5'-oxo-5'H- spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (20.0 mg, 22 μmol, 57 %) as a white solid. LC purity (0.1%FA): 89.51 % (UV at 254 nm)/MS: 535.2 [M+H]; Retention time: 1.43 min. Synthesis of 4'-chloro-3-(dimethylamino)-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one (B34) [0600] A solution of tert-butyl 4-(4'-chloro-3-(dimethylamino)-5'-oxo-5'H-spiro[cyclobutane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (20.0 mg, 1 eq, 22.4 μmol) in HCl/EA (2 mL, 4M) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with MeCN in H2O from 5% to 80% (0.1% NH4HCO3) to get 4'-chloro-3- 239 282341894 v2 PRSC-068/001WO (343170-2269) (dimethylamino)-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-5'-one (2.69 mg, 6.04 μmol, 26.9 %) as a yellow solid. LC purity (0.1%FA): 93.80 % (UV at 254 nm)/MS: 435.2 [M+H]; Retention time: 1.01 min.1H NMR (400 MHz, MeOD) δ 8.55-8.62 (m, 1H), 8.38- 8.46 (m, 1H), 8.02 (s, 1H) 7.84-7.96 (m, 2H), 7.66-7.72 (m, 1H), 7.41-7.46 (m, 1H), 4.55-4.66 (m, 3H), 3.55 (d, J = 12.8 Hz, 2H), 3.07-3.20 (m, 4H), 2.87-2.99 (m, 3H), 2.66-2.75 (m, 2H), 2.15- 2.19 (m, 2H), 2.02-2.08 (m, 2H). Compound B35.4'-chloro-3-(methylamino)-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one
Figure imgf000241_0001
indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 2) [0601] To a solution of tert-butyl 4-(4'-chloro-3,5'-dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (100.0 mg, 1 eq, 197.6 μmol) in MeOH (1 mL) were added TEA (59.99 mg, 3 eq, 592.9 μmol), methylamine (61.38 mg, 10 eq, 1.98 mmol), NaCNBH3 (37.26 mg, 3 eq, 592.9 μmol) and DCM (0.2 mL). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (100 mL), then washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford tert-butyl 4- (4'-chloro-3-(methylamino)-5'-oxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidine-1-carboxylate (14.0 mg, 26 μmol, 44 %) as a white solid. LC purity (0.1%TFA): 83.74 % (UV at 254 nm)/MS: 521.2 [M+1]; Retention time: 1.43 min. Synthesis of 4'-chloro-3-(methylamino)-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one (B35) [0602] A solution of tert-butyl 4-(4'-chloro-3-(methylamino)-5'-oxo-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (14.0 mg, 1 eq, 26.9 μmol) in HCl/EA (2 mL, 4M) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was 240 282341894 v2 PRSC-068/001WO (343170-2269) filtered and concentrated under vacuum. The residue was purified by prep-HPLC eluted with MeCN in H2O from 5% to 80% (0.1% FA) to get 4'-chloro-3-(methylamino)-10'-(piperidin-4-yl)- 5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-5'-one (1.89 mg, 4.38 μmol, 16.3 %) as a yellow solid. LC purity (0.1%FA): 93.80 % (UV at 254 nm)/MS: 421.1 [M+H]; Retention time: 0.95 min.1H NMR (400 MHz, MeOD) δ 8.46-8.52 (m, 1H), 8.38-8.44 (m, 1H), 8.01 (s, 1H), 7.83- 7.95 (m, 2H), 7.65-7.69 (m, 1H), 7.40-7.45 (m, 1H), 4.03-4.06 (m, 1H), 3.56 (d, J= 12 Hz, 2H), 3.09-3.21(m, 3H), 3.01-3.03 (m, 1H), 2.90-2.92 (m, 2H), 2.78 (s, 3H), 2.53-2.57 (m, 1H), 2.16- 2.19 (m, 2H), 2.04-2.09 (m, 2H), 1.29-1.33 (m, 1H). Compound B36.4'-chloro-3-fluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one
Figure imgf000242_0001
a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 2) [0603] To a solution of tert-butyl 4-(4'-chloro-3-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (30.0 mg, 1 eq, 59.1 μmol) in DCM (4 mL) was added DAST (19.0 mg, 2 eq, 118 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl 4-(4'-chloro-3-fluoro-5'-oxo- 5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (30.0 mg, 47 μmol, 80 %) as a yellow solid. LC purity (0.1%FA): 87.61 % (UV at 254 nm)/MS: 510.2 [M+H]; Retention time: 1.609 min. Synthesis of 4'-chloro-3-fluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-5'-one (B36) [0604] To a solution of tert-butyl 4-(4'-chloro-3-fluoro-5'-oxo-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (30.0 mg, 1 eq, 47.1 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated 241 282341894 v2 PRSC-068/001WO (343170-2269) completion of reaction. The reaction was filtered and concentrated under vacuum. The residue was purified by prep-HPLC eluted with MeCN in H2O from 17% to 67% (0.1% FA) to get 4'-chloro- 3-fluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-5'-one (4.68 mg, 10.1 μmol, 21.6 %) as a white solid. LC purity (0.1%FA): 82.47 % (UV at 254 nm)/MS: 410.1 [M+H]; Retention time: 1.31 min.1H NMR (400 MHz, MeOD) δ 8.38 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.82-7.87 (m, 2H) 7.66 1H), 7.42 (d, J=8 Hz, 1H), 5.60-5.77 (m, 1H), 3.56
Figure imgf000243_0001
(d, J=12.4 Hz, 2H), 3.04-3.22 (m, 5H), 2.84-2.94 (m, 2H), 2.19 (d, J=14.0 Hz, 2H), 1.96-2.07 (m, 2H). Compound B37.4'-chloro-3,3-difluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-5'-one
Figure imgf000243_0002
a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 3) [0605] To a solution of tert-butyl 4-(4'-chloro-3,5'-dioxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidine-1-carboxylate (100 mg, 1 eq, 197.6 μmol) in DCM (2 mL) was added DAST (131.2 mg, 3 eq, 592.9 μmol) at -70 oC. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 35% of THF in PE) to afford tert- butyl 4-(4'-chloro-3,3-difluoro-5'-oxo-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidine-1-carboxylate (20.0 mg, 35 μmol, 18 %) as a yellow solid. LC purity (0.1%FA): 44.76% (UV at 254 nm)/MS: 528.2 [M+1]; Retention time: 1.62 min. Synthesis of 4'-chloro-3,3-difluoro-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-5'-one (B37) [0606] To a solution of tert-butyl 4-(4'-chloro-3,3-difluoro-5'-oxo-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (10 mg, 1 eq, 18.9 μmol) in DCM (2 242 282341894 v2 PRSC-068/001WO (343170-2269) mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction mixture was filtered. The filter cake was purified by prep- HPLC, eluted with MeCN in H2O from 18% to 28% (0.1% FA) to get 4'-chloro-3,3-difluoro-10'- (piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-5'-one (4.82 mg, 11.2 μmol, 59.3 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 428.1 [M+1]; Retention time: 1.30 min.1H NMR (400 MHz, MeOD) δ 8.39 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.82-7.86 (m, 2H) 7.63 (d, J=8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 3.45-3.58 (m, 4H), 3.03-3.21 (m, 5H), 2.17-2.20 (m, 2H), 2.05-2.09 (m, 2H). Compound B38. N-(4'-chloro-5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'- indolo[1,2-a]quinazolin]-3-yl)-N-methylacetamide
Figure imgf000244_0001
indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (Intermediate 2) [0607] To a solution of tert-butyl 4-(4'-chloro-3-(methylamino)-5'-oxo-5'H-spiro[cyclobutane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (25.0 mg, 1 eq, 48.0 μmol) in DCM (2 mL) were added TEA (14.6 mg, 3 eq, 144 μmol), and acetyl chloride (11.3 mg, 3 eq, 144 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl 4-(4'-chloro-3-(N-methylacetamido)-5'-oxo-5'H- spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (25 mg, 40 μmol, 83 %) as a yellow solid. LC purity (0.1%FA): 65.74 % (UV at 254 nm)/MS: 563.2 [M+1]; Retention time: 1.59 min. Synthesis of N-(4'-chloro-5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-3-yl)-N-methylacetamide (B38) 243 282341894 v2 PRSC-068/001WO (343170-2269) [0608] To a solution of tert-butyl 4-(4'-chloro-3-(N-methylacetamido)-5'-oxo-5'H- spiro[cyclobutane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-1-carboxylate (15.0 mg, 1 eq, 26.6 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O from 15% to 25% (0.1% FA) to get N-(4'-chloro-5'-oxo-10'-(piperidin-4-yl)-5'H-spiro[cyclobutane-1,7'-indolo[1,2- a]quinazolin]-3-yl)-N-methylacetamide (1.12 mg, 2.31 μmol, 8.69 %) as a white solid. LC purity (0.1%FA): 92.55 % (UV at 254 nm)/MS: 463.2 [M+H]; Retention time: 1.28 min.1H NMR (400 MHz, MeOD) δ 8.36-8.40 (m, 1H), 7.82-7.97 (m, 3H), 7.64-7.68 (m, 1H), 7.40-7.43 (m, 1H), 5.17- 5.18 (m, 1H), 3.56 (d, J=14.40Hz, 2H), 3.07-3.25 (m, 8H), 2.86-2.95 (m, 2H), 2.15-2.29 (m, 5H), 1.99-2.06 (m, 2H). 2.. Biological Activity For “A” Compound Kd Measurements for binding to SMARCA2/4 [0609] The binding potency was determined using BLI(Biayer interferometry) assay technology. Purified recombinant SMARCA2/4 protein was biotinylated using the Thermo EZ-Link long- chain biotinylation reagent. Briefly, protein and biotinylation reagent were mixed with 1:1 molar ratio in PBS at 4 °C. Low biotinylation reagent concentration was applied to avoid protein over- biotinylation. This reaction mixture was incubated at 4 °C for 2 hours to allow reaction being finished. Reaction mixture was then dialyzed using Fishersci 10K MWCO dialysis cassettes to remove unreacted biotinylation reagent. Bio-Layer Interferometry (BLI) assays were performed using an OctetRED96 instrument from PALL/ForteBio. All assays were run at 30 °C with continuous 1000 RPM shaking. PBS with 0.1% BSA, 0.01% Tween-20 and 2% DMSO was used as the assay buffer. Biotinylated DCN1 protein was tethered on Super Streptavidin (SSA) biosensors (ForteBio) by dipping sensors into 50 µg/mL protein solutions. Average saturation response level of 4-5 nm was achieved in 15 minutes. Biotinylated blocked Super Streptavidin (SSA) biosensors were prepared as well by following the protocol provided by the manufacturer which were used as the inactive reference controls. Sensors with proteins tethered were washed in assay buffer for 10 minutes to eliminate loose nonspecific bound protein molecules and establish stable base line before starting association-dissociation cycles of compound. Different association 244 282341894 v2 PRSC-068/001WO (343170-2269) and dissociation times were used depending on the potencies of compounds being tested. DMSO only reference was included in all assays. Raw kinetic data collected were processed in the Data Analysis software provided by the manufacturer using double reference subtraction in which both DMSO only reference and inactive protein reference were subtracted. Resulting data were analyzed based on 1:1 binding model from which kon and koff values were obtained and then Kd values were calculated. Table E1. Compound. No. BD_BLI_Kd(nM) BD_BLI_Kd(nM) SMARCA 2 SMARCA 4
Figure imgf000246_0001
245 282341894 v2 PRSC-068/001WO (343170-2269) Compound. No. BD_BLI_Kd(nM) BD_BLI_Kd(nM) SMARCA 2 SMARCA 4
Figure imgf000247_0001
IC50 Measurements for binding to SMARCA2/4 [0610] The binding potency was determined using homogeneous time-resolved fluorescence (HTRF) assay technology (Perkin Elmer). Compounds were serially diluted in DMSO and 0.02 µL volume was transferred to white non-binding 384-well plate. The reaction was conducted in total volume of 20 µL with addition of 5 uL of SMARCA4 at 0.12 ng/ul followed (or SMARCA2 at 0.5 ng/uL) by 30 min incubation at 25 oC. 5 uL of 120-fold diluted bromodomain ligand 2 (peptide histone H3; sequence: ARTKQTARKSTGGKAPRKQLA (Ala-Arg-Thr-Lys-Gln-Thr- Ala-Arg-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-Lys-Gln-Leu-Ala)) for SMARCA4 or 90-fold diluted bromodomain ligand 2 for SMARCA2 was added followed by addition of diluted terbium 246 282341894 v2 PRSC-068/001WO (343170-2269) (Tb)-labeled donor and 5 uL of diluted dye-labeled acceptor (BPS Biosciences cat# 40341). After 120 min incubation at 25 °C , the HTRF signals were read on Envision reader (Perkin Elemer) at 340 nm excitation and 620 nm and 665 nm emission. Data was analyzed using XLfit using four parameters dose response curve to determine IC50s. Table E2. Compound. No. BD_TR-FRET_IC50(nM) BD_TR-FRET_IC50(nM) SMARCA 2 SMARCA 4
Figure imgf000248_0001
. . = no n ng For “B” Series Compounds IC50 Measurements for binding to SMARCA2/4 [0611] The binding potency was determined using HTRF assay technology (Perkin Elmer). Compounds were serially diluted in DMSO and 0.02 µL volume was transferred to white non-binding 384-well plate. The reaction was conducted in total volume of 20 µL with addition of 5 uL of SMARCA4 at 0.12 ng/ul followed (or SMARCA2 at 0.5 ng/uL) by 30 min incubation at 247 282341894 v2 PRSC-068/001WO (343170-2269) 25 oC. 5 uL of 120-fold diluted bromodomain ligand 2 for SMARCA4 or 90-fold diluted bromodomain ligand 2 for SMARCA2 was added followed by addition of diluted Tb-labeled donor and 5 uL of diluted dye-labeled acceptor (BPS Biosciences cat# 40341). After 120 min incubation at 25 °C , the HTRF signals were read on Envision reader (Perkin Elemer) at 340 nm excitation and 620 nm and 665 nm emission. Data was analyzed using XLfit using four parameters dose response curve to determine IC50s. Table E3. Compound. No. BD_TR-FRET_IC50(nM) BD_TR-FRET_IC50(nM) SMARCA 2 SMARCA 4
Figure imgf000249_0001
248 282341894 v2 PRSC-068/001WO (343170-2269) Compound. No. BD_TR-FRET_IC50(nM) BD_TR-FRET_IC50(nM) SMARCA 2 SMARCA 4
Figure imgf000250_0001
1. Synthetic procedures Compound C1. (2S,4R)-1-((S)-2-((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 249 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000251_0001
eq, 14.7 mmol) in DCM (15 mL) was added TBS-Cl (1.66 g, 3 eq, 11.0 mmol). The solution was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (80 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to obtain 2 (1.69 g, 2.56 mmol, 69.8 %) as a white solid. LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 659.4 [M+1]; Retention time: 1.67 min. [0613] Synthesis of 3, To a solution of 2 (1.54 g, 1 eq, 2.34 mmol) in DCM (20 mL) was added TFA (8 mL). The mixture was stirred at 5 °C for 1 h. LCMS showed the reaction was complete. To the mixture was added aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (60 mL X 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated 250 282341894 v2 PRSC-068/001WO (343170-2269) under vacuum to give 3 (1.20 g, 2.15 mmol, 91.9 %) as a yellow solid. LC purity (0.1% FA): 71% (UV at 254 nm)/MS: 559.4 [M+1]; Retention time: 1.13 min. [0614] Synthesis of 5,To a solution of 3 (860 mg, 1 eq, 1.54 mmol) in DMF (15.0 mL) were added (1r,4r)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid 4 (487 mg, 2 eq, 3.08 mmol), N-ethyl- N-isopropylpropan-2-amine (597 mg, 3 eq, 4.62 mmol) and BOP (3.40 g, 5 eq, 7.69 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL X 2). The combined organic layer was washer with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to 5 (750 mg, 1.07 mmol, 69.7 %) as a yellow oil. LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 721.4 [M+23]; Retention time: 2.21 min. [0615] Synthesis of 6, To a solution of 5 (100.00 mg, 0.144 mmol, 1 eq ) in DCM (5 mL) was added DMP (121.00 mg, 0.288 mmol, 2 eq ) at 0 °C under Argon atmosphere. The reaction was stirred at 25 °C for 2 h. LCMS and TLC showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh size, 30% of EtOAc in PE) to afford 6 (80.0 mg, 0.044 mmol, 80.2% yield). as a yellow oil. LC purity (0.1% FA): 60.08% (UV at 254 nm)/MS: 697.4 [M+1]; Retention time: 1.81 min [0616] Synthesis of 8,To a solution of 6 (80.00 mg, 0.115 mmol, 1.5 eq ) and 4-chloro-7,7- dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one 7 (30.00 mg, 0.079 mmol, 1 eq ) in MeOH (5 mL) was added NaBH3CN (66.00 mg, 0.789 mmol, 10 eq ) at 25 °C under Argon atmosphere. The reaction was stirred at 25 °C for 16 h. LCMS and TLC showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL X 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh size, 10% of DCM in MeOH) to afford 8 (50.0 mg, 0.047 mmol, 59.7% yield). as a white solid. LC purity (0.1% FA): 61.73% (UV at 254 nm)/MS: 1061.6 [M+1]; Retention time: 1.53 min Synthesis of (2S,4R)-1-((S)-2-((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 251 282341894 v2 PRSC-068/001WO (343170-2269) [0617] To a solution of (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-((1r,4S)-4-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)methyl)cyclohexane-1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 8 (50.0 mg, 0.047 mmol, 1 eq ) in DCM (10 mL) was added TFA (2.5 mL, 0.44 mmol, 10 eq ). The reaction was stirred at 25 °C for 2 h. LCMS and TLC showed the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with 5% to 95% acetonitrile in water (containing 0.03% ammonium carbonate) to afford (2S,4R)-1-((S)-2-((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide Compound C1 (4.96 mg, 2.47 µmol, 10.7 %, 94.73% Purity) as a yellow solid. LC purity (0.1% NH3.H2O): 96.38% (UV at 254 nm)/MS: 946.8 [M+1]; Retention time: 1.73 min. [0618] 1H NMR (400 MHz, CD3OD) δ 8.87 (m, 1H), 8.42 (m, 1H), 8.07 (m, 1H), 7.84 (m, 1H), 7.67 – 7.52 (m, 2H), 7.42 (m, 5H), 5.00 (m, 2H), 4.56 (m, 2H), 4.43 (s, 1H), 3.86 (m, 1H), 3.75 (m, 1H), 3.13 (s, 2H), 2.72 (s, 1H), 2.48 (s, 3H), 2.36 (s, 2H), 2.24 – 2.15 (m, 2H), 1.96 (m, 2H), 1.91 (m, 6H), 1.85 – 1.77 (m, 1H), 1.61 (s, 6H), 1.51 (m, 4H), 1.28 (s, 1H), 1.09 (s, 1H), 1.04 (s, 9H), 1.01 (s, 2H). Compound C2. (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide 252 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000254_0001
253 282341894 v2 PRSC-068/001WO (343170-2269) [0619] To a solution of 4-bromobenzoic acid (30.0 g, 1 eq, 149 mmol) in DMF (300 mL) was added DIEA (96.4 g, 130 mL, 5 Eq, 746 mmol), HATU (68.1 g, 1.2 Eq, 179 mmol), N,O- dimethylhydroxylamine (10.9 g, 1.2 Eq, 179 mmol). The mixture was stirred at 25 °C for 3 hours. LCMS indicated completion of reaction. The reaction was pouried into H2O (100.0 mL) and extated with EA(200.0 mL), then washed with brine (100.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 4-bromo-N-methoxy- N-methylbenzamide (30.0 g, 0.11 mol, 76 %, 92%Purity) as a yellow oil. LC purity (0.1% TFA): 95% (UV at 254 nm) /MS: 245 [M+H]; Retention time: 1.32 min. Synthesis of N-methoxy-N-methyl-4-(4-methylthiazol-5-yl)benzamide (Intermediate 4) [0620] To a solution of 4-bromo-N-methoxy-N-methylbenzamide (30.0 g, 1 Eq, 123.0 mmol) in DMA (50.0 mL) was added 4-methylthiazole (24.4 g, 2 Eq, 246.0 mmol), Potassium acetate (36.2 g, 23.0 mL, 3 Eq, 369.0 mmol), Palladium diacetate (478 mg, 0.1Eq, 2.13 mmol). The mixture was stirred at 130 °C for 4 hours under N2. LCMS indicated completion of reaction. The reaction was pouried into H2O(100.0 mL) and extated with EA(200.0 mL), then washed with brine (100.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford N-methoxy-N-methyl-4-(4-methylthiazol-5-yl)benzamide (21.0 g, 76 mmol, 62 %, 95% Purity) as a yellow solid. LC purity (0.1%TFA): 96% (UV at 254 nm) /MS: 263.1 [M+H]; Retention time: 1.24 min. Synthesis of 1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-one (Intermediate 5) [0621] To a solution of N-methoxy-N-methyl-4-(4-methylthiazol-5-yl)benzamide (21.0 g, 1 Eq, 80.1 mmol) in 2-THF (50.0 mL) was added pent-4-en-1-ylmagnesium bromide (55.5 g, 4 Eq, 320 mmol).The mixture was stirred at 0 °C for 2 hours. LCMS indicated completion of reaction. The reaction was pouried into H2O (100.0 mL) and extated with EA(200.0 mL), then washed with brine (100.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford 1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-one (8.20 g, 29 mmol, 36 %, 96% Purity) as a yellow oil. LC purity (0.1%TFA): 89% (UV at 254 nm) /MS: 272 [M+H]; Retention time: 1.64 min. 254 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (R,Z)-2-methyl-N-(1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-ylidene)propane -2- sulfinamide (Intermediate 7) [0622] To a solution of 1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-one (8.20 g, 1 Eq, 30.2 mmol) in THF (20.0 mL) was added 2-methylpropane-2-sulfinamide (36.6 g, 10 Eq, 302 mmol). The mixture was stirred at 80 °C for16 hours. LCMS indicated completion of reaction. LCMS indicated completion of reaction. The reaction was pouried into H2O (100.0 mL) and extated with EA(200.0 mL), then washed with brine (100.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 20% of EtOAc in PE) to afford (R,Z)-2-methyl-N-(1-(4-(4-methylthiazol-5- yl)phenyl)hex-5-en-1-ylidene) propane-2-sulfinamide (7.90 g, 19 mmol, 64 %, 92% Purity) as a yellow solid. LC purity (0.1%FA): 100% (UV at 254 nm) /MS: 375.2 [M+H]; Retention time: 1.77 min; Synthesis of (R)-2-methyl-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-yl)propane -2- sulfinamide (Intermediate 8) [0623] To a solution of (R,Z)-2-methyl-N-(1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1- ylidene) propane-2-sulfinamide (9.00 g, 1 Eq, 24.0 mmol) in THF (100 mL) was added Lithium Tri-sec-butylborohydride (L-selectride), 1M in THF (5.94 g, 6.7 mL, 1.3 Eq, 31.2 mmol) at -70oC. The mixture was stirred at -70 °C for 1 hour. LCMS indicated completion of reaction. The reaction was pouried into water(50.0 mL) and extated with EA(100.0 mL), then washed with brine (50.0 mL) and dried over sodium sulfate,, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford (R)-2-methyl-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)hex -5-en-1-yl)propane-2-sulfinamide (7.80 g, 17 mmol, 69 %, 80%Purity) as a yellow solid. LC purity (0.1%TFA): 92.2% (UV at 214 nm) /MS: 377.2 [M+H]; Retention time: 1.60 min. Synthesis of (R)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-2-methylpropane-2-s ulfinamide(Intermediate 9) [0624] To a solution of (R)-2-methyl-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)hex-5-en-1-yl) propane-2-sulfinamide (5.00 g, 1 eq, 13.3 mmol) in THF (80.0 mL) was added 9- Borabicyclo[3.3.1]nonaneSolution (6.48 g, 7.60 mL, 4 Eq, 53.1 mmol). The mixture was stirred at 0 oC for 2 hours. H2O2 (4.52 g, 4.07 mL, 10 Eq, 133 mmol), H2O (20.0 mL) and NaOH (5.31 g, 10 Eq, 133 mmol) were added to the mixture under N2. The mixture was stirred at 0 °C for 4 hours. 255 282341894 v2 PRSC-068/001WO (343170-2269) LCMS indicated completion of reaction. The reaction was pouried into water (50.0 mL) and extated with EA(100.0 mL), then washed with brine (50.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford (R)-N-((S)-6-hydroxy -1-(4-(4- methylthiazol-5-yl)phenyl)hexyl)-2-methylpropane-2-sulfinamide (2.80 g, 6.7 mmol, 51%, 95% Purity) as a yellow oil.LC purity (0.1%TFA): 85.3% (UV at 254 nm) /MS: 395.2 [M+H]; Retention time: 1.413 min. Synthesis of (S)-6-amino-6-(4-(4-methylthiazol-5-yl)phenyl)hexan-1-ol (Intermediate 10) [0625] To a solution of (R)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl) -2- methylpropane-2-sulfinamide (2.80 g, 1 Eq, 7.10 mmol)in DCM (20.0 mL)was added HCl (2.59 g, 10 Eq, 71.0 mmol), 1, 2-Dioxane (6.25 g, 10 Eq, 71.0 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to obtain (S)-6-amino-6-(4-(4-methylthiazol-5-yl)phenyl)hexan-1-ol (2.20 g, 7.0 mmol, 98 %, 92% Purity) as a yellow oil. LC purity (0.1%TFA): 95.99% (UV at 254 nm) /MS: 291.2 [M+H]; Retention time: 1.03 min. Synthesis of (S)-6-amino-6-(4-(4-methylthiazol-5-yl)phenyl)hexan-1-ol (Intermediate 12) [0626] To a solution of (S)-6-amino-6-(4-(4-methylthiazol-5-yl)phenyl)hexan-1-ol (900 mg, 1 Eq, 3.10 mmol) in DMF (10.0 mL) were added TEA (941 mg, 1.30 mL, 3 Eq, 9.30 mmol), HATU (1.18 g, 1 Eq, 3.10 mmol), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1- fluorocyclopropane- 1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (1.52 g, 1.1 Eq, 3.41 mmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was pouried into water (30.0 mL) and extated with EA (50.0 mL), then washed with brine (30.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane- 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)hexyl)pyrrolidine-2-carboxamide (820 mg, 1.1 mmol, 35 %, 95% Purity) as a blue solid. LC purity (0.1%TFA): 68.26% (UV at 254 nm) /MS: 717.1 [M+H]; Retention time: 1.79 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane-1-carboxam ido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-oxohexyl)pyrrolidine-2-c arboxamide (Intermediate 13) 256 282341894 v2 PRSC-068/001WO (343170-2269) [0627] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane - 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)hexyl)pyrrolidine-2-carboxamide (780 mg, 1 Eq, 1.09 mmol) in DCM (10.0 mL) was added Dess-Martin periodinane (692 mg, 507 µL, 1.5 Eq, 1.63 mmol). The mixture was stirred at 25oC for 2 hours. LCMS indicated completion of reaction. The reaction was pouried into water (20.0 mL) and extated with EA (20.0 mL), then washed with brine (10.0 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford (2S,4R)-4- ((tert-butyldimethylsilyl)oxy) -1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-oxohexyl)pyrrolidine-2- carboxamide (480.0 mg, 0.64 mmol, 59 %, 95% Purity) as a blue oil. LC purity (0.1%TFA): 78.21% (UV at 254 nm) /MS: 715.1 [M+H]; Retention time: 1.784min. Synthesis of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazol in-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-4-((tert-butyldimethylsilyl)oxy)-1 -((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (Intermediate 15) [0628] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane - 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6- oxohexyl)pyrrolidine-2-carboxamide (50.0 mg, 1 Eq, 69.9 µmol) in MeOH (2.00 mL)was added 4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (35.6 mg, 1.2 Eq, 83.9 µmol), and Sodium cyanoborohydride (17.6 mg, 16.5 µL, 4 Eq, 280 µmol) under N2. The mixture was stirred at 25 °C for 3 hours. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford (2S,4R)-N-((S)-6-(4- (4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4- methylthiazol-5-yl)phenyl)hexyl)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (35.0 mg, 30 µmol, 42 %, 95% Purity) as a yellow solid. LC purity (0.1%FA): 91.97% at 254nm/MS: 562.8 Retention time: 1.65min. 257 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazol in-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1-fluorocyclopropane- 1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound C2) [0629] To a solution of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-4- ((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2-carboxamide (30.0 mg, 1 Eq, 26.7 µmol) in DCM (1.00 mL) was added TFA (2.96 g, 2.00 mL). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was quenched with methanol, concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted MeCN in H2O from 10% to 85% (0.1% TFA) to afford (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7 -dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide Compound C2 (5.01 mg, 4.91 µmol, 18.4 %, 98.84% purity) as a white solid. LC purity (0.1%FA): 94.77% 254 nm/MS: 505.8 Retention time: 1.358 min. 1H NMR (400 MHz, MeOD) δ 8.88 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.49 – 7.44 (m, 5H), 4.95 – 4.92 (m, 1H), 4.77-4.76 (m, 1H), 4.62 – 4.60 (m, 1H), 4.47 – 4.45 (m, 1H), 3.83-3.81 (m, 2H), 3.67 – 3.65 (m, 2H), 3.13 – 3.02 (m, 5H), 2.49 (s, 3H), 2.22 – 2.18 (m, 3H), 2.02 – 1.87 m, 7H), 1.62 – 1.61 (m, 7H), 1.51 – 1.50 (m, 3H), 1.40 – 1.35 (m, 4H), 1.07 (s, 9H). Compound C3. (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- cyanocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide 258 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000260_0001
do)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)pyrrolidine -2-carboxamide (Intermediate 3) [0630] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane - 1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (311 mg, 1 Eq, 689 µmol) in DMF (2.00 mL) was added HATU (340 mg, 1.3 eq, 895 µmol), DIEA (356 mg, 480 µL, 4 eq, 2.75 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction mixture was poured into water (50 mL), extracted with EA (40 mL X 3). The combined organic layers were washed with brine (30.0 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash chromatography, eluted with 20% EA in PE to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1- ((S)-2-(1-cyanocyclopropane -1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4- methylthiazol-5-yl)phenyl)hexyl)pyrrolidine-2-carboxamide (250 mg, 0.33 mmol, 48% yield) as a yellow solid. LC purity (0.03% TFA): 99.54% (UV at 254 nm)/MS: 724.2 [M+H]; Retention time: 1.09 min 259 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane-1-carboxami do)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)pyrrolidine -2-carboxamide (Intermediate 4) [0631] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane- 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-6-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)hexyl)pyrrolidine-2-carboxamide (30.0 mg, 1 eq, 41.4 µmol) in DCM (1.00 mL) was added DMP (26.4 mg, 1.5 eq, 62.2 µmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy) -1-((S)-2-(1-cyanocyclopropane-1-carboxamido)- 3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-oxohexyl)pyrrolidine-2- carboxamide (30 mg, 0.31 mmol, 75% yield) as a yellow solid. LC purity (0.1% FA): 75.68% (UV at 254 nm)/MS: 722.4 [M+H]; Retention time: 1.86 min. Synthesis of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazol in-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-4-((tert-butyldimethylsilyl)oxy)-1 -((S)-2-(1-cyanocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (Intermediate 6) [0632] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane - 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6- oxohexyl)pyrrolidine-2-carboxamide (30.0 mg, 1 eq, 41.5 μmol) in MeOH (0.50 mL) was added 4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (21.2 mg, 1.2 eq, 49.9 μmol), and TEA (12.6 mg, 17.4 μL, 3 eq, 125 μmol). The mixture was stirred for 30 min, Sodium cyanoborohydride (7.83 mg, 7.35 μL, 3 eq, 125 μmol) was added, the mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by flash chromatography, eluted with 15% MeOH in DCM to afford (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2-carboxamide (40.0 mg, 35.4 μmol, 68.08% yield) as a yellow solid. LC purity (0.1% FA): 80.31% (UV at 254 nm)/MS: 565.4 [M/2+H]; Retention time: 1.57 min. 260 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- cyanocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide (Compound B3) [0633] To a solution of (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2 -a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-4-((tert-butyldimeth ylsilyl)oxy)-1-((S)-2-(1-cyanocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2 -carboxamide (30.0 mg, 1 eq, 26.5 µmol) in DCM (2.00 mL) was added TFA (0.30 mL, 3.9 mmo l), and the reaction was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The r eaction was concentrated under vacuum and purified by prep-HPLC, eluted with CH3CN in H2O (0.03% NH4CO3) from 5.0 % to 95.0 % (0.1% FA) to afford (2S,4R)-N-((S)-6-(4-(4-bromo-7,7-di methyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-y l)phenyl)hexyl)-1-((S)-2-(1-cyanocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydro xypyrrolidine-2-carboxamide Compound C3 (5.02 mg, 4.78 µmol, 18.0% yield, 96.8% purity) a s a white solid. LC purity (0.1% FA): 98.38% (UV at 254 nm)/MS: 508.4 [M/2+1]; Retention ti me: 1.36 min.1H NMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8 .6 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 8.3 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.52 – 7.4 3 (m, 5H), 4.96-4.93 (m, 1H), 4.69 – 4.58 (m, 2H), 4.50-4.48 (m, 1H), 3.86 - 3.83 (m, 1H), 3.78 – 3.67 (m, 3H), 3.23 – 3.00 (m, 5H), 2.50 (s, 3H), 2.28 – 2.15 (m, 3H), 2.14 – 2.01 (m, 2H), 1.98 - 1.85 (m, 5H), 1.70 – 1.64 (m, 11H), 1.58 –1.51 (m, 3H), 1.09 (s, 9H). Compound C4. (2S,4R)-1-((R)-2-(3-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1, 2-a]quinazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(( S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 261 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000263_0001
[0634] To a solution of but-3-yn-1-ol (27.6 g, 4 eq, 394 mmol) and Potassium bicarbonate (29.6 g, 3 eq, 296 mmol) in EA (200 mL) and Water (20.0 mL) was added hydroxycarbonimidic dibromide (20.0 g, 1 eq, 98.6 mmol) in EA (50 mL). The mixture was stirred at room temperature for 16 hours. LCMS indicated completion of reaction. Water(100mL) was added, extracted with EA (200 mL X 3), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(3-bromoisoxazol-5- yl)ethan-1-ol (32.0 g, 83.0 mmol, 85 %, 95% Purity) as a yellow oil. LC purity (0.1% FA): 95% (UV at 214 nm)/MS: 192.0 [M+H]; Retention time: 0.59 min. Synthesis of 2-(3-bromoisoxazol-5-yl)acetic acid (Intermediate 4) [0635] To a solution of 2-(3-bromoisoxazol-5-yl)ethan-1-ol (18.0 g, 1 eq, 93.7 mmol) in Acetone (250 mL) was added Jones reagent (46.9 g, 187 mL, 2.50 molar, 5 eq, 469 mmol) dropwise . The reaction was stirred at room temperature for 16 hours. LCMS indicated completion of reaction. 262 282341894 v2 PRSC-068/001WO (343170-2269) Water(100mL) was added, extracted with EA (200 mL X 3), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(3-bromoisoxazol-5-yl)acetic acid (17.0 g, 66 mmol, 52% Purity) as a yellow oil. LC purity (0.1% FA): 52% (UV at 214 nm)/MS: 206.0 [M+H]; Retention time: 0.75 min. Synthesis of methyl 2-(3-bromoisoxazol-5-yl)acetate (Intermediate 5) [0636] To a solution of 2-(3-bromoisoxazol-5-yl)acetic acid (17.0 g, 1 eq, 82.5 mmol) in MeOH (250 mL) was added sulfuric acid (80.9 g, 10 eq, 825 mmol) dropwise . The reaction was stirred at 70 °C for 6 hours. LCMS indicated completion of reaction. Water (100mL) was added, extracted with EA(200 mL X 3), the combined organic layers were washed with brine(100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get give methyl 2-(3- bromoisoxazol-5-yl)acetate (16.0 g, 72.7 mmol, 88.1 %) as a green oil. LC purity (0.1% FA): 42% (UV at 214 nm)/MS: 220.0 [M+H]; Retention time: 1.19 min. Synthesis of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (Intermediate 7) [0637] To a solution of methyl 2-(3-bromoisoxazol-5-yl)acetate (16.0 g, 1 eq, 72.7 mmol) and 2- methylpropan-2-olate pottasium (12.2 g, 13.7 mL, 1.5 eq, 109 mmol) in THF (200 mL) was added Isopropyl iodide (18.5 g, 10.9 mL, 1.5 eq, 109 mmol) dropwise at 0oC under N2. The solution was stirred at room temperature for 16 hours. LCMS indicated completion of reaction. Water(300mL) was added, extracted with EA (200mL X 2), the combined organic layers were washer with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (17.0 g, 64.9 mmol, 89.2 %) as a yellow oil. LC purity (0.1% FA): 30% (UV at 214 nm)/MS: 262.0 [M+H]; Retention time: 1.59 min. Synthesis of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (Intermediate 8) [0638] To a solution of methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (17.0 g, 1 eq, 64.9 mmol) in MeOH (40.0 mL) was added Potassium hydroxide (36.4 g, 37.8 mL, 10 eq, 649 mmol) at 0 oC. The reaction was stirred at 90 °C for 16 hours. LCMS indicated completion of reaction. Water (300mL) was added, adjusted PH to 6 by 1N HCl，extracted with EA (200 mL X 2), the combined organic layers were washed with brine(100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (7.00 g, 40.2 mmol, 54.1 %) as a yellow oil. LC purity (0.1% FA): 88% (UV at 214 nm)/MS: 200.0 [M+H]; Retention time: 0.20 min. Synthesis of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (Intermediate 9) 263 282341894 v2 PRSC-068/001WO (343170-2269) [0639] To a solution of 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (7.00 g, 1 eq, 35.1 mmol) in Acetic Acid (30.0 mL) was added Hydrogen bromide in water (30.0 mL, 48% Wt, 7.48 eq, 263 mmol) at 0 oC. The reaction was stirred at 60 °C for 16 hours. LCMS indicated completion of reaction. The resulting residue was purified by Combi-flash, eluted with MeCN in H2O from 10% to 90%(0.1% TFA) to give 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (3.60 g, 19.4 mmol, 55.3 %) as a yellow oil. LC purity (0.1% FA): 90% (UV at 214 nm)/MS: 186.0 [M+H]; Retention time: 1.02 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl) -3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 11) [0640] To a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (300 mg, 1 eq, 1.62 mmol) in DMF (14.0 mL) was added 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimideHydrochloride (EDCI) (404 mg, 1.3 eq, 2.11 mmol)， N-ethyl-N- isopropylpropan-2-amine (1.05 g, 5 eq, 8.10 mmol)， 1H-benzo[d][1,2,3]triazol-1-ol hydrate (323 mg, 1.3 eq, 2.11 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (722 mg, 1 eq, 1.62 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was quenched by water, extracted with EA(50 mL X 3), washed with brine(50 mL), dried over sodium sulfate, filtered and concentrate dunder vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to get (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N- ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (230 mg, 375 µmol, 23.2 %) as a white solid. LC purity (0.1% FA): 70% (UV at 254 nm)/MS: 613.3 [M+H]; Retention time: 1.70 min. Synthesis of (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl) -4-((tert- butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Intermediate 13) [0641] To a solution of ((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)- 3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (455.0 mg, 1 eq, 0.74 mmol) and 1,2-Dibromoethane (1.39 g, 10 eq, 7.42 mmol) in DMF (3.0 mL) were added and K2CO3 (308.0 mg, 3 eq, 2.23 mmol) at 25 °C, the mixture solution was stirred at 264 282341894 v2 PRSC-068/001WO (343170-2269) 25 °C for 16 hours. The reaction was extracted with EtOAc (20.0 mL X 3) and the combined organic layers were washed with water (20.0 mL X 3) and washed with brine (20.0 mL) dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O from 50% to 90%, (0.1% of FA) to give (2S,4R)-1-((R)- 2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide (150.0 mg, 0.21mmol, 28.1% yield) as a white solid. LC purity (0.1% FA): 98% (UV at 254 nm)/MS: 719.0 [M+H]; Retention time: 1.97 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(4-chloro-7,7-dimethyl -5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 15) [0642] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-o ne (42.2 mg, 2 eq, 111 μmol) in DMF (5.0 mL) was added sodium hydrogen carbonate (70.0 mg, 15 eq , 834 μmol) and (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxamide (40.0 mg, 1 eq, 55.6 μmol). The mixture was stirred at 65 °C for 16 hours. LCMS indica ted completion of reaction. Water (30.0 mL) was added, extracted with EA (20.0 mL X 2), the or ganic layers werewasher with brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concen trated under vacuum to get (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(4-chloro-7, 7-dimethyl -5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)- 3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 .0 mg, 39.3 μmol, 35.4%) as a white solid. LC purity (0.1% TFA): 63% (UV at 254 nm)/MS: 101 8.0 [M+H]; Retention time: 1.57 min. Synthesis of (2S,4R)-1-((R)-2-(3-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]qui nazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-m ethylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C4) [0643] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(4-chloro-7,7- dimethyl -5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40. 0 mg, 1 Eq, 39.3 μmol) in DCM (1.00 mL) was added 2,2,2-trifluoroacetic acid (4.48 mg, 1.00 m 265 282341894 v2 PRSC-068/001WO (343170-2269) L, 1 Eq, 39.3 μmol) at room temperature. The reaction was stirred 35 °C for 2 hours. LCMS indic ated completion of reaction. The mixture was added DCM (20 mL) and concentrated under vacu um, repeated three times. The residue was purified by prep-HPLC, eluted with CH3CN in water ( 0.1%FA) to afford (2S,4R)-1-((R)-2-(3-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1, 2-a]quinazolin-9-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (22.45 mg, 24.57 μmol, 62.6% yield, 99.42% purity) as a white solid. LC purity (0.03% NH3 .H2O): 99.42% (UV at 254 nm)/M S: 904.4 [M+H]; Retention time: 1.36 min.1H NMR (400 MHz, MeOD) δ 8.40 (m, 1H), 8.08 (m, 1H), 7.83 (m, 1H), 7.65 (m, 1H), 7.56 (s, 1H), 7.48 – 7.33 (m, 5H), 6.05 (m, 1H), 5.02 (m, 1H), 4.80 – 4.36 (m, 5H), 3.85 (m, 1H), 3.67 (m, 2H), 3.51 – 3.42 (m, 2H), 3.26 (s, 2H), 2.95 – 2.73 ( m, 3H), 2.45 (s, 3H), 2.24 – 2.13 (m, 1H), 2.08 – 1.92 (m, 5H), 1.59 (s, 6H), 1.55 – 1.50 (m, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). Compound C5. (2S,4R)-1-((S)-2-(2-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a] quinazolin-9-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
Figure imgf000267_0001
-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 2) [0644] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S) -1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.20 g, 1 eq, 2.70 mmol), TEA (546.0 mg, 0.75 mL, 2 eq, 5.40 mmol) in DCM (10.0 mL) was added 2-chloroacetyl chloride (366 mg, 1.2 Eq, 3.24 mmol). The mixture was then stirred at 25oC for 1 hour. LCMS indicated completion of reaction. The mixture was poured into sat NH4Cl (20 mL), extracted with EtOAc (20 mL X 2). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford (2S,4R)-1-((S)- 266 282341894 v2 PRSC-068/001WO (343170-2269) 2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.73 g, 1.4 mmol, 52 %) as a yellow oil. LC purity (0.1% FA): 80.30% (UV at 254 nm)/MS: 521.1[M+H]; Retention time: 1.104 min. Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2- a]quinazolin-9-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C5) [0645] To a solution of (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy - N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80.0 mg, 1 eq, 0.15 mmol) in DMF (4.00 mL) was added NaHCO3 (129.0 mg, 10 eq, 1.54 mmol) , NaI (169.0 mg, 10 eq, 1.54 mmol), 4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (78.2 mg, 1.2 eq, 0.18 mmol).The mixture was stirred at 65°C for 16 hours. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1 FA%) to afford (2S,4R)-1-((S)-2-(2-(4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Compound C5 (60.0 mg, 0.065 mmol, 42.1 %, 97.85% purity) as a white soild. LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 455.8[M/2+H]; Retention time: 0.910 min.1H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.07-8.09 (m, 1H), 7.80-7.90 (m, 1H), 7.76-7.72 (m, 1H), 7.59 (s, 1H), 7.46 – 7.39 (m, 5H), 5.02 (d, J = 7.2 Hz, 1H), 4.68 (s, 1H), 4.56-4.60 (m, 4H), 4.45 (s, 1H), 3.787(d, J = 10.8 Hz, 1H), 3.80 – 3.73 (m, 1H), 3.27 – 3.25 (m, 2H), 3.14-3.13 (s, 2H), 2.77-2.76 (m, 1H), 2.53 (s, 1H), 2.47-2.46 (m, 3H), 1.96-1.92 (m, 5H), 1.62 (s, 6H), 1.53-1.51 (m, 2H), 1.07 (s, 9H). Compound C6. (2S,4R)-1-((S)-2-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2- a]quinazolin-9-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 267 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000269_0001
Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin-9-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound C6) [0646] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (70.0 mg, 1 eq, 184 µmol) in DMF (0.30 mL) was added sodium bicarbonate (46.4 mg, 21.5 µL, 3 Eq, 553 µmol), (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- ((S) -1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (57.6 mg, 0.6 eq, 111 µmol) under N2, and the mixture was stirred at 70 °C for 2 hours. LCMS indicated completion of reaction. The reaction was poured into water (20 mL) and extated with EA (20 mL), then washed brine (10 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% TFA) to afford (2S,4R)-1-((S)-2-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin -9- yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide Compound C6 (41.02 mg, 46.47 µmol, 25.2 %, 97.94% purity) as a white solid. LC purity (0.1% FA): 93.5% (UV at 254 nm) /MS: 864.4 [M+H]; Retention time: 1.34 min; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.41 (t, J = 9.0 Hz, 2H), 8.18 – 8.06 (m, 2H), 7.82 (t, J = 8.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.47-7.46 (m, 4H), 7.37 (d, J = 8.2 Hz, 3H), 7.11 (d, J = 7.8 Hz, 2H), 5.13 (d, J = 3.0 Hz, 1H), 4.92 (d, J = 7.3 Hz, 1H), 4.56 (d, J = 9.8 Hz, 1H), 4.45 (t, J = 8.4 Hz, 1H), 4.31-4.30 (m, 1H), 3.60-3.59 (m, 2H), 3.02-2.98 (m, 3H), 2.45 (s, 3H), 2.01-1.95 (m, 7H), 1.54-1.53 (s, 7H), 1.39 (d, J = 7.0 Hz, 3H), 0.98-0.97 (s, 10H). 268 282341894 v2 PRSC-068/001WO (343170-2269) Compound C7. (2S,4R)-N-((S)-6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide
Figure imgf000270_0001
5 ,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)- 1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamid e (Intermediate 3) [0647] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(1-fluorocyclopropane- 1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6- oxohexyl)pyrrolidine-2-carboxamide (30.0 mg, 1 Eq, 42.0 μmol)in MeOH (3.00 mL)was added4- chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (20.7 mg, 1.3 Eq, 54.5 μmol), sodium cyanotrihydroborate (7.9 mg, 3 Eq, 126 μmol)triethylamine (12.7 mg, 3 Eq, 126 μmol)and the reaction was stirred at 25℃for 16 hours. LCMS indicated completion of reaction. Water (100 mL) was added, extracted with EA (80 mL X 2), the combined organic layers were washed with brine, dried over anhydrous Na2SO4 to get tert-butyl (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (30 mg, 15.8 μmol, 56.96%) as a white solid. LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 540.0 [M/2+H]; Retention time: 1.69 min . Synthesis of (2S,4R)-N-((S)-6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide (Compound C7) 269 282341894 v2 PRSC-068/001WO (343170-2269) [0648] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-6-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-1-(4-(4-methylthiazol- 5-yl)phenyl)hexyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2-carboxamide (30.0 mg, 1 Eq, 27.8 μmol)in DCM (3.00 mL)was added2,2,2-trifluoroacetic acid (3.17 mg, 0.6 mL, 1 Eq, 27.8 μmol), and the reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% TFA) to afford (2S,4R)-N-((S)-6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)hexyl)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide Compound C7 (7.17 mg, 7.00 μmol, 25.2% yield, 94.22% purity) as a white solid. LC purity (0.1% TFA): 95% (UV at 254 nm)/MS: 482.8 [M/2+H]; Retention time: 1.43 min. 1H NMR (400 MHz, MeOD) δ 8.92 (s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.47 – 7.41 (m, 5H), 4.94 – 4.91 (m, 1H), 4.82 – 4.81 (m, 1H), 4.65 – 4.53 (m, 1H), 4.45 – 4.43 (m, 1H), 3.86-3.85 (m, 1H), 3.78 – 3.74 (m, 1H), 3.60 – 3.58 (m, 2H), 3.00 – 2.93 (m, 5H), 3.35 – 2.86 (m, 13H), 2.48 (s, 3H), 2.22 – 2.12 (m, 3H), 2.00-1.70 (m, 7H), 2.09 – 1.61-1.60 (m, 7H), 1.50-1.45 (m, 3H), 1.32 – 1.28 (m, 4H), 1.08 (s, 9H). Compound C8. (2S,4R)-1-(2-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl) piperidin -1-yl)methyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N- ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 270 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000272_0001
[0649] To a solution of 2-(benzyloxy) ethan-1-ol (30.0 g, 1 eq, 197 mmol) in acetonitrile (300 mL) was added IBX (110 g, 2 eq, 394 mmol). The mixture was stirred at 90 °C for 1 hour. LCMS indicated completion of reaction. The mixture was filtered, diluted with water (200 mL), extracted with EA (200 mL) and the organic layer was washed with water (200 mL X 2), then saturated brine (300 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of 271 282341894 v2 PRSC-068/001WO (343170-2269) EtOAc in PE) to afford 2-(benzyloxy) acetaldehyde (25.0 g, 166 mmol, 84.4 %) as a colorless oil. LC purity (0.1% FA in H2O，0.1% FA in ACN): 90.16% (UV at 214 nm)/MS: 151.1 [M+H]; Retention time: 1.33 min. Synthesis of (E)-2-(benzyloxy) acetaldehyde oxime (Intermediate 3) [0650] To a solution of 2-(benzyloxy) acetaldehyde (24.0 g, 1 eq, 160 mmol) and hydroxylamine hydrochloride (11.1 g, 1 eq, 160 mmol) in EA (100 mL) and Water (100 mL) was added NaHCO3 (27 g, 2 eq, 320 mmol). The mixture was stirred at 0 °C for 2 hours. TLC (PE: EA = 3: 1, Rf = 0.3) indicated completion of reaction. The mixture was extracted with EA (200 mL), washed with brine (300 mL), dried over sodium sulfate, filtered, concentrated under vacuum to afford (20.0 g, 97 mmol, 61 %, 80% purity) as colorless oil. LC purity (0.1% FA in H2O，0.1% FA in ACN): 90.16% (UV at 2514 nm)/MS: 200.0 [M+H]; Retention time: 1.21 min. Synthesis of (Z)-2-(benzyloxy)-N-hydroxyacetimidoyl chloride (Intermediate 4) [0651] To a solution of (E)-2-(benzyloxy) acetaldehyde oxime (20.0 g, 1 eq, 121 mmol) in DMF (20.0 mL) was added N-Chlorosuccinimide (32.3 g, 19.6 mL, 2 eq, 242 mmol). The mixture was stirred at 90 °C for 2 hours. TLC (PE: EA = 3: 1, Rf = 0.4) indicated completion of reaction. The mixture was extracted with EA (200 mL), washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to to get (Z)-2-(benzyloxy)-N- hydroxyacetimidoyl chloride (21.0 g, 84 mmol, 70 %, 80% Purity) as a white solid. LC purity (0.1% FA in H2O，0.1% FA in ACN): 80.16% (UV at 214 nm)/MS: 200.0 [M+H]; Retention time: 1.21 min. Synthesis of compound 2-(3-((benzyloxy)methyl) isoxazol-5-yl) ethan-1-ol (Intermediate 5) [0652] To a solution of (Z)-2-(benzyloxy)-N-hydroxyacetimidoyl chloride (22.0 g, 1 eq, 110 mmol) and but-3-yn-1-ol (8.50 g, 1.1 eq, 121 mmol) in ethyl acetate (10.0 mL) and water (10 mL) was added NaHCO3 (27 g, 3 eq, 331 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was poured into water (800 mL), extracted with ethyl acetate (300 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 2-(3- ((benzyloxy)methyl) isoxazol-5-yl) ethan-1-ol (7.00 g, 30.0 mmol, 27.2 %) as colorless oil. LC purity (0.1% FA): 40.05% (UV at 214 nm)/MS: 234.11 [M+1]; Retention time: 1.50 min. 272 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of compound 2-[3-(3-phenylmethoxypropyl)-1,2-oxazol-5-yl] acetic acid (Intermediate 6) [0653] To a solution of 2-(3-((benzyloxy)methyl) isoxazol-5-yl) ethan-1-ol (4.50 g, 1 eq, 19.3 mmol) in acetone (10 mL), was added CrO3 (5.79 g, 3 eq, 57.9 mmol) and H2SO4 (397 mg, 0.216 mL, 0.223 eq, 4.05 mmol) under N2. The mixture was stirred at 25°C for 2 hours. TLC (PE: EtOAc = 1: 1, Rf = 0.5) indicated completion of reaction. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 2- [3-(3-phenylmethoxypropyl)-1,2-oxazol-5-yl] acetic acid (1000 mg, 3.55 mmol, 71.5% yield) as colorless oil.1HNMR (CD3OD-d4, 400 MHz): δ 12.858 (s,1H), 7.284-7.387 (m,5H), 6.334-6.445 (s,1H), 4.483-4.647 (m,4H), 3.884-4.031 (m,2H). Synthesis of compound methyl 2-(3-((benzyloxy)methyl) isoxazol-5-yl) acetate (Intermediate 7) [0654] To a solution of 2-(3-((benzyloxy)methyl) isoxazol-5-yl) acetic acid (4.50 g, 1 eq, 18.2 mmol) in MeOH (5 mL) and was added con. H2SO4 (397 mg, 0.216 mL, 0.223 eq, 4.1 mmol). the reaction was stirred at 70 °C for 2 hours. LCMS indicated completion of reaction. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford methyl 2-(3-((benzyloxy) methyl) isoxazol-5-yl) acetate (2.30 g, 8.80 mmol, 48.4 %) as colorless oil. LC purity (0.1% FA): 55.72% (UV at 214 nm)/MS: 262.10 [M+1]; Retention time: 1.67 min. Synthesis of compound methyl 2-(3-((benzyloxy)methyl) isoxazol-5-yl)-3-methylbutanoate (Intermediate 8) [0655] To a solution of methyl 2-(3-((benzyloxy)methyl) isoxazol-5-yl) acetate (2.30 g, 1 eq, 8.80 mmol) in THF (200 mL) was added t-BuOK (1.97 g, 2 eq, 17.6 mmol) and 2-iodopropane (2.99 g, 2 eq, 17.6 mmol) dropwise at 0 oC under N2. The solution was stirred at rt for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude methyl 2-(3- 273 282341894 v2 PRSC-068/001WO (343170-2269) ((benzyloxy)methyl) isoxazol-5-yl)-3-methylbutanoate (1.40 g, 4.61 mmol, 52.4 %) as colorless oil. LC purity (0.1% TFA): 58.79% (UV at 214 nm)/MS: 304.15 [M+1]; Retention time: 1.77 min. Synthesis of 2-(3-(hydroxymethyl) isoxazol-5-yl)-3-methylbutanoate (Intermediate 9) [0656] To a solution of methyl 2-(3-((benzyloxy)methyl) isoxazol-5-yl)-3-methylbutanoate (1.40 g, 1 eq, 4.6 mmol) in DCM (20.0 mL) was added BBr3 (2.31 g, 873 µL, 2 eq, 9.2 mmol) dropwise at -78 oC under N2. The reaction was stirred at -78 oC for 2 hours. LCMS indicated completion of reaction. The reaction was quenched by water (50 mL), extracted with DCM (30 mL X 2). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford methyl 2-(3-(hydroxymethyl) isoxazol-5-yl)-3-methylbutanoate (640 mg, 3.00 mmol, 65.0 %) as colorless oil. LC purity (0.1% TFA): 71.40% (UV at 214 nm)/MS: 214.10 [M+1]; Retention time: 1.79 min. Synthesis of compound 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 10) [0657] To a solution of methyl 2-(3-(hydroxymethyl) isoxazol-5-yl)-3-methylbutanoate (640 mg, 1 eq, 3.00 mmol) in MeOH (20.0 mL) was added potassium hydroxide (505 mg, 3 eq, 9.00 mmol) in water (3 mL), the reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was adjusted pH to 7 with 2M HCl and extrated with EA (150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 2-(3- (hydroxymethyl) isoxazol-5-yl)-3-methylbutanoic acid (420 mg, 2.11 mmol, 70.4 %) as colorless oil. LC purity (0.1% FA in H2O，0.1% FA in ACN): 75.20% (UV at 214 nm)/MS: 200.21 [M+1]; Retention time: 1.41 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)eth yl)pyrrolidine-2-carboxamide (lntermediate 12) [0658] To a solution of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrro lidine-2-carboxamide (2.00 g, 1 eq, 6.04 mmol) and imidazole (1.35 g, 4 eq, 18.0 mmol) in DCM (15 mL) was added TBSCl (2.23 g, 3 eq, 18.1 mmol). The reaction was stirred at 25 °C for 16 ho urs. LCMS indicated completion of reaction. The reaction was poured into water (100 mL), extra cted with DCM (8mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)- 274 282341894 v2 PRSC-068/001WO (343170-2269) N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.69 g, 3.79 mmol, 6 2.8 %) as a white solid. LC purity (0.1% TFA): 100% (UV at 254 nm)/MS: 446.2 [M+1]; Retenti on time: 1.67 min. Synthesis of compound(2S,4R)-4-((tert-butyldimethylsilyl) oxy)-1-(2-(3-(hydroxymethyl) isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2- carboxamide (Intermediate 13) [0659] To a solution of 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid (500 mg, 1 eq, 2.51 mmol) in DMF (5.00 mL) was added (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.12 g, 1 eq, 2.51 mmol), HATU (1.91 g, 2 eq, 5.02 mmol).then the mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford methylbutanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (1500 mg, 2.393 mmol, 95.3 %) as yellow oil. LC purity (0.1% FA): 96.1% (UV at 214 nm)/MS: 627.30 [M+1]; Retention time: 1.18 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(2-oxoethyl) isoxazol-5- yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 14) [0660] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3- (hydroxymethyl)isoxazol-5-yl) -3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50.0 mg, 1 eq, 0.08 mmol) in acetonitrile (20.0 mL) was added IBX (33.5 mg, 1.5 eq, 0.12 mmol). The mixture was stirred at 80 °C for 1 hour. LCMS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated under vacuum to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2- (3-formylisoxazol-5-yl)-3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50.0 mg, 0.08 mmol, 98.1% yield) as yellow oil. LC purity (0.1% FA): 68.16% (UV at 254 nm)/MS: 624.87 [M+H]; Retention time: 1.82 min. Synthesis of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-((4-(4-chloro-7,7-dimethyl -5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)isoxazol-5-yl)-3- 275 282341894 v2 PRSC-068/001WO (343170-2269) methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 16) [0661] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazol-5-yl) -3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50.0 mg, 1 eq, 0.08 mmol) in MeOH (2.00 mL) was added 4-chloro-7,7-dimethyl-9-(piperidin-4- yl) indolo[1,2-a]quinazolin-5(7H)-one (30.4 mg, 1 eq, 0.08 mmol). After 30 mins, NaCNBH3 (15.1 mg, 3eq, 0.24 mmol) was added. The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated under vacuum to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-((4-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)isoxazol-5-yl)-3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (30.0 mg, 0.030 mmol, 37.9% yield) as colorless oil. LC purity (0.1% FA): 32.83% (UV at 254 nm)/MS: 988.76 [M+H]; Retention time: 1.54 min. Synthesis of (2S,4R)-1-(2-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [0662] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-((4-(4-chloro-7,7- dimethyl-5 -oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)isoxazol-5-yl)-3- methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (30.0 mg, 1 eq, 0.03 mmol) in DCM (1.00 mL) was added TFA (1.00 mL).The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% TFA) to afford (2S,4R)-1-(2-(3-((4-(4-chloro-7,7-dimethyl-5-oxo -5,7-dihydroindolo[1,2- a]quinazolin-9-yl) piperidin-1-yl)methyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Compound C8 (2.21 mg, 0.002 mmol, 7.65% yield, 91.9% purity) as a white solid. LC purity (0.03% NH3.H2O): 91.90% (UV at 214 nm)/MS: 874.5[M+H]; Retention time: 7.874 min.1H NMR (400 MHz, MeOD) δ 8.65 – 8.60 (m, 1H), 8.40-8.38 (m, 1H), 8.10-8.09 (m, 1H), 7.86-7.85 (m, 1H), 7.66-7.64 (m, 1H), 7.57- 7.55 (m, 4H), 7.46 – 7.32 (m, 3H), 6.59 (s, 1H), 4.59 – 4.37 (m, 5H), 4.10-4.08 (m, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.85 (m, 1H), 3.76 (m, 2H), 3.70 – 3.59 (m, 2H), 3.52 – 3.44 (m, 1H), 3.17 – 3.07 276 282341894 v2 PRSC-068/001WO (343170-2269) (m, 1H), 2.50 – 2.35 (m, 5H), 2.25-2.23 (m, 3H), 2.10-2.08 (m, 2H), 2.03 – 1.88 (m, 2H), 1.58 (m, 2H), 1.53-1.52 (m, 3H), 1.29 (m, 1H), 1.10 (m, 3H), 0.94 – 0.89 (m, 3H). Compound C9. (2S,4R)-1-((R)-2-(3-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo [1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide
Figure imgf000278_0001
277 282341894 v2 PRSC-068/001WO (343170-2269) [0663] To a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (3.00 g, 1 Eq, 16.2 mmol) in MeOH (250 mL) was added SOCl2 (1.92 g, 1.0 Eq, 16.2 mmol) dropwise. The reaction was stirred at 70 °C for 6 hours. LCMS indicated completion of reaction. Water (100 mL) was added, extracted with EA (200 mL), the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get methyl 2-(3-hydroxyisoxazol- 5-yl)-3-methylbutanoate (2.30 g, 11.5 mmol, 71.3 %) as a green oil. LC purity (0.1% FA): 95.00% (UV at 254 nm)/MS: 200.0[M+H]; Retention time: 1.240 min. Synthesis of methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (Intermediate 3) [0664] To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (3.20 g, 1.0 eq, 16.1 mmol) and Potassium carbonate (1.11 g, 0.5 eq, 8.03 mmol) in MeCN (20.0 mL) was added 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (9.71 g, 2.0 Eq, 32.1 mmol) dropwise at 0 oC under N2. The reaction was stirred at 15 °C for 16 hours. LCMS showed 40% of methyl 3- methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate was detected. The reaction mixture was diluted with water (100 mL), extracted with EA (50 mL). The resulting organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under vacuum. The resulting residue was purified by flash, eluted with MTBE in PE (0% ~ 40%) to get methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (3.70 g, 7.69 mmol, 47.9 %). LC purity (0.1% FA): 94.00% (UV at 254 nm)/MS: 482.0 [M+H]; Retention time: 1.312 min. Synthesis of methyl methyl 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoate (Intermediate 5) [0665] To a solution of methyl 3-methyl-2-(3-(((4,4,4,4,4,4,4,4,4-nonafluoro-4l12-buta-1,3-diyn- 1-yl)sulfonyl)oxy)isoxazol-5-yl)butanoate (3.70 g, 1.0 eq, 7.69 mmol) in DMF (74.0 mL) was added 4-(dimethoxymethyl)piperidine (3.06 g, 2.5 eq, 19.2 mmol) and DIEA (2.98 g, 3.0 Eq, 23.1 mmol). The mixture was stirred at 80 °C for 4 hours. LCMS indicated completion of reaction. The mixture was poured into H2O and extated with EA (50 mL), then washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0%~30% of MTBE in PE) to obatin methyl methyl 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoate (1.19 g, 3.50 mmol, 45.5 %) as a yellow oil. LC purity (0.1% FA): 96.00% (UV at 254 nm)/MS: 278 282341894 v2 PRSC-068/001WO (343170-2269) 341.2[M+H]; Retention time: 1.586 min.1H NMR (400 MHz, CDCl3) δ 5.92 (d, J = 1.9 Hz, 1H), 4.06 (d, J = 4.8 Hz, 1H), 3.72 (dd, J = 6.5, 4.5 Hz, 5H), 3.47 (dd, J = 8.8, 1.8 Hz, 1H), 3.42 – 3.30 (m, 6H), 2.81 (t, J = 12.4 Hz, 2H), 2.33 (td, J = 13.1, 6.4 Hz, 1H), 1.80 (d, J = 12.2 Hz, 3H), 1.48 – 1.25 (m, 2H), 0.99 (dd, J = 6.5, 1.8 Hz, 3H), 0.92 (dd, J = 6.6, 1.8 Hz, 3H). Synthesis of 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoic acid (Intermediate 6) [0666] To a solution of methyl 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoate (790 mg, 1 Eq, 2.32 mmol) in THF (2.30 mL) and MeOH (2.30 mL) was added lithium hydroxide (108 mg, 1.95 Eq, 4.53 mmol) in Water (2.30 mL). The mixture was stirred at 40 °C for 11 hours. LCMS indicated completion of reaction. The reaction was concertrated, then pouried into H2O and added TFA to pH=5-6. The resulting residue was purified by prep-HPLC to get 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoic acid (0.35 g, 1.1 mmol, 45 %) as a colourless oil. LC purity (0.03% TFA): 98.00% (UV at 254 nm)/MS: 327.2[M+H]; Retention time: 0.984 min. Synthesis of (2S,4R)-1-(2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide(Intermediate 10) [0667] To a solution of 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoic acid (800 mg, 1 Eq, 2.45 mmol) in DMF (18.0 mL) was added (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (1.31 g, 1.2 Eq, 2.94 mmol), EDCI (612 mg, 1.3 Eq, 3.19 mmol), HOBT (430 mg, 1.3 Eq, 3.19 mmol) and DIEA (949 mg, 3 Eq, 7.35 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was pouried into H2O and extated with EA(100 mL), then washed brine and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 70% of EA in PE) to get (2S,4R)-1-(2-(3-(4-(dimethoxymethyl)piperidin-1- yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (900 mg, 1.4 mmol, 56 %) as a yellow oil. LC purity (0.03% TFA): 98% (UV at 254 nm)/MS: 639.81[M+H]; Retention time: 3.506 min. Then the (2S,4R)-1-[2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4- hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (900 mg, 279 282341894 v2 PRSC-068/001WO (343170-2269) 1.0 eq, 1.41 mmol) was sererated by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [0.1%NH4OH/ IPA]; B%: 45%) to afford (2S,4R)-1-[(2S)- 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1- [4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (378 mg, 0.59 mmol, 42% yield) (analytical retention time 1.88 min) as a yellow oil and (2S,4R)-1-[(2R)-2-[3-[4- (dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methylthiazol-5-yl) phenyl]ethyl]pyrrolidine-2-carboxamide (400 mg, 0.63 mmol, 44% yield) as a yellow oil. Synthesis of (2S,4R)-1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 11) [0668] A solution of (2S,4R)-1-((R)-2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (50.0 mg, 1.0 Eq, 78.1 μmol) in FA (2.00 mL) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford (2S,4R)- 1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50.0 mg, 67 μmol, 86 %) as a yellow oil. LC purity (0.1% FA): 90.00% (UV at 254 nm)/MS: 594.7 [M+H]. Retention time: 1.270 min. Synthesis of (2S,4R)-1-((R)-2-(3-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C9) [0669] To a solution of (2S,4R)-1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (50.0 mg, 1.0 Eq, 84.2 μmol) in MeOH (2.00 mL) was added TEA (25.6 mg, 35.2 μL, 3.0 Eq, 253 μmol), 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (32.0 mg, 1.0 Eq, 84.2 μmol) and striied at 25 oC for 0.5 hour. Then NaCNBH4 (26.5 mg, 5.0 Eq, 421 μmol) was added to above mixture. The mixture was stirred at 25 °C for 16 hours. L LCMS indicated completion of reaction. The reaction was pouried into water (10 mL) and extated with EA (20 mL), then washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC,eluted with MeCN in H2O 280 282341894 v2 PRSC-068/001WO (343170-2269) from 10% to 95% (0.1% NH4HCO3) to afford (2S,4R)-1-((R)-2-(3-(4-((4-(4-chloro-7,7-dimethyl- 5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5- yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (2.25 mg, 2.23 μmol, 2.65 %, 95% Purity) as a purple solid. LC purity (0.01% FA): 100.00% (UV at 254 nm)/MS: 958.63[M+H]; Retention time: 1.33 min. 1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.50 – 7.29 (m, 5H), 6.08 (d, J = 21.4 Hz, 1H), 5.04 (d, J = 6.6 Hz, 1H), 4.50 (d, J = 8.3 Hz, 1H), 4.44 (s, 1H), 3.85 (d, J = 6.7 Hz, 1H), 3.70 (d, J = 12.1 Hz, 2H), 3.66 – 3.55 (m, 2H), 3.48 (s, 1H), 3.36 (s, 2H), 3.11 (d, J = 18.7 Hz, 2H), 2.87 (t, J = 11.7 Hz, 2H), 2.73 – 2.62 (m, 1H), 2.48 (s, 3H), 2.37 (s, 1H), 2.31 (s, 2H), 2.15 (s, 3H), 1.88 (s, 4H), 1.85 (s, 2H), 1.61 (s, 6H), 1.52 (d, J = 7.1 Hz, 2H), 1.31 (s, 2H), 1.05 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 9.4 Hz, 3H). Compound C10. (2S,4R)-1-((R)-2-(3-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-8-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide [0670] Compound C10 was synthesized employing a procedure analogous to that described for C9. LC purity (0.1%FA): 94.84 % (UV at 254 nm)/MS: 957.4 [M+H]; Retention time: 1.38 min. 1H NMR (400 MHz, DMSO-d6) δ 8.97-8.98 (m, 1H), 8.38-8.43 (m, 2H), 8.03-8.04 (s, 1H), 7.63- 7.65 (m, 1H), 7.52-7.55 (m, 1H), 7.45-7.69 (m, 1H), 7.39-7.43 (m, 2H), 7.36-7.37 (m, 2H), 7.15- 7.18 (m, 1H), 6.17-6.19 (m, 1H), 5.11-5.13 (m, 1H), 4.90-4.94 (m, 1H), 4.35-4.39 (m, 1H), 4.28- 4.29 (m, 1H), 3.63-3.68 (m, 4H), 3.57-3.59 (m, 1H), 3.40-3.42 (m, 1H), 3.28-3.32 (m, 1H), 2.79- 2.85 (m, 1H), 2.45 (s, 3H), 2.21-2.35 (m, 2H), 1.97-2.04 (m, 2H), 1.67-1.85 (m, 5H), 1.57 (s, 6H), 1.42-1.56 (m, 2H), 1.39-1.41 (m, 3H), 1.23-1.27 (m, 2H), 0.95-0.99 (m, 3H), 0.78-0.83 (m, 3H). Compound D1.5-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 281 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000283_0001
[0671] To a solution of 1 (50 mg, 0.12 mmol, 1.0 eq) in DMF (3 mL) was added DIPEA (62 mg, 0.47 mmol, 3.0 eq), and 2 (60 mg, 0.24 mmol, 2.0 eq). the mixture was stirred for 16 h at 90 °C. After reaction, the mixture was diluted by adding EA (20 mL), washed by water twice. After dried by anhydrous Na2SO4 and concentrated, the crude product was received and dissolved into DCM (2 mL), then TFA (2 mL) was added. The reaction was stirred for 30 min. After that, the solution was concentrated. The residue was purified by reversal C-18 column chromatography (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product 4 (30 mg, 52%) as a colorless oil. Synthesis of compound D1 [0672] To a solution of 4 (30 mg, 0.061 mmol, 1.0 eq) in DMF (3 mL) was added DIPEA (31 mg, 0.24 mmol, 4.0 eq), and 5 (34 mg, 0.12 mmol, 2.0 eq). the mixture was stirred for 16 h at 100 °C. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product D1 (23 mg, 50%) as a yellow solid. ESI MS m/z: 745.30 [M+H]. Compound D2.5-(3-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 282 282341894 v2 PRSC-068/001WO (343170-2269) ESI
Figure imgf000284_0001
MS m/z: 789.22 [M+H]. Compound D3.5-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione
Figure imgf000284_0002
ESI MS m/z: 773.32 [M+H]. Compound D4.5-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 283 282341894 v2 PRSC-068/001WO (343170-2269) ESI
Figure imgf000285_0001
MS m/z: 817.25 [M+H]. Compound D5.3-(5-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione
Figure imgf000285_0002
ESI MS m/z: 759.32 [M+H]. Compound D6.3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione 284 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000286_0001
Synthesis of 3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0677] To a solution of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)propyl methanesulfonate (35.0 mg, 1.1 eq, 67.8 μmol) in DMF (1 mL) were added sodium bicarbonate (15.5 mg, 7.19 μL, 3 eq, 185 μmol)，(S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (24.2 mg, 1 eq, 61.7 μmol). The mixture was stirred at 65 °C for 16 hours under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95% (0.1% TFA) to afford 3-(1'-(3-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)propyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.17 mg, 6.52 μmol, 10.6 %) as a white solid. LC purity (0.1%FA): 92.71 % (UV at 254 nm)/MS: 775.4 [M+H]; Retention time: 1.028 min.1H NMR (400 MHz, MeOD) δ 8.44-8.46 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.84-7.88 (t, J = 8.2 Hz, 1H), 7.62-7.68 (m, 2H), 7.36-7.44 (m, 3H), 5.12-5.17 (m, 1H), 4.70 (s, 2H), 4.38-4.50 (m, 2H), 3.65-3.85 (m, 4H), 3.13-3.29 (m, 7H), 2.71-2.98 (m, 3H), 2.43-2.57(m, 1H), 2.11-2.40 (m, 12H), 1.60 (s, 6H). Compound D7. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione 285 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000287_0001
Synthesis of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0678] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (300 mg, 1 eq, 790 μmol) in MeOH (2 mL) were added TEA (240 mg, 330 μL, 3 eq, 2.37 mmol), 4-(hydroxymethyl)cyclohexan-1-one (202 mg, 2 eq, 1.58 mmol), sodium cyanoborohydride (99.2 mg, 93.1 μL, 2 eq, 1.58 mmol) and the reaction was stirred at 65 °C for 4 hours. LCMS indicated completion of reaction. The reaction was concentrated and purified by prep-TLC (10% MeOH in DCM) to afford 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (220 mg, 0.42 mmol, 54 %, 95% purity) as a yellow solid. LC purity (0.1%TFA): 90 % (UV at 254 nm)/MS: 492.4 [M+H]; Retention time: 1.220 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde [0679] To a solution of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (65.0 mg, 1 eq, 132 μmol) in DCM (1.5 mL) was added DMP (112 mg, 2 eq, 264 μmol), and the reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated and purified by prep-TLC (20% MeOH in DCM) to give 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (25.0 mg, 46 286 282341894 v2 PRSC-068/001WO (343170-2269) μmol, 35 %) as a white solid. LC purity (0.1%TFA): 84.5 % (UV at 254 nm)/MS: 490.4 [M+H]; Retention time: 1.247 min. Synthesis of (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0680] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (30.0 mg, 1 eq, 61.2 μmol) in DCM (0.5 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (26.1 mg, 1.2 eq, 73.5 μmol), TEA (9.29 mg, 12.8 μL, 1.5 eq, 91.8 μmol), AcOH (6.25 mg, 5.96 μL, 1.7 eq, 104 μmol) and sodium triacetoxyborohydride (25.9 mg, 18.1 μL, 2 eq, 122 μmol). The reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was purified by prep-HPLC, eluted with MeCN in H2O from 5% to 95% (0.1% FA) to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (15.39 mg, 18.49 μmol, 30.2 %) as a white solid. LC purity (0.1%FA): 96.07 % (UV at 254 nm)/MS: 829.4 [M+H]; Retention time: 1.06 min.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s,1H), 8.46-8.47 (d, J = 8.8 Hz,1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.86-7.82 (m,,1H), 7.64-7.59 (m, 2H), 7.40-7.38 (m, 1H), 7.28- 7.25 (m, ,1H), 5.10-5.06 (m, 1H), 4.52 (s, 2H), 4.37 (d, J = 17.6 Hz,1H), 4.23-4.19 (m, 1H), 2.99- 2.95 (m, 3H), 2.90-2.79 (m, 3H), 2.67-2.56 (m, 3H), 2.40-2.32 (m, 4H), 2.12-2.10 (m, 3H), 1.98- 1.95 (m, 4H), 1.92-1.70 (m, 7H), 1.67-1.66 (m, 2H),1.50 (s, 6H),1.30-1.27 (m, 2H), 0.90-0.88 (m, 2H). Compound D8. (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione 287 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000289_0001
spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoate [0681] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (30 mg, 1 eq, 84.4 μmol) in DMF (1 mL) were added sodium bicarbonate (21.3 mg, 3 eq, 253 μmol) and tert-butyl 4-bromobutanoate (28.3 mg, 1.5 eq, 127 μmol). The re action was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added H2O (10 mL), extracted with EA (10 mL X 3). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)butanoate (37.0 mg, 59 μmol, 70 %, 81% purity) as white solid. LC purity (0.1%TFA): 81.89 % (UV at 254 nm)/MS: 498.4 [M+H]; Retention time: 0.939 min. Synthesis of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid [0682] To a solution of tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoate (60 mg, 1 eq, 121 μmol) in DCM (2 mL) was added TFA (20.6 mg, 13.9 μL, 1.5 eq, 181 μmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated under vacuum to afford (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro- 2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid (49.0 mg, 0.10 mmol, 84 %, 91% purity) as white oil. LC purity (0.1%FA): 83.47 % (UV at 254 nm)/MS: 441.4 [M+H]; Retention time: 1.07 min. 288 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0683] To a solution of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid (30 mg, 1 eq, 68.0 μmol) in DMF (1 mL) was added DIEA (26.3 mg, 3 eq, 204 μmol) and HATU (51.7 mg, 2 eq, 136 μmol). The mixture was stirred at room temperature for 0.5 hour. Then 4-chloro-7,7-dimethyl-9-(piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (31.0 mg, 1.2 eq, 81.5 μmol) was added and the reaction was stirred at 25 °C for 3 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 5% to 90% (0.03%NH4HCO3) to afford (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.13 mg, 3.74 μmol, 5.50 %) as a white solid. LC purity (0.1%NH4HCO3): 88.65 % (UV at 254 nm)/MS:803.4 [M+H]; Retention time: 1.27 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.40-8.41 (d, J = 8.7 Hz, 1H), 8.08-8.10 (d, J = 8.5 Hz, 1H), 7.81-7.83 (t, J = 8.2 Hz, 1H), 7.67-7.56 (m, 2H), 7.37-7.39 (d, J = 7.0 Hz, 2H), 7.27-7.29 (d, J = 7.2 Hz, 1H), 5.11-5.06 (m, 1H), 4.75-4.46 (m, 3H), 4.38-4- 40 (d, J = 17.2 Hz, 1H), 4.21-4.23 (d, J = 17.4 Hz, 1H), 4.10-4.01(m, 1H), 3.17-3.11 (m, 2H), 2.99- 2.81 (m, 4H), 2.68-2.55 (m, 3H), 2.35-2.46 (m, 4H), 2.03-1.64 (m, 12H), 1.52 (s, 6H). Compound D9.5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 289 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000291_0001
9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate [0684] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (70.0 mg, 1 eq, 184 μmol) in MeOH (1 mL) was added sodium cyanoborohydride (11.6 mg, 10.9 μL, 1 eq, 184 μmol), tert-butyl ((1s,4s)-4-formylcyclohexyl)carbamate (50.3 mg, 1.2 eq, 221 μmol), TEA (18.6 mg, 25.7 μL, 1 eq, 184 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (50% of EtOAc in PE) to afford tert-butyl ((1s,4s)-4-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1 yl)methyl)cyclohexyl)carbamate (86.0 mg, 87 μmol, 47 %)as a white solid. LC purity (0.1%TFA): 70 % (UV at 254 nm)/MS: 591 [M+H]; Retention time: 1.04 min. Synthesis of 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0685] To a solution of tert-butyl ((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate (86.0 mg, 1eq, 145 μmol) in EA (1 mL) was added HCl/EA (0.3 mL) and the reaction was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The reaction was filtered and the residue was concentrated under vacuum to afford 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4- 290 282341894 v2 PRSC-068/001WO (343170-2269) chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50.0 mg, 102 μmol, 70.0 %) as a yellow solid. LC purity (0.1%FA): 79.56 % (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 0.91 min. Synthesis of 5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0686] To a solution of 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 81.5 μmol) in DMSO (1 mL) was added DIEA (31.6 mg, 3 eq, 244 μmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione (33.7 mg, 1.5 eq, 122 μmol), and the reaction was stirred at 120 °C for 8 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1%FA) to give 5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4.00 mg, 4.84 μmol, 5.94 %) as a yellow solid. LC purity (0.1 %FA): 97.69 % (UV at 254 nm)/MS: 747.4 [M+H]; Retention time: 1.28 min.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.39-8.41 (d, J = 8.4Hz, 1H), 8.23 (s, 1H), 8.05-8.07 (d, J = 8.4 Hz, 1H), 7.79-7.83 (t, J = 16.4 Hz, 1H), 7.55–7.65 (m, 3H), 7.35-7.37 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 6.91-6.94 (m, 2H), 5.00-5.05 (m, 1H), 3.69-3.70 (m, 1H), 2.97-2.99 (d, J = 11.2Hz, 2H), 2.83-2.91 (m, 1H), 2.58-2.60 (m, 2H), 2.22-2.23 (d, J = 6.8 Hz, 2H), 1.96-2.03 (m, 3H), 1.78-1.73 (m, 5H), 1.63-1.55 (m, 6H), 1.52-1.53 (m, 7H), 1.38-1.43 (m, 2H). Compound D10. (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione 291 282341894 v2 PRSC-068/001WO (343170-2269)
Figure imgf000293_0001
spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoate [0687] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (60.0 mg, 1 eq, 169 μmol) in DMF (4 mL) was added sodium bicarbonate (284 mg 20.0 eq, 3.38 mmol) and tert-butyl 3-bromopropanoate (106 mg, 3 eq, 506 μmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with saturated brine (20 mL X 3), dried over sodium sulfate, concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-70% of ethyl acetate in petroleum ether) to get tert-butyl (S)-3-(7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)propanoate (40.0 mg, 79 μmol, 47 %) as a yellow solid. LC purity (0.1%FA): 87.87 % (UV at 254 nm)/MS: 631.4 [M+H]. Retention time: 1.023 min. Synthesis of (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid [0688] A solution of tert-butyl (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoate (40 g, 1 eq, 82.7 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to give (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo- 7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid (40.0 mg, 84 μmol, 0.10 %) as yellow oil. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 428.2 [M+H]; Retention time: 0.420 min. 292 282341894 v2 PRSC-068/001WO (343170-2269) Synthesis of (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0689] To a solution of (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid (20.0 mg, 1 eq, 46.8 μmol) in DMF (1 mL) was added DIEA (18.1 mg, 3 eq, 140 μmol), 4-chloro-7,7-dimethyl-9-(piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (17.8 mg, 1.0 eq, 46.8 μmol) and HATU (35.6 mg, 2 eq, 93.6 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with saturated brine (20 mL X 3), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.05%FA) to give (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.10 mg, 1.15 μmol, 2.45 %) as a white solid. LC purity (0.1% FA): 100 % (UV at 254 nm)/MS: 789.4 [M+H]; Retention time: 1.350 min. 1H NMR (400 MHz, MeOD) δ 8.42-8.45 (d, J = 8.6 Hz, 1H), 8.07-8.12 (t, J = 7.7 Hz, 1H), 7.84- 7.89 (t, J = 8.3 Hz, 1H), 7.54-7.69 (m, 2H), 7.29-7.51 (m, 2H), 5.08-5.39 (m, 1H), 4.73-4.75 (m, 1H), 4.61 (s, 1H), 4.41-4.56 (q, J = 17.1 Hz, 1H), 3.93-3.95 (m, 1H), 3.40- 3.60 (m, 1H), 3.15 (s, 3H), 2.98-3.02 (m, 4H), 2.91-2.93 (m, 1H), 2.79-2.81 (m, 2H), 2.47-2.50 (m, 1H), 2.15-2.17 (m, 2H), 2.03-2.05 (m, 2H), 1.81-1.83 (m, 4H), 1.61 (d, J = 4.1 Hz, 6H), 1.44-1.45 (m, 1H), 1.31-1.33 (m, 2H), 1.30-1.32 (m, 2H). 2. Biological Activity [0690] The HiBit assay was performed using engineered HT1080 CRISPR knock-in cell utilizing the Nano-Glo HiBiT Lytic Detection System from Promega, Cat # N3040. Compounds were transferred, 25 nL DMSO or test compounds(final DMSO @ 0.1%) to intermediate plates (Corning3570) using ECHO550. Cells were seeded onto compounds at 2000 cells/25 uL/well and incubated for 6 hrs in a tissue culture incubator at 37oC and 5% CO2. The LgBiT Protein was diluted at 1:100 and the Nano-Glo® HiBiT Lytic Substrate 1:50 into an appropriate volume of room temperature using the Nano-Glo® HiBiT Lytic Buffer. At the end of compound incubation time, 15 ul of the detection reagent was added to each well (without LgBiT for negative control 293 282341894 v2 PRSC-068/001WO (343170-2269) wells) using the Thermo Scientific multidrop combi. The plate was shaken for 10 mins at RT using Combi. After briefly centrifugation (2000 rpm 1 mins), plate was read on Envision(Ultrasensitive luminescence model). The results of the HiBiT Assay are summarized in Table E3 below. Table E4. SMARC A2 SMARC A4 Compound No. HT1080 HiBit HT1080 HiBit
Figure imgf000295_0001
HiBiT Assays for protein degradation of SMARCA2 and SMARCA4 [0691] Hela cells were genetically modified via CRISPR/Cas9 to fuse HiBiT to the carboxy terminus of SMARCA2 (Promega CS302365) or SMARCA4 (Promega CS3023225). Cells were cultured in DMEM containing 10% FBS and 1% (Vol : Vol) penicillin-streptomycin. At the time of experiment, cells were seeded at a density of 20,000 cells per well in a 96-well plate (Corning Cat. #3903) and treated with serial dilutions of testing compounds for 24 hours. At the end of experiment, levels of SMARCA2 or SMARCA4 expression were assessed with Nano-Glo® HiBiT Lytic Detection Assay (Promega N3050). IC50 was obtained using the GraphPad Prism data analysis software. The results of the HiBiT Assay are summarized in Table E5 below. Table E5. Compound SMARCA 2 SMARCA 2 SMARCA 4 SMARCA 4
Figure imgf000295_0002
294 282341894 v2 PRSC-068/001WO (343170-2269) Compound SMARCA 2 SMARCA 2 SMARCA 4 SMARCA 4 No. (DC50 nm) (Dmax, %) (DC50 nm) (Dmax, %)
Figure imgf000296_0001
295 282341894 v2 PRSC-068/001WO (343170-2269) INCORPORATION BY REFERENCE [0692] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0693] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. [0694] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. 296 282341894 v2

Claims

PRSC-068/001WO (343170-2269) CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula II: , or a pharmaceutically acceptable thereof, wherein:
Figure imgf000298_0001
A1 is CRA1 or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D 297 282341894 v2 PRSC-068/001WO (343170-2269) ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000299_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or one of RE2, RE3, or RE4 is , wherein:
Figure imgf000299_0002
298 282341894 v2 PRSC-068/001WO (343170-2269) Ring F is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or - wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heteroaryl is optionally substituted with one or more Ru; and
Figure imgf000300_0001
f is an integer selected from 0 to 10, as valency permits, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and 299 282341894 v2 PRSC-068/001WO (343170-2269) each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 2. The compound of claim 1, wherein 1) the compound is not 2) when
Figure imgf000301_0001
i) RA1 is hydrogen; and ii) E1 is CRE1, E2 is CRE2, E3 is CRE3, and E4 is CRE4; wherein RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy, then i) RC are not both optionally substituted phenyl; and ii) when one RC is optionally substituted thiophenyl, then the other RC is not optionally substituted phenyl. 3. The compound of claim 1 or 2, wherein the compound is a compound of Formula II-1 or II-2 2), 282341894 v2
Figure imgf000301_0002
PRSC-068/001WO (343170-2269) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 4. A compound of Formula II , or a thereof, wherein
Figure imgf000302_0001
A1 is CRA1 or N; A2 is CRA2 or N; A3 is CRA3 or N; A4 is CRA4 or N; RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - 301 282341894 v2 PRSC-068/001WO (343170-2269) OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RC together form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-
Figure imgf000303_0001
each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - - -
Figure imgf000303_0002
heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1 is CRE1 or N; E2 is CRE2 or N; E3 is CRE3 or N; E4 is CRE4 or N; and 302 282341894 v2 PRSC-068/001WO (343170-2269) RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or one of RE2, RE3, or RE4 is ; wherein:
Figure imgf000304_0001
Ring F is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Rb, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - 303 282341894 v2 PRSC-068/001WO (343170-2269) OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 5. The compound of any one of claims 1-4, wherein RA1 is halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 6. The compound of claim 5, wherein RA1 is halogen, -CN, -OH, -NH2, C1-6 alkyl, or - C(=O)NRcRd. 304 282341894 v2 PRSC-068/001WO (343170-2269) 7. The compound of any one of claims 1-6, wherein RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 8. The compound of any one of claims 1-6, wherein one or two of E1, E2, E3, and E4 is N. 9. The compound of claim 8, wherein two or three of RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 10. The compound of claim 9, wherein two or three of RE1, RE2, RE3, and RE4 are hydrogen or halogen. 11. The compound of any one of claims 1-6, wherein RE2, RE3, or RE4 is .
Figure imgf000306_0001
12. The compound of claim 1, wherein the compound is a compound of Formula II-1-i, II-1- ii, II-1-iii, II-2-i, II-2-ii, or II-2-iii 305 282341894 v2 PRSC-068/001WO (343170-2269) i), , or a
Figure imgf000307_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 13. The compound of any one of claims 1-3 and 7-11, wherein RA1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 306 282341894 v2 PRSC-068/001WO (343170-2269) 14. The compound of claim 13, wherein RA1 is halogen, -OH, or -NH2. 15. The compound of claim 12, wherein the compound is a compound of Formula II-1-iv, II- 1-v, II-1-vi, II-2-iv, II-2-v, or II-2-vi , , vi)
Figure imgf000308_0001
each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and RA1 is halogen. 307 282341894 v2 PRSC-068/001WO (343170-2269) 16. The compound of any one of claims 1-15, wherein Ring F is C5-10 carbocyclyl, 5- to 10- membered heterocyclyl, or 5- to 6-membered heteroaryl. 17. The compound of any one of claims 1-16, wherein each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 18. The compound of any one of claims 1-16, wherein each RF is independently oxo, C1-6 alkyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)ORb, or -C(=O)Rb, wherein the alkyl is optionally substituted with one or more -NH2, C1-6 alkylamino, or 3- to 12-membered heterocyclyl. 19. The compound of any one of claims 1-18, wherein f is 0 or 1. 20. The compound of any one of claims 11-19, wherein RE1, RE2, and RE4 or RE1, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 21. The compound of any one of claims 11-19, wherein each of RE1, RE2, and RE4 or each of RE1, RE3, and RE4 is hydrogen. 22. The compound of any one of claims 11-19, wherein one or two of E1, E2, and E4 or one of E1, E3, and E4 is N. 23. The compound of claim 22, wherein two or three of RE1, RE2, and RE4 or two of RE1, RE3, and RE4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1- 6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 308 282341894 v2 PRSC-068/001WO (343170-2269) aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 24. The compound of claim 23, wherein two or three of RE1, RE2, and RE4 or two of RE1, RE3, and RE4 are hydrogen. 25. The compound of any one of claims 1-24, wherein one of A2 or A4 is N. 26. The compound of claim 25, wherein one of A2, A3, and A4 is N. 27. The compound of any one of claims 1-24, wherein none of A2, A3, and A4 is N. 28. The compound of any one of claims 25-27, wherein RA2, RA3, and RA4, RA3 and RA4, or RA2 and RA3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 29. The compound of claim 27 or 28, wherein each of RA2, RA3, and RA4 is hydrogen. 30. The compound of any one of claims 1-29, wherein Ring D is C4-12 carbocycle or 3- to 12- membered heterocycle. 31. The compound of any one of claims 1-30, wherein each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 32. The compound of any one of claims 1-31, wherein each RD is independently oxo, halogen, -OH, C1-6 alkylamino, or -NRbC(=O)Ra. 309 282341894 v2 PRSC-068/001WO (343170-2269) 33. The compound of any one of claims 1-32, wherein d is 0 or 1. 34. The compound of any one of claims 1-29, wherein each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. 35. The compound of any one of claims 1-29, wherein at least one RC is C1-6 alkyl. 36. The compound of any one of claims 1-29, wherein each of RC is C1-6 alkyl. 37. A compound selected from the compounds in Tables 1’ and 2, or a pharmaceutically acceptable salt thereof. 38. A pharmaceutical composition comprising the compound of any one of claims 1-37, and a pharmaceutically acceptable excipient. 39. A method of inhibiting a SMARCA2 or SMARCA4 protein in a patient or biological sample comprising contacting said patient or biological sample with a compound of any one of claims 1-37. 40. Use of a compound of any one of claims 1-37 in the manufacture of a medicament for inhibiting a SMARCA2 or SMARCA4 protein in a patient or biological sample. 41. A compound of any one of claims 1-37 for use in inhibiting a SMARCA2 or SMARCA4 protein in a patient or biological sample. 42. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of claims 1-37. 310 282341894 v2 PRSC-068/001WO (343170-2269) 43. Use of a compound of any one of claims 1-37 in the manufacture of a medicament for treating a disease or disorder. 44. A compound of any one of claims 1-37 for use in treating a disease or disorder. 45. The method, use, or compound for use of any one of claims 42-44, wherein the disease or disorder is a SMARCA2 or SMARCA4 protein-mediated disease or disorder. 46. The method, use, or compound for use of any one of claims 42-44, wherein the disease or disorder is a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder. 47. The method, use, or compound for use of claim 46, wherein the cancer is selected from NSCLC, adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS). 48. The method, use, or compound for use of claim 47, wherein the cancer is selected from NSCLC, adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC). 311 282341894 v2
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